CADTH Reimbursement Review

Nivolumab (Opdivo)

Sponsor: Bristol Myers Squibb

Therapeutic area: Non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Abbreviations

AE

adverse event

AJCC

American Joint Committee on Cancer

ALK

anaplastic lymphoma kinase

BICR

Blinded Independent Central Review

BIPR

Blinded Independent Pathologic Review

CCO

Cancer Care Ontario

CI

confidence interval

CrI

credible interval

DAC

Drug Advisory Committee

ECOG PS

Eastern Cooperative Oncology Group Performance Status

EFS

event-free survival

EFS2

event-free survival on the next line of therapy

EGFR

epidermal growth factor receptor

HER

electronic health record

EQ-5D-3L

3-Level EQ-5D

HR

hazard ratio

HRQoL

health-related quality of life

IA1

first interim analysis

iKM

iKnowMed

ITC

indirect treatment comparison

ITT

intention to treat

KM

Kaplan-Meier

LCC

Lung Cancer Canada

MID

minimally important difference

MPR

major pathologic response

NMA

network meta-analysis

NOC

Notice of Compliance

NSCLC

non–small cell lung cancer

OH

Ontario Health

OS

overall survival

pCR

pathologic complete response

PD-1

programmed cell death 1 protein

PD-L1

programmed cell death 1 ligand 1

PD-L2

programmed cell death 1 ligand 2

PICO

patient, intervention, comparison, outcome

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT

randomized controlled trial

RECIST

Response Evaluation Criteria in Solid Tumours

SAE

serious adverse event

SLR

systematic literature review

TNM

tumour, node, metastasis

TTDM

time to death or distant metastases

TTLRR

time to locoregional recurrence

VAS

visual analogue scale

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

Item

Description

Drug product

Nivolumab (Opdivo), 360 mg intravenously, every 3 weeks for up to 3 cycles

Indication

In combination with platinum-doublet chemotherapy for the neoadjuvant treatment of adult patients with resectable NSCLC (tumours ≥ 4 cm or node-positive)

Reimbursement request

In combination with platinum-doublet chemotherapy for the neoadjuvant treatment of adult patients with resectable NSCLC (tumours ≥ 4 cm or node-positive)

Health Canada approval status

Post-NOC

Health Canada review pathway

Project Orbis

NOC date

August 18, 2022

Sponsor

Bristol Myers Squibb

NSCLC = non–small cell lung cancer; NOC = Notice of Compliance.

Introduction

Lung cancer is the most frequently diagnosed cancer in Canada, and the leading cause of cancer-related death.1 About 30,000 new diagnoses (50% in males and 50% in females)2 and 20,700 cancer-related deaths were projected in Canada in 2022,1,3 with about 98% of all cases anticipated in people 50 years and older.4 The adjusted 5-year net survival (based on 2015 to 2017 estimates) for all forms of lung cancer is only 22% (19% in males and 26% in females in Canada).1,2 Non–small cell lung cancers (NSCLCs) are the most common forms of lung cancer, accounting for more than 80% of all lung cancers in Canada.5,6 About 47.1% of all new cases of NSCLC are diagnosed at stage IV, 19.0% are diagnosed at stage III, 9.1% are diagnosed at stage II, and only 23.1% are diagnosed at stage I.7

The primary goal of treating patients with resectable NSCLC is to cure the disease, improve 5-year overall survival (OS), and prevent disease recurrence. Surgery with curative intent is the current gold standard for clinical stage I to stage IIIA NSCLC that is amenable to resection.8,9 The standard of care, according to joint guidelines from the American Society of Clinical Oncology and Ontario Health (OH) Cancer Care Ontario (CCO) for completely resectable stage IIA to IIB and stage IIIA NSCLC (American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 7th edition [AJCC 7th edition]), is surgical resection followed by adjuvant cisplatin-based chemotherapy. Cisplatin-based chemotherapy is not recommended for patients with stage IA disease and not routinely recommended for patients with stage IB disease; however, postoperative evaluations are recommended.10 Stereotactic ablative radiation with curative intent is available to some patients with early-stage disease who are ineligible for surgery (e.g., because of significant comorbidities that make them a high risk for general anesthetic) or who refuse surgery, whereas patients with resectable stage III cancer may be offered chemotherapy and/or radiation in current practice before surgery.11

Neoadjuvant chemotherapy is seldom used in Canada, as it has not been shown to provide survival benefit over adjuvant therapy, and in the process of pursuing neoadjuvant chemotherapy, some patients may become ineligible for surgery (due to disease progression or treatment-related toxicity), according to the clinical experts consulted. However, neoadjuvant therapy has several advantages; for instance, it can reduce tumour size, increase resectability, and remove micrometastasis and tumour cells in more distant lymph nodes, which reduces the risk of recurrence caused by tumour cells that are not removed by surgery.12,13

Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that binds to the programmed cell death 1 protein (PD-1) receptor and blocks its interaction with programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2), releasing PD-1 pathway-mediated inhibition of the immune response, including antitumour immune response.14 Nivolumab underwent review through the Project Orbis route at Health Canada and received a notice of compliance (NOC) on August 18, 2022, for the treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease) when used in combination with platinum-doublet chemotherapy.12 The Health Canada–recommended dose of nivolumab is 360 mg administered intravenously over 30 minutes as neoadjuvant treatment in combination with platinum-doublet chemotherapy every 3 weeks for 3 cycles.14 The sponsor’s reimbursement request and patient population aligns with the Health Canada indication.

The objective of this CADTH report is to perform a systematic review of the beneficial and harmful effects of nivolumab (360 mg) in combination with platinum-doublet chemotherapy every 3 weeks for up to 3 cycles, for the neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease).

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Lung Cancer Canada (LCC), a member of Global Lung Cancer Coalition and the only national organization in Canada focused exclusively on lung cancer, engages in patient support, education, research, and advocacy. LCC submitted patient group input based on interviews conducted in Canada in September and October 2022 (1 patient with stage I to II NSCLC, 1 patient with stage III NSCLC, and 2 patients with stage IV NSCLC, and 1 caregiver for a patient with large-cell neuroendocrine carcinoma) and 1 interview with a patient who had stage IV NSCLC and had undergone an environmental scan (1 patient with stage IV NSCLC). All participants had experience with nivolumab. The LCC submitted information collected from 4 patients with stage I to IV NSCLC and from 1 patient with large-cell neuroendocrine carcinoma. The CADTH patient input summary will focus on the 2 patients with stage I to stage III NSCLC to align with the requested indication.

One patient said she used to be extremely active and was an avid runner for 10 years before her lung cancer diagnosis. The patient explained that lung cancer made exercise harder and made her feel more tired than ever, which impacted her independence. She also said that she experienced cough and some mild chest pain before her diagnosis of lung cancer. Another patient who had been diagnosed with early-stage NSCLC had two-thirds of his lung surgically removed, leaving him with 50% of his initial lung capacity. As a result, he explained, he became unable to do any vigorous exercise or activity because he tires quickly. As for improved outcomes, the input indicated that patients would value new treatment options that maintain or improve quality of life, delay the onset of symptoms, improve survivorship, improve or maintain functionality and/or mobility, and, ultimately, provide a cure. In addition, respondents said they would prefer a treatment that can be administered at a hospital located near home, or in a community clinic for those in rural settings, to minimize travel time and burden on caregivers. The input also noted that because the CheckMate 816 trial excluded patients with EGFR or ALK alterations, owing to a lack of evidence supporting neoadjuvant immunotherapy in this population, a biomarker screening (a routine practice) must be performed before neoadjuvant treatment with nivolumab.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted for this review highlighted improved OS (prolonged life) and delay of disease relapse as important treatment goals in NSCLC curative settings. The clinical experts highlighted the infrequent use of neoadjuvant chemotherapy across jurisdictions in Canada because it has not been shown to provide a survival benefit over adjuvant therapy and noted that in the process of receiving neoadjuvant chemotherapy, some patients may become ineligible for surgery (due to disease progression or drug-related toxicity that may affect a patient’s performance status). The clinical experts highlighted an unmet need for patients with resectable NSCLC tumours, as some patients who undergo surgical resection and receive adjuvant chemotherapy may experience disease relapse. The clinical experts added that patients who experience relapse after surgery and/or adjuvant chemotherapy are generally incurable. Both clinical experts agreed that neoadjuvant nivolumab in combination with chemotherapy will cause a shift in the current Canadian treatment paradigm in the curative-intent setting.

The clinical experts indicated that patients with NSCLC who have tumours 4 cm or larger and/or node-positive disease, who have EGFR-negative or ALK-negative tumours, and who are eligible for upfront surgical resection (including patients with locoregional spread of the disease to lymph nodes who remain eligible for upfront surgical resection) would be eligible for treatment, provided they have no contraindications (severe and uncontrolled autoimmune disease, frailty, or poor baseline organ function). The experts explained that neoadjuvant nivolumab in combination with chemotherapy would not be appropriate for patients who are eligible for upfront surgery for borderline resectable NSCLC when the goal of neoadjuvant therapy is to downsize the tumour so the patient can become eligible for surgery. According to the clinical experts, patients are identified by a surgical and medical oncologist after appropriate review. The clinical experts added that the identification of driver mutations, like EGFR and ALK, is important but may not be routinely performed for early-stage disease at all centres.

The clinical experts added that patient response to treatment would be assessed in clinical practice using preoperative CT scans completed after neoadjuvant systemic chemotherapy, pathologic response, disease recurrence, and OS. The clinical experts emphasized that the schedule of follow-up assessments after completion of curative-intent surgery is not standardized across jurisdictions in Canada because of a lack of definitive literature suggesting the most appropriate timing for serial radiography. The clinical experts noted that nivolumab, platinum-doublet chemotherapy, or both could be discontinued at a patient’s request, in the event of disease progression during the 3 cycles of neoadjuvant therapy, or in the case of medically dangerous side effects or intolerable toxicity.

Clinician Group Input

Two clinician groups, the OH-CCO Lung Cancer Drug Advisory Committee (DAC) and LCC, each submitted inputs. The OH-CCO’s DAC provides guidance on drug-related issues, in support of CCO’s mandate, and collected information from 3 clinicians during a DAC meeting. LCC, a national charity and the only organization in Canada solely focused on lung cancer (education, advocacy, research) gathered information from published clinical data and 12 lung cancer medical oncologists across Canada.

Unmet Needs

According to the OH-CCO input, despite current treatments, a number of patients develop a recurrence quickly and do not survive. Therefore, neoadjuvant nivolumab would be an additional option for patients with resectable NSCLC. In its input, LCC cited several advantages of the neoadjuvant approach: it limits the risk of systemic dissemination of the cancer; downsizes tumours (leading to decreased postoperative complications [e.g., pain, infection], decreased performance status, improved surgical outcomes, and improved recovery times); makes the possibility of surgery easier, safer, and more efficacious; improves patient capacity to receive postoperative therapies; provides the opportunity for smoking cessation, physical therapy, and medical evaluations for surgery; helps to manage the surgical wait list; and improves the ability to provide prognosis and risk-stratification after surgery.

Place in Therapy

According to the OH-CCO clinicians, neoadjuvant nivolumab would be an additional option for patients with resectable NSCLC and could potentially replace adjuvant chemotherapy in some patients. Similarly, the LCC clinicians said that neoadjuvant nivolumab therapy would eliminate the need of postoperative, prolonged, and more expensive therapies (chemotherapy, radiation, immunotherapy). LCC clinicians noted that eligible patients might not choose neoadjuvant nivolumab therapy, such as patients with stage II, node-negative disease considered eligible for upfront surgery with optional adjuvant therapies, those at high risk of chemotherapy-associated or immunotherapy-associated complications, and those preferring upfront surgery.

Patient Population

The OH-CCO clinicians said that patients who meet the clinical trial inclusion criteria (i.e., resectable stage IIA to stage IIIB NSCLC [per AJCC 8th edition]) and/or those eligible for chemotherapy would be best suited for treatment with nivolumab. (Of note, the inclusion criterion for the CheckMate 816 trial was stage IB [tumour ≥ 4 cm] to stage IIIA NSCLC per AJCC 7th edition, which corresponds to stage IB to stage IIIB, non N3, non N2T4 per AJCC 8th edition.) LCC clinicians said that neoadjuvant therapy may be favoured for patients with stage IIIA and/or PD-L1-positive NSCLC, based on the favourable results in these strata in the CheckMate 816 study. However, the LCC group noted that a discussion with every eligible patient would be warranted and the treatment of all eligible patients with neoadjuvant therapy would be favoured to decrease the treatment burden after surgery (e.g., postoperative chemotherapy and/or atezolizumab). According to LCC clinicians, nivolumab would be least suited to patients with a contraindication to chemotherapy or immunotherapy treatments, such as those with renal failure, heart failure, severe hearing loss, severe neuropathy, an organ transplant, active and symptomatic autoimmune disease (e.g., Crohn disease being treated with immunosuppressive therapy or multiple sclerosis), and an Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2 to 4. The LCC clinicians added that a history of autoimmune disease or autoimmune disease that is clinically silent (e.g., immune thyroiditis) or well controlled without active immunosuppression is not a major contraindication. According to LCC input, the use of neoadjuvant immunotherapy in patients with EGFR, ALK, ROS1, RET, or NTRK alterations needs further investigation and/or will have to be addressed on a case-by-case basis, as these groups have not been specifically addressed in clinical trials.

Assessing Response to Treatment

The OH-CCO clinician group stated that response to nivolumab can be determined with clinical assessment of progression, the need for surgery, and pathologic assessment of a tumour. The LCC clinician group said that a CT scan would be needed after neoadjuvant therapy evaluate a patient’s eligibility for surgery. According to LCC clinicians, currently there is no clinical, biologic, or imaging tool that can be used to identify patients who will have a pathologic complete response (pCR) after neoadjuvant treatment and can be excluded from surgical treatment. At present, patients are followed with standard postoperative care, LCC clinicians reported. However, they anticipate that in the future, as more experience is gained with neoadjuvant approaches, risk-adapted follow-up strategies will be possible, based on, for example, circulating tumour DNA postoperative monitoring in combination with other clinical and pathologic features of the cancer.

Discontinuing Treatment

The OH-CCO clinicians said that intolerable toxicity and clinically obvious disease progression are factors to consider when deciding whether to discontinue nivolumab treatment. The LCC clinicians stated that clinical and biologic evaluations are performed at every cycle of therapy, as they are for patients undergoing chemotherapy and/or immunotherapy in the advanced disease setting, per standard practice in oncology.

Prescribing Conditions

The OH-CCO clinicians noted that a specialist, ideally part of a multidisciplinary team, is required in a hospital outpatient clinic to diagnose, treat, and monitor patients receiving nivolumab. The LCC clinicians also stated that, ideally, a multidisciplinary cancer tumour board, consisting of (nonexclusively) respirologists, radiologists, pathologists, thoracic surgeons, medical oncologists, and radiation oncologists, should discuss a multimodal treatment approach for patients who are usually referred to oncologic thoracic surgeons affiliated with major cancer centres. The LCC clinicians added that the delivery of care should be planned according to local structures; ideally, systemic therapies will be administered as close to a patient’s home as possible, while patients are continuously monitored by the cancer centre to coordinate neoadjuvant therapies with posttreatment imaging, preoperative evaluations, and the surgical admission itself.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. Key factors identified that could potentially impact the implementation of the CADTH recommendation for neoadjuvant nivolumab plus chemotherapy included considerations for the initiation of therapy, considerations for the discontinuation of therapy, considerations for the prescribing of therapy, and generalizability.

Clinical Evidence

Pivotal Study

Description of Study

CheckMate 816 is an ongoing, open-label, randomized, phase III trial comparing the efficacy and safety of 3 treatment regimens in patients 18 years and older with resectable (stage IB [tumours ≥ 4 cm], stage II, or stage IIIA) NSCLC: neoadjuvant nivolumab (3 mg/kg every 2 weeks for up to 3 cycles) in combination with ipilimumab (a single 1 mg/kg dose); neoadjuvant nivolumab (a 360 mg flat dose) in combination with platinum-based chemotherapy every 3 weeks for 3 cycles; and platinum-based chemotherapy alone.15 This CADTH review did not include findings from the ipilimumab plus nivolumab arm, as the indication under review is for nivolumab monotherapy in combination with platinum-based chemotherapy. Disease staging at screening was based on the AJCC/Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours, 7th edition.15 After the completion of neoadjuvant treatment, all patients who remained operative candidates underwent definitive surgery for NSCLC within 6 weeks. Patients were also allowed to receive adjuvant chemotherapy with or without radiation after definitive surgery, per institutional standard at the discretion of the investigator.

pCR assessed by blinded independent pathologic review (BIPR) and event-free survival (EFS) assessed by blinded independent central review (BICR) were coprimary end points in the trial. Secondary end points included OS, time to death or distant metastases (TTDM), and major pathologic response (MPR). Safety, tolerability, and health-related quality of life (HRQoL) were exploratory outcomes.15 Radiologic tumour assessments were reviewed by a third-party vendor for BICR and BIPR. All investigator-assessed radiographic progressions and all disease recurrences were confirmed by BICR, per Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1 guidelines.

The CheckMate 816 trial was initially designed as a 2-arm trial in which patients were randomized in a 1:1 ratio to 1 of 2 treatment regimens: nivolumab plus ipilimumab (arm A); or platinum-doublet chemotherapy (arm B). An update to the protocol (protocol revision 2) introduced a third arm, nivolumab plus platinum-doublet chemotherapy (arm C) and allowed patients to be subsequently randomized in a 1:1:1 scheme to any treatment arm. A third update to the protocol (protocol revision 3) discontinued the randomization of patients to the nivolumab plus ipilimumab arm. Subsequently, patients enrolled in the study were randomized to the nivolumab plus chemotherapy arm or the chemotherapy arm in a 1:1 ratio and were stratified by 3 factors: PD-L1 expression level (1% or more versus less than 1%, not evaluable, indeterminate); disease stage (IB or II versus stage IIIA); and sex.

The primary data cut-off date for the prespecified final pCR analysis was September 16, 2020, and the data cut-off date for the first EFS interim analysis (IA1 EFS) was October 20, 2021. By the October 20, 2021, data cut-off date (IA1 EFS), ||| ||||||| |||||||| || ||| ||||| ||| ||||||||| ||||||||||| ||||| |||||||||| ||| |||| |||| || ||||||. Most patients in the nivolumab plus chemotherapy and the chemotherapy arms were male (71.5% and 70.9%, respectively), and about half were either ||||| |||||| ||| |||||| ||||||||||||| ||| ||||| |||||| ||| |||||| |||||||||||||. In total, 48.6% and 53.1% of patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively, had squamous tumour histology; 63.1% and 64.2%, respectively, had stage IIIA disease, and 89.4% and 88.3%, respectively, were current or former smokers.15

Efficacy Results

Table 2 presents key efficacy end points and Table 3 presents key safety results from the CheckMate 816 trial.

Overall Survival

OS was formally tested at the IA1 EFS data cut-off date (October 20, 2021), as EFS was significant at the IA1 cut-off date. The median OS was not reached in either the nivolumab plus chemotherapy arm or the chemotherapy arm. The hazard ratio [HR] for death was 0.57 (99.67% confidence interval [CI] 0.30 to 1.07). The P value for OS (P = 0.008) did not cross the significance boundary (0.0033). A second OS testing is planned after ||| || |||||| |||| |||||||| ||| | |||| ||||| ||| ||| |||| |||||||||15

Event-Free Survival

By the October 20, 2021 cut-off date, ||| || ||| ||||||| |||||||| || ||| ||||||||| |||| |||||||||||| ||| ||| || || ||| ||||||| || ||| |||||||||||| ||| |||| |||||||| ||| ||| || ||||.15 In total, ||||| ||| || |||| EFS events had occurred in the nivolumab plus chemotherapy arm, and the median EFS was 31.57 months (95% CI, 30.16 to not available months). In the chemotherapy arm, ||||| ||| || |||| EFS events had occurred and the median EFS was 20.80 months (95% CI, 14.03 to 26.71 months). The estimated HR between nivolumab plus chemotherapy and chemotherapy was 0.63 (97.38% CI, 0.43 to 0.91), with a P value of 0.0052 from a stratified log-rank test.15 Sensitivity analyses for EFS were consistent with the primary analysis.15

Pathologic Complete Response and Major Pathologic Response

pCR and MPR analyses were conducted at the September 16, 2020, data cut-off date. The pCR rate per BIPR was 24.0% (43 of 179 patients; 95% CI, 18.0% to 31.0%) in the nivolumab plus chemotherapy arm and 2.2% (4 of 179 patients; 95% CI, 0.6% to 5.6%) in the chemotherapy arm. The stratified odds ratio between the nivolumab plus chemotherapy arm and the chemotherapy arm was 13.94 (99% CI, 3.49 to 55.75), with a P value of less than 0.0001, and the strata-adjusted difference based on the Cochran-Mantel-Haenszel method was 21.6% |||| ||| ||||| || ||||||.15 pCR sensitivity analyses were consistent with the primary analyses. In total, 36.9% of patients (95% CI, 29.8% to 44.4%) in the nivolumab plus chemotherapy arm and 8.9% (95% CI, 5.2% to 14.1%) in the chemotherapy arm were MPR responders.15

Health-Related Quality of Life

Patients completed the 3-Level EQ-5D (EQ-5D-3L) questionnaire at baseline, before on-treatment clinic visits, at postneoadjuvant visits 1 and 2, and at designated time points during the survival follow-up phase. Completion rates for the nivolumab plus chemotherapy and chemotherapy study arms were similar at baseline (EQ-5D-3L descriptive system: 94.4% versus 95.5%; EQ-5D-3L visual analogue scale [VAS]: 94.4% versus 95.0%) and did not change significantly at postneoadjuvant visit 1 (EQ-5D-3L descriptive system: 88.6% versus 83.9%; EQ-5D-3L VAS: 88.6% versus 83.9%). The EQ-5D index (based on the UK time trade-off value set) was collected for both study arms. The mean change from baseline to different time points (week 4, week 7, and postneoadjuvant visits 1 and 2) were minimal for the EQ-5D VAS and EQ-5D utility index scores of the questionnaire in the 2 treatment arms.15 Table 2 presents the change from baseline to different time points (week 4, week 7, and postneoadjuvant visits 1 and 2) in the EQ-5D VAS and EQ-5D utility index score portion of the EQ-5D-3L questionnaire.

Time to Death or Distance Metastasis

By the October 20, 2021, data cut-off date, || |||||| ||||||| ||| |||||||| || ||| ||||||||| |||| |||||||||||| ||| |||||| |||||| ||||||| || ||| |||||||||||| |||. The median time to death or distant metastasis was not reached in either study arm at the October 20, 2021, cut-off date, and the HR was 0.53 (95% CI, 0.36 to 0.77).15

EFS on Next Line of Therapy

By the October 20, 2021, data cut-off date, the median event-free survival on the next line of therapy (EFS2), per investigator assessment, was not reached in either the nivolumab plus chemotherapy or chemotherapy arm. || |||||| || |||||| ||| |||||||| || ||| ||||||||| |||| |||||||||||| ||| ||| || |||||| || ||| |||||||||||| |||. The estimated HR was 0.54 (95% CI, 0.37 to 0.80).15

Harms Results

Overall, 92.6% (n = 163) of patients in the nivolumab plus chemotherapy arm and 97.2% (n = 171) in the chemotherapy arm reported at least 1 adverse event (AE) in the CheckMate 816 trial. The most frequently reported AEs in the nivolumab plus chemotherapy arm were nausea (38.1%), constipation (33.5%), anemia (29.0%), decreased appetite (20.5%), fatigue (16.5%), and neutropenia (16.5%), and in the chemotherapy arm were nausea (44.9%), constipation (32.4%), anemia (26.7%), decreased appetite (23.3%), and neutrophil count decrease (21.0%) of any grade. AEs of grade 3 to 4 were reported in 40.9% (n = 72) and 43.8% (n = 77) of patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively.15

Serious adverse events (SAEs) of any grade were reported in 30 (17.0%) patients in the nivolumab plus chemotherapy arm and 24 (13.6%) in the chemotherapy arm. SAEs of grades 3 or 4 were reported in 19 (10.8%) patients in the nivolumab plus chemotherapy arm and 17 (9.7%) patients in the chemotherapy arm.15

AEs leading to a dose delay or reduction were reported in || ||||||| ||| || ||||||| treated patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively. AEs leading to discontinuation of study treatments were reported in 18 (10.2%) patients in the nivolumab plus chemotherapy arm and 20 (11.4%) in the chemotherapy arms.15

By the October 20, 2021, data cut-off date, ||||| ||| ||| || |||||||| ||| |||| || ||| ||||||||| |||| |||||||||||| ||| ||| ||||| ||| ||| patients in the chemotherapy arm.15 Notable harms reported in the nivolumab plus chemotherapy and chemotherapy arms of the CheckMate 816 trial are presented in Table 3.15

Table 2: Summary of Key Efficacy Results From the CheckMate 816 Trial

Characteristic

Nivolumab plus chemotherapy (n = 179)

Chemotherapy

(n = 179)

OS

Median OS (95% CI)

NR

NR

HR for death (99.67% CI)

0.57 (0.30 to 1.07)

P value

0.008

EFS

Events, n (%)

64 (35.8)

87 (48.6)

Median EFS (95% CI), monthsa

31.57 (30.16 to NA)

20.80 (14.03 to 26.71)

HR (97.38% CI) P valueb

0.63 (0.43 to 0.91) P = 0.0052c

95% CI

0.45 to 0.87

EFS rates, % (95% CI)a

At 6 months

85.6 (79.3 to 90.1)

81.9 (75.1 to 87.0)

At 12 months

76.1 (68.8 to 81.9)

63.4 (55.3 to 70.4)

At 18 months

68.3 (60.4 to 74.9)

53.1 (44.9 to 60.7)

At 24 months

63.8 (55.7 to 70.9)

45.3 (37.0 to 53.2)

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pCRd (September 8, 2020, data cut-off date)

Responders, n (%)

43 (24.0)

4 (2.2)

95% CIf

18.0 to 31.0

0.6 to 5.6

Difference, %f,g

21.6

99% CI

||||| || |||||

95% CI

15.1 to 28.2

Estimate of odds ratiog,h

13.94i

99% CI

3.49 to 55.75

95% CI

4.86 to 40.02

MPRd (September 8, 2020, data cut-off date)

Responders, n (%)

66 (36.9)

16 (8.9)

95% CIe

29.8 to 44.4

5.2 to 14.1

Difference, % (95% CI) f,g

27.9 (19.6 to 36.1)

Estimate of odds ratio (95% CI)g,h

5.70 (3.16 to 10.26)

TTDM

Events, n (%)

|| (25.1)

|| (41.9)

Median TTDM (95% CI), monthsa

Not reached (36.60 to NA)

26.71 (22.41 to NA)

HR (95% CI)b

0.53 (0.36 to 0.77)

TTDM rates (95% CI)

At 12 months

85.7 (79.4 to 90.2)

76.0 (68.8 to 81.8)

At 24 months

75.8 (68.3 to 81.7)

57.1 (48.8 to 64.6)

EFS2

Events, n (%)

|| (23.5)

|| (39.1)

Median EFS2 (95% CI), montha

Not reached (NA to NA)

Not reached (27.40 to NA)

HR (95% CI)b

0.54 (0.37 to 0.80)

HRQoL

EQ-5D utility index scores

Baseline, n

169

171

Mean (SD)

0.89 (0.13)

0.89 (0.16)

Change from baseline to week 4, n

163

153

Mean (SD)

0.02 (0.16)

0.00 (0.17)

Change from baseline to week 7, n

148

141

Mean (SD)

–0.01 (0.18)

–0.01 (0.18)

Change from baseline to postneoadjuvant visit 1, n

152

143

Mean (SD)

–0.01 (0.18)

–0.02 (0.21)

Change from baseline to postneoadjuvant visit 2, n

131

129

Mean (SD)

–0.09 (0.20)

–0.09 (0.23)

EQ-5D VAS

Baseline, n

169

170

Mean (SD)

83.1 (15.8)

82.4 (14.2)

Change from baseline to week 4, n

163

153

Mean (SD)

–0.2 (12.1)

–1.2 (13.1)

Change from baseline to week 7, n

148

141

Mean (SD)

–1.3 (13.8)

–0.7 (12.6)

Change from baseline to postneoadjuvant visit 1, n

152

142

Mean (SD)

–0.2 (13.9)

–1.0 (15.4)

|||||| |||| |||||||| || |||||||||||||||| ||||| || |

|||

|||

Mean (SD)

–2.5 (16.5)

–2.5 (17.3)

BICR = blinded independent central review; BIPR = blinded independent pathologic review; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; EFS = event-free survival; EFS2 = event-free survival on the next line of therapy; HR = hazard ratio; HRQoL = health-related quality of life; IRT = Interactive Response Technology; MPR = major pathologic response; NA = not available; nivo = nivolumab; NR = not reported; pCR = pathologic complete response; PD-L1 = programmed cell death 1 ligand 1; SD = standard deviation; TTDM = time to death or distant metastases; VAS = visual analogue scale.

Note: The data cut-off date was October 20, 2021 (minimum follow-up was 21.0 months), except pCR and MPR were assessed at the September 2020 data cut-off date.

aBased on Kaplan-Meier estimates.

bHR of arm C to concurrent arm B from a Cox model stratified by PD-L1 expression level (≥ 1% vs. < 1%, not evaluable, or indeterminate), disease stage (IB or II vs. stage IIIA), and sex (male vs. female), as entered into the Interactive Response Technology.

cLog-rank test stratified by the same factors as in the Cox proportional hazards model. The P value threshold for statistical significance was 0.0262.

dPatients without samples for evaluation were counted as nonresponders.

eCI based on the Clopper-Pearson method.

fStrata-adjusted difference (arm C – concurrent arm B), based on the Cochran-Mantel-Haenszel method of weighting.

gStratified by PD-L1 expression level (≥ 1% vs. < 1%, not evaluable, indeterminate), disease stage (IB or II vs. stage IIIA), and sex (male vs. female), as entered into the Interactive Response Technology.

hStrata-adjusted odds ratio (arm C over concurrent arm B), the Mantel-Haenszel method.

iP < 0.0001 (2-sided P value for pCR from the stratified Cochran-Mantel-Haenszel test).

Source: Clinical Study Report.15

Table 3: Summary of Key Safety Results From the CheckMate 816 Trial

Safety parameters

Nivolumab plus chemotherapy (n = 176)

Chemotherapy (n = 176)

Any grade (n, %)

Grade 3 or 4 (n, %)

Any grade (n, %)

Grade 3 or 4 (n, %)

All-causality AEs

163 (92.6)

72 (40.9)

171 (97.2)

77 (43.8)

All-causality SAEs

30 (17.0)

19 (10.8)

24 (13.6)

17 (9.7)

All-causality AEs leading to discontinuation

18 (10.2)

10 (5.7)

20 (11.4)

7 (4.0)

AEs leading to dose delay or reduction

53 (30.1)

28 (15.9)

66 (37.5)

33 (18.8)

||||||

|| ||||||

|| ||||||

Notable harms

Diarrhea or colitis

0

0

0

0

Hepatitis

0

0

0

0

Pneumonitis

2 (1.1)

0

1 (0.6)

1 (0.6)

Nephritis or renal dysfunction

0

0

0

0

Rash

15 (8.5)

3 (1.7)

1 (0.6)

0

Hypersensitivity or infusion reaction

2 (1.1)

0

0

0

AE = adverse event; SAE = serious adverse event.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Critical Appraisal

CheckMate 816 is an ongoing, randomized, open-label, phase III trial. Randomization was conducted using an Interactive Response Technology, and treatment allocation was concealed. Patients were stratified by 3 factors: PD-L1 expression level, disease stage, and gender or sex. The methods of randomization and the stratification factors were considered appropriate by the clinical experts consulted. Baseline characteristics in the 2 arms of interest were balanced, suggesting that randomization was successful. The methods of randomization and treatment allocation were considered appropriate.

The treatment effect for EFS and pCR was estimated during a prespecified interim analysis, adjusted using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries, which accounted for the actual number of events at an overall alpha of 4% or 5%. Overall, the treatment effect of the coprimary end points was estimated during the interim analysis. There is uncertainty about the magnitude of the treatment effect, given that interim analyses have the tendency to overestimate treatment effect.

OS was statistically nonsignificant at the preplanned interim analysis stopping rule (P = 0.008 against a prespecified level of significance at the interim analysis of 0.0033). Although the results showed a promising trend toward a significant treatment effect on OS, the final analysis may be needed to confirm the findings, particularly the exact estimate of the difference in median survival, which were not estimable at the data cut-off date. A follow-up OS analysis is planned after 128 OS events have occurred in both study arms.

Performance and assessment biases due to the open-label design of the trial were considered unlikely, given that radiologic assessments of CT scans for EFS and pathologic review of tumour sections were completed by a blinded independent review team, based on prespecified, and validated (RECIST 1.1) guidelines.

Further, the proportion of patients exposed to 3 doses of chemotherapy drugs was slightly higher in the nivolumab plus chemotherapy arm than in the chemotherapy arm. There were also slight differences reported in the cumulative dose intensity, which could bias the findings in favour of nivolumab plus chemotherapy.

More patients received subsequent anticancer therapy in the chemotherapy arm than in the nivolumab plus chemotherapy arm, and a higher proportion of patients received post-surgery adjuvant therapy in the chemotherapy arm, which could bias EFS and OS. However, the potential bias from the use of subsequent anticancer and adjuvant therapies was considered low.

The sponsor’s reimbursement request aligns with the Health Canada indication. The CheckMate 816 trial enrolled only patients with an ECOG PS of 0 or 1. The magnitude of benefit of nivolumab plus chemotherapy in patients with an ECOG PS of 2 or higher is uncertain.

The baseline and demographic characteristics in the trial were considered by the clinical experts to be generalizable to the population of patients with NSCLC in Canada. The experts highlighted notable differences between the patients enrolled in the CheckMate 816 trial and the patient population in Canada (younger, more stage IIIA disease, and more expression of PD-L1); however, the impact of these differences on the generalizability of the findings was considered low.

The dosing of nivolumab in the reimbursement request aligns with the Health Canada indication. Dose adjustments were allowed for chemotherapy drugs in the trial, but not for nivolumab, which aligns with the Health Canada indication. The experts indicated that a flat-dose approach to nivolumab, as implemented in the CheckMate 816 trial, would be used in practice.

Concomitant medications administered in the trial were considered appropriate by the clinical experts, and no major discrepancies in concomitant medications administered were identified that could have had a negative impact on the findings.

Indirect Comparisons

Description of Study

The sponsor provided a network meta-analysis (NMA)16 that compared the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy with other relevant treatments, including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone, in patients diagnosed with resectable nonmetastatic NSCLC. The primary efficacy end points used for NMA estimates were EFS and OS. The secondary outcomes included time to locoregional recurrence (TTLRR), TTDM, and pCR. For each outcome, base-case and sensitivity analyses were carried out whenever data were available. The base-case analysis involved patients who were deemed candidates for surgery and who had undergone third-generation platinum-based doublet chemotherapy. The sensitivity analyses expanded to include second-generation platinum-based chemotherapies, resected patient populations, data stratified by PD-L1 expression level (i.e., ≥ 1% versus < 1%), and data from the intention-to-treat (ITT) population of the CheckMate 816 trial, instead of the subpopulations of the CheckMate 816 trial (i.e., stage IB to II, stage IIIA, and stage IIIA N2) used in the base-case stage-specific networks. Furthermore, for each outcome, in addition to the stage-agnostic network, which included studies regardless of the staging of the patient population, the network was stratified by tumour staging (i.e., stage IB to II, stage IIIA, and stage IIIA N2). Eight randomized controlled trials (RCTs) were eventually included in the base-case analyses, 5 additional RCTs were included in the sensitivity analyses that involved second-generation chemotherapies, and 4 additional RCTs were included in the sensitivity analyses expanded to include resected patients.

Efficacy Results

Although both EFS and OS were selected as primary end points in the sponsor-submitted NMA, OS data from the CheckMate 816 trial were based on an immature data cut-off date. According to the base analysis of EFS, patients with stage IIIA NSCLC who received neoadjuvant nivolumab in combination with chemotherapy had a significantly lower risk of an event (i.e., EFS HR < 1, credible interval [CrI] excluding 1) than those who received neoadjuvant chemotherapy or underwent surgery alone. The risk of an event in patients with stage IIIA N2 NSCLC who received neoadjuvant nivolumab in combination with chemotherapy was also significantly lower than in those who received neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy. However, in patients with stage IB to II NSCLC, EFS improvement was not significantly different between neoadjuvant nivolumab plus chemotherapy and neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone. For stage-agnostic patients (i.e., stage IB to stage IIIA), although the EFS results showed that neoadjuvant nivolumab plus chemotherapy led to a significantly lower risk of an event than neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone, they were considered significantly biased because of the high heterogeneity in tumour staging, supported by significant differential treatment effects observed between patients with stage IB to II NSCLC and those with stage IIIA or stage IIIA N2 NSCLC.

Harms Results

The sponsor-submitted NMA did not quantitively synthesize evidence on safety outcomes due to the sparseness of the data and the differences in treatment regimens across the base-case studies. As a result, the sponsor provided a narrative description only.

Critical Appraisal

The systematic literature review (SLR) conducted by the sponsor to identify potentially eligible studies for the NMA was methodologically sound. The sponsor used a comprehensive literature search strategy, performed study selection and data extraction in duplicate, assessed the risk of bias appropriately, and described the characteristics of the included studies and narratively summarized the results in adequate detail. However, it was unclear whether the risk-of-bias assessment was carried out by a single assessor or multiple assessors. The reporting of the sponsor-submitted NMA generally followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.17

According to the clinical experts consulted by CADTH, the heterogeneity in tumour staging for patients with stage-agnostic NSCLC in the sponsor-submitted NMA was significant. And indeed, the effects of neoadjuvant nivolumab plus chemotherapy on EFS by stage, for example, were inconsistent between patients with stage IB to II NSCLC and those with stage IIIA or IIIA N2 NSCLC (i.e., statistically significant versus nonsignificant) compared to neoadjuvant chemotherapy in the base-case analysis. Because of the significant differential treatment effects of the 2 stage categories (IB or II versus IIIA or IIIA N2), the pooled indirect treatment comparison (ITC) results from the patients with stage-agnostic disease were deemed to be significantly biased, and the pooling to be inappropriate, methodologically, although neoadjuvant nivolumab plus chemotherapy markedly improved EFS relative to neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone in patients with stage-agnostic NSCLC.

For each outcome examined in the NMA, both random-effects and fixed-effects models were run. The random-effects model was considered by the sponsor as the default model. However, the fixed-effects model was selected by the sponsor for all analyses in the NMA due to the sparseness of network not being able to estimate the between-study standard deviation with enough precision. Although it was considered appropriate to use the fixed-effects model instead of the random-effects model when the network is sparce, it is important to note that the fixed-effects model is not capable of capturing heterogeneity.

The misclassification of tumour stage with different versions of tumour classification criteria could have also had an impact on the ITC estimation. In the sponsor-submitted NMA, of the 8 RCTs in the base-case analysis, the CheckMate 816 trial was the only study to use TNM 7th edition to classify tumours; 2 other trials used the TNM 5th edition, 3 used the TNM 6th edition, and 2 used the 1997 International Staging System. Different staging criteria could lead to different classifications of NSCLC and would consequently result in differences in prognosis estimation and treatment selection.

Safety outcomes were only narratively described in the NMA. Without a quantitative synthesis, a balanced judgment of comparative benefits relative to comparative harms could not be made. In addition, outcomes that are important to patients, such as HRQoL, were not reported in the NMA. Furthermore, analyses comparing neoadjuvant nivolumab plus chemotherapy with adjuvant atezolizumab was determined by the sponsor to not be feasible and to be inappropriate because of significant methodological challenges. Nonetheless, feedback from the clinical experts consulted by CADTH emphasized that adjuvant atezolizumab is an appropriate treatment option for patients with resected stage IB to stage IIIA NSCLC (the 7th lung cancer TNM classification) with a PD-L1 expression level of at least 50%. Therefore, the lack of relevant analyses might have introduced uncertainty into the sponsor’s submitted analysis.

Other Relevant Evidence

Description of Study

As part of the submission for nivolumab, the sponsor submitted a systematic review and a meta-analysis that described clinical evidence in patients with nonmetastatic resectable NSCLC. The sponsor-conducted meta-analysis assessed the potential use of pathologic response (pCR or MPR) as a surrogate end point for long-term outcomes (EFS, OS) in patients with resectable NSCLC. The systematic review was informed by patient-level data from 32 studies that presented evidence of an association between OS and/or EFS and pCR and/or MPR, measured as an HR, or reported Kaplan-Meier curves for OS and/or EFS by pCR and/or MPR status, which allowed for the reconstruction of HRs.12

Efficacy Results

||||||| |||||||| || |||||||||||| |||||||| |||||||| |||||| |||| |||||| || |||||||||||||||| ||||||||||| ||||||| || ||||||||| ||| || ||| |||| |||| ||| |||| || ||||| |||||| ||| || ||||||| ||||||||| |||||||||| |||| ||||||||| ||| ||| |||||||||| |||| |||||| |||||||||||| |||||||||||| ||||||||| |||| ||||||| || ||| || || ||| |||||||| |||| |||| |||||||| ||| |||| |||| ||| |||| || ||||||

Critical Appraisal

The sponsor-submitted meta-analysis was informed by studies selected from an adequately conducted systematic review, with a clearly prespecified patient, intervention, comparison, outcome (PICO) model, in accordance with the PRISMA guidelines. The study-selection and data-extraction methods were considered appropriate. In the absence of detailed information on the baseline and study characteristics of patients enrolled in the studies included in the meta-analysis, the degree of heterogeneity between the included studies could not be assessed. Studies included had considerable variation in terms of study design (observational versus RCT) and sample size. Heterogeneity was not reported for the Bayesian analysis and, owing to the lack of baseline data on the trials included an assessment of the level of heterogeneity could not be made. The meta-analysis suggests that achievement of a pCR was associated with improved OS, based on the Bayesian and frequentist methods implemented in the analyses.

Description of Study

The sponsor submitted 1 real-world study conducted with data from electronic health records (EHRs) supplemented with chart reviews. The purpose of this retrospective, observational study was to generate real-world evidence to characterize the relationship between pathologic responses and survival and to describe patient profiles and neoadjuvant treatment patterns for patients with surgically resectable NSCLC (stage IB [tumour ≥ 4 cm] to stage IIIA) treated in the community oncology setting in the US. Neoadjuvant treatment regimens were characterized as chemotherapy or chemoradiotherapy in the study.

Efficacy Results

||| |||||| ||||||||| ||| |||| ||||||| ||| || |||||| ||||| ||||| |||||||| || ||||||| |||||||||| || |||||| |||||| || || ||||||| |||||||| |||||||| |||| ||| |||||| || || ||||||| |||||||| |||||||| || |||| ||||||||| |||||||| |||| ||| || ||||| ||||||| |||| ||| |||||||||| || || ||||||||||| ||| |||||||| ||| || ||| |||| |||| ||| |||| || |||||| |||| |||||||| ||| |||| ||||||| ||||| |||||| ||| ||||||||||| |||||||| ||| ||||||| |||||||||| |||| |||||||| || ||||||||| ||| |||| |||| ||| |||| || ||||||| |||| |||||| || ||||| |||||||| |||| |||| ||| |||| |||| ||| |||| || |||||| |||||| |||||||| || |||| |||| || |||| || ||||| |||||| ||||| |||||||| ||||||| ||||| |||| |||||||| |||| ||| |||| |||||||| || ||||| ||||||| |||| ||| |||||||||| || || ||||||||||| ||| |||||||| ||| || ||| |||| |||| ||| |||| || |||||| |||| |||||||| ||| |||| ||||||| ||||| |||||| ||||||| ||||| |||||| ||| ||||||||||| |||||||| ||| ||||||| |||||||||| |||| |||||||| || ||||||||| ||| |||| |||| ||| |||| || ||||||| ||| ||||||| ||| |||||||||||| ||||||| ||||||| ||| ||| |||||| ||||||| ||||||||| |||| |||||| || ||||| |||||||| |||| || ||| ||| |||| |||| || |||| || |||||| |||||| |||||||| || |||| |||| ||| |||| || ||||| |||||| ||||| |||||||| ||||||| || |||| ||| ||||| ||| ||||||||| |||| ||||| || || |||||| ||||||| |||||| |||| |||||||||| || ||| ||||||||| ||| |||| ||| |||| |||||||||| ||| ||||||||| ||||||||| || |||||||| ||||||||||||| |||||| ||||||||| |||||||| ||||||| || ||| || |||||||| ||||||||

Critical Appraisal

Several limitations of the study were identified: neoadjuvant treatment consisted only of chemotherapy and chemoradiotherapy, several variables had incomplete or missing data in the analyses, and sample size was reduced (and had reduced power) to assess the relationship between pCR and/or MPR and survival end points. Thus, it is difficult to conclude that this retrospective, observational study (i.e., real-world evidence), which characterizes the relationship between pathologic responses and survival, as well as patient profiles and neoadjuvant treatment patterns in patients with surgically resectable NSCLC (stage IB [tumours ≥ 4 cm] to stage IIIA) treated in the community oncology setting in the US, provides all the information required to address gaps in the evidence in support of the validity of end points in the pivotal trial.

Conclusions

Although statistically significant EFS and favourable OS outcomes were observed in the CheckMate 816 trial for nivolumab plus chemotherapy compared to chemotherapy alone for the neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease), there remains uncertainty about the magnitude of the treatment effect, given that the results are based on interim analyses, OS data were immature at the October 20, 2021, cut-off date, and the HR for death was not statistically significant. Although EFS is a validated surrogate for OS, final analyses may be warranted to increase confidence in the trial findings. Prespecified EFS subgroup analyses suggested that the majority of the benefit derived from nivolumab plus chemotherapy was in subgroups of patients with stage IIIA disease and a PD-L1 expression level above 50%. However, efficacy results from these subgroup analyses should be interpreted with caution, as the study was not statistically powered to assess subgroups individually. The clinical experts indicated that patients with the highest risk of recurrence (i.e., patients with stage IIIA disease) and with a PD-L1 expression level above 50% may derive more benefit from the treatment and clinicians may be more apt to treat them with this regimen. However, regardless of the magnitude of response observed, a benefit was observed in all subgroups and in the overall study population. No detriment to quality of life was observed for patients in the trial, and the mean differences from baseline to predefined time points did not exceed minimally important differences (MIDs) for the VAS and utility score portion of the EQ-5D-3L questionnaire. Notable differences between the trial population and patients treated in Canada were related to the younger population in the trial than in the patient population in Canada, the higher proportion of patients with stage IIIA NSCLC in the trial than is seen in clinical practice, and the lack of a comparator arm with the current standard of care. However, the clinical experts noted that these differences were unlikely to affect the generalizability of the efficacy results to the patient population in Canada. The clinical experts noted that this treatment will typically be administered to patients with surgically resectable NSCLC (tumours ≥ 4 cm and or node-positive disease) and a good ECOG PS (0 and 1). The safety profile of nivolumab was consistent with the known safety profile of immunotherapies, and no new safety signals were identified. The AEs reported were considered manageable in practice by the clinical exerts consulted.

It is worth noting that the comparator in the CheckMate 816 trial (neoadjuvant chemotherapy) is not the current standard of care in Canada for patients with resectable NSCLC (which is upfront surgery with curative intent, followed by adjuvant chemotherapy), and no direct evidence was available to assess the efficacy of nivolumab plus chemotherapy relative to surgery followed by adjuvant chemotherapy. Findings from the sponsor-submitted NMA suggest an improvement in EFS in the nivolumab plus chemotherapy arm for patients with stage IIIA resectable NSCLC, compared with surgery and adjuvant chemotherapy. However, there were sources of uncertainty identified, such as the significant heterogeneity in the RCTs included, sparse networks, and immature data for OS. In addition, there were no quantitative safety data presented, so no conclusions could be drawn. The sponsor-submitted meta-analysis and real-world evidence showed favourable OS outcomes with neoadjuvant nivolumab for those who achieved a pCR compared to those who did not. However, both studies have study design limitations that preclude definitive conclusions.

Introduction

Disease Background

Lung cancer is the most frequently diagnosed cancer in Canada, and the leading cause of cancer-related death.1 About 30,000 new diagnoses (50% in males and 50% in females)2 and 20,700 cancer-related deaths were projected in Canada in 2022,1,3 with about 98% of all cases anticipated in people 50 years and older.4 The adjusted 5-year net survival (based on 2015 to 2017 estimates) for all forms of lung cancer is only 22% (19% in males and 26% in females in Canada).1,2 NSCLCs are the most common forms of lung cancer, accounting for more than 80% of all lung cancers in Canada,5,6 and adenocarcinomas are the most commonly diagnosed forms, accounting for 48% of new cases in Canada.4 The 5-year survival rate for patients with NSCLC is poor and highly dependent on disease stage at diagnosis; it is higher in patients with early-stage (stage IB) disease (66% to 68%) than in patients with stage IIA disease (52% to 60%), stage IIB disease (47% to 53%), and stage IIIA disease (36%).18

Diagnosis is based on symptoms and histology at initial presentation.19,20 Staging is key in determining disease prognosis and facilitates treatment selection.20,21 The current standard staging system recommended in Canada is the 8th edition of the AJCC/UICC staging guidelines, which involves a tumour, node, metastasis (TNM) classification of the disease based on the size and spread of the primary tumour (T), lymph node involvement (N), and occurrence of metastasis (M).22 About 47.1% of all new cases of NSCLC are diagnosed at stage IV, 19.0% at stage III, 9.1% at stage II, and only 23.1% at stage I.7 Patients with early-stage NSCLC have a higher risk of disease recurrence than patients with later-stage disease, despite curative surgery.23

General symptoms of NSCLC include worsening cough, chest pain, hemoptysis, malaise, weight loss, dyspnea, and hoarseness at clinical presentation or upon chest imaging.4,20 Patients with advanced or metastatic disease may experience additional symptoms such as trouble breathing, chronic cough and chest pain, pain in bones or the spine, yellowing of the skin or eyes, weakness or numbness of arms or legs, fatigue and unexplained weight loss, depression, insomnia, and pain.21,24 Diagnostic procedures currently recommended include imaging with CT, PET, and/or MRI scans, bronchoscopy with or without endobronchial ultrasound, and tissue biopsy.25

Available treatment options for NSCLC depend on disease stage at diagnosis, the potential for tumour resection with surgery, and eligibility of the patient for surgery (e.g., performance status, comorbidities). Treatment options include surgery, radiotherapy, and systemic therapy (with chemotherapy or immunotherapy). Patients may receive treatments before surgery (neoadjuvant setting), after surgery (adjuvant setting), before and after surgery (perioperative therapy), or after they have achieved disease control (consolidation therapy with radiation with or without chemotherapy).12 For patients with early-stage disease, eligibility for surgical resection depends on various clinical factors that determine the safety of a lung resection (e.g., overall respiratory function, tumour location, and the presence of ipsilateral vocal cord paralysis, Horner syndrome, phrenic nerve palsy, and neurologic deficits associated with Pancoast superior sulcus tumours) and on general health factors that determine eligibility for major surgery (e.g., comorbidities such as active cardiac disease).25

Standards of Therapy

The treatment goal for patients with resectable NSCLC is to cure, improve 5-year OS, and prevent disease recurrence.

Surgery with curative intent is the current gold standard for patients with clinical stage I to stage IIIA NSCLC amenable to resection.8,9 The standard of care for completely resectable stage IIA or IIB and stage IIIA NSCLC (AJCC 7th edition), according to joint guidelines from the American Society of Clinical Oncology and CCO, is surgical resection followed by adjuvant cisplatin-based chemotherapy.10 Cisplatin-based chemotherapy is not recommended for patients with stage IA disease and not routinely recommended for patients with stage IB disease; however, a postoperative evaluation is recommended.10,26 The British Colombia guidelines recommend adjuvant platinum-based therapy (cisplatin-based treatment is preferred or, if cisplatin is contraindicated, carboplatin-based treatment) as the standard of care for patients with completely resected stage II or stage IIIA (AJCC 7th edition) disease.27

Neoadjuvant chemotherapy is seldom used in Canada for resectable NSCLC, as it has not been shown to provide a survival benefit over adjuvant therapy, and in the process of pursuing neoadjuvant chemotherapy, some patients may become ineligible for surgery (owing to disease progression or treatment-related toxicity), according to the clinical experts consulted. Still, neoadjuvant therapy has several advantages: it can reduce tumour size, increase resectability, and remove micrometastasis and tumour cells in distant lymph nodes, thereby reducing the risk of recurrence from tumour cells that are not removed by surgery.12,13

Stereotactic ablative radiation with curative intent is available to some patients with early-stage disease who are ineligible for surgery (e.g., because of significant comorbidities that make them a high risk for general anesthetic) or who refuse surgery, according to the clinical experts. Patients with borderline resectable stage III cancer may be offered chemotherapy and/or radiation in current practice before surgery, whereas those with unresectable stage III NSCLC will be typically managed with combined chemoradiation followed by a year of consolidation with durvalumab if the patient has stable or responsive disease at postchemoradiation reassessment, the clinical experts explained.11 Adjuvant chemotherapy options consist of cisplatin plus vinorelbine, carboplatin plus paclitaxel for patients with a contraindication to cisplatin, gemcitabine plus carboplatin, paclitaxel plus carboplatin, pemetrexed plus cisplatin, and immune-checkpoint inhibitors (atezolizumab and durvalumab). The experts indicated that patients with node-positive NSCLC or who have tumours 4 cm or larger may receive additional postoperative treatment, such as adjuvant chemotherapy (4 cycles of cisplatin-based doublet chemotherapy with vinorelbine or pemetrexed) or adjuvant osimertinib (for 3 years, but only for patients with the common exon 19 deletion or an exon 21 insertion L858R EGFR mutation).

For patients with PD-L1 Tumour Proportion Scores above 50%, a recent Health Canada NOC for atezolizumab has recommended funding in the adjuvant setting after adjuvant chemotherapy; however, at present, it is not available outside private insurance or patient self-pay options. Postoperative adjuvant radiation is limited to use in patients with R1 resections (i.e., positive surgical margins). The experts noted that evidence from the IMPOWER010 trial supports a year of adjuvant therapy with atezolizumab after adjuvant chemotherapy. However, the Health Canada NOC limits this treatment to patients whose tumours exhibit a PD-L1 Tumour Proportion Score of 50% or more. Although this therapy has received an initial recommendation for funding by CADTH, it is not yet funded in any health jurisdiction in Canada, nor is it available through patient support programs. Adjuvant chemotherapy leads to an absolute improvement in 5-year OS of approximately 5% for all outcomes (although this is likely an underestimate in patients with higher-stage disease,28 and patients with stage IIIA disease [according to the AJCC 7th edition] have a high risk of recurrence [approximate 5-year survival in these patients is 30%]).

The clinician group input generally highlighted treatment options for resectable NSCLC similar to those described by the clinical experts consulted during this review. The clinician group input noted that adjuvant chemotherapy is not indicated for patients with stage I cancers, based on the 8th edition of the UICC staging system (tumours < 4 cm, node-negative disease).

Drug

Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including antitumour immune response. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.14 The Health Canada–recommended dose of nivolumab is 360 mg administered intravenously over 30 minutes as neoadjuvant treatment in combination with platinum-doublet chemotherapy every 3 weeks for 3 cycles.14 The key characteristics of nivolumab, carboplatin, paclitaxel, and pemetrexed are presented in Table 4.

Nivolumab underwent a review at Health Canada under Project Orbis and received a NOC on August 18, 2022, for the neoadjuvant treatment of adult patients with resectable NSCLC (tumours ≥ 4 cm or node-positive) in combination with platinum-doublet chemotherapy.12 The sponsor’s reimbursement request and population aligns with the Health Canada indication. This submission is a post-NOC request.

Table 4: Key Characteristics of Nivolumab, Carboplatin, Pemetrexed, and Paclitaxel

Characteristics

Nivolumab14

Carboplatin29

Pemetrexed30

Paclitaxel31

Mechanism of action

Nivolumab is an IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumour immune response. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.

Carboplatin is a synthetic analogue of cisplatin, that, like cisplatin, interferes with DNA intrastrand and interstrand crosslinks in cells exposed to the drug. DNA reactivity has been correlated with cytotoxicity.

Pemetrexed disodium is an antifolate antineoplastic drug that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.

Paclitaxel is an antimicrotubule drug that blocks cell replication in the late G2 and/or M phases of the cell cycle. Additionally, it produces unusual cytoskeletons characterized by discrete bundles or microtubules and the formation of abnormal spindle asters during mitosis.

Indicationa

Neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease) in combination with platinum-doublet chemotherapy.

The treatment of ovarian cancer of epithelial origin in first-line therapy, and in second-line therapy after other treatments have failed.

In combination with cisplatin therapy for the initial treatment of patients with a good performance status and locally advanced or metastatic nonsquamous NSCLC.

For the maintenance treatment of locally advanced or metastatic nonsquamous NSCLC in patients with a good performance status and no disease progression immediately after 4 cycles of first-line platinum-doublet chemotherapy.

First-line treatment of advanced NSCLC.

Route of administration

IV

IV

IV

IV

Recommended dose

A flat dose of 360 mg IV infusion over 30 minutes

400 mg/m2 as a single 15 minute to 60-minute IV infusion

In combination with cisplatin therapy, 500 mg/m2 administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle

175 mg/m2 IV infusion over 3 hours every 3 weeks, followed by cisplatin

Serious adverse effects or safety issues

Fatal immune-mediated adverse reactions, including pneumonitis, interstitial lung disease, encephalitis, myocarditis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and autoimmune hemolytic anemia

Hypersensitivity reactions

Hematologic toxicity

Bone marrow suppression

Neurologic toxicity

Fatal veno-occlusive disease

Fatal hemolytic anemia

Fatal hemolytic-uremic syndrome

Hepatotoxicity

Contraindication to concomitant yellow fever vaccine bullous Epidermolysis

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Severe hypersensitivity reactions (dyspnea, hypotension, angioedema, generalized urticaria) Bradycardia

Peripheral neuropathy

IgG4 = human immunoglobulin G4; NSCLC = non–small cell lung cancer; PD-1 = programmed cell death 1 protein; PD-L1 = programmed cell death 1 ligand 1; PD-L2 = programmed cell death 1 ligand 2.

aHealth Canada–approved indication.

Sources: Nivolumab PM,14 carboplatin PM,29 paclitaxel PM,31 pemetrexed PM.30

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

LCC, a member of Global Lung Cancer Coalition and the only national organization in Canada focused exclusively on lung cancer, engages in patient support, education, research, and advocacy. LCC submitted patient group input based on interviews conducted in Canada in September and October 2022 ([1 patient with stage I/II NSCLC, 1 patient with stage III NSCLC, 2 patients with stage IV NSCLC, and 1 caregiver for a patient with large-cell neuroendocrine carcinoma] and [1 interview with a patient who had stage IV NSCLC and had undergone an environmental scan]). All participants had experience with nivolumab. The patient input summary will focus on the 2 patients with stage I to stage III NSCLC to align with the requested indication.

One patient said she used to be extremely active and was an avid runner for 10 years before her lung cancer diagnosis. Lung cancer made exercise harder and made her feel more tired than before, which had an impact on her independence, she explained. She experienced cough and some mild chest pain before her diagnosis of lung cancer. Another patient who had been diagnosed with early-stage NSCLC had two-thirds of his lung surgically removed, leaving him with 50% of his initial lung capacity. As a result, he became unable to do any vigorous exercise or activity and tires quickly. The input indicated that patients value treatment options that maintain or improve quality of life, delay the onset of symptoms, improve survivorship, improve, or maintain functionality and/or mobility, and ultimately provide a cure. Also, patients prefer treatments that can be administered at a hospital located near home, or in a community clinic for those in rural settings, to minimize travel time and burden on caregivers. The input emphasized that because the CheckMate 816 trial excluded patients with EGFR or ALK alterations, owing to a lack of evidence of supporting neoadjuvant immunotherapy in this population, a biomarker screening (a routine practice) must be performed before neoadjuvant treatment with nivolumab.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of NSCLC.

Unmet Needs

The clinical experts consulted noted that the treatment goal in this setting is to cure patients (improve survival by eradicating micrometastasis) and prolong life. Secondary treatment goals include the delay of disease relapse, which will allow patients to live longer in a disease-free state.

The clinical experts noted that many patients receiving the current standard of care (surgery followed by adjuvant chemotherapy) still experience disease relapse, after which the disease generally becomes incurable. The clinical experts added that although adjuvant chemotherapy adds a survival benefit to patients in current practice, the benefit observed is modest and adjuvant treatment is associated with a toxicity burden. The clinical experts explained that many patients treated with the current standard of care decline or are ineligible for adjuvant chemotherapy because of the potential for AEs related to cisplatin doublet chemotherapy, some of which may be irreversible (e.g., kidney or nerve damage, impaired hearing). The clinical experts also mentioned that many patients are not clinically fit to undergo 4 cycles of cisplatin-based adjuvant treatment, and therefore do not receive any adjuvant therapy. Thus, there is an unmet need for new treatments for patients with resectable NSCLC.

Place in Therapy

The clinical experts explained that nivolumab would change the treatment paradigm for early-stage resectable NSCLC, as neoadjuvant therapy is not common practice in Canada. The clinical experts indicated that there might be a shift in the treatment paradigm for patients who experience disease recurrence while receiving neoadjuvant nivolumab and chemotherapy, or shortly after completion (usually within 6 months), given that the standard first-line therapy for patients diagnosed with incurable disease is based on an immunotherapy backbone with single-drug pembrolizumab or cemiplimab, or on platinum-doublet chemotherapy combined with pembrolizumab or nivolumab and ipilimumab. However, the clinical experts noted that backbone immunotherapy may not be appropriate if clinicians believe the disease is resistant to PD-1 inhibition. The clinical experts also noted that the order of therapies in the current treatment paradigm may shift, given that patients were allowed to receive additional postoperative adjuvant chemotherapy and/or radiation at the discretion of the treating physician in the CheckMate 816 trial. For the majority of patients treated with neoadjuvant chemotherapy and nivolumab in practice, this would be considered a replacement for adjuvant chemotherapy, and in most cases no further adjuvant systemic therapy would be offered.

According to the clinical experts, nivolumab plus chemotherapy would only be used in the curative-intent setting before surgery to increase the time before disease recurrence and, presumably, reduce the number of patients who will experience disease recurrence, thereby increasing cure rates and OS. The clinical experts noted that this treatment may increase the number of patients who have a complete (R0) surgical resection, and may reduce the extent of the lung removed during surgery (e.g., a patient who otherwise would have had to have a full lung removed [pneumonectomy] may be able to have a smaller surgery limited to the removal of a single lobe of the lung [lobectomy] after the downsizing effect of preoperative chemotherapy plus nivolumab). The clinical experts noted that nivolumab will be administered in practice, in addition to 3 cycles of chemotherapy, to patients with tumours 4 cm or larger or with node-positive disease.

Patient Population

The clinical experts consulted indicated that eligible patients will include those who have tumours larger than 4 cm and/or node-positive disease, who have no EGFR or ALK mutations, and who are deemed fit for upfront surgical resection, including patients with locoregional spread of disease to the lymph nodes but who remain fit for upfront resection, provided there were no contraindications (e.g., severe or uncontrolled autoimmune diseases, frailty, poor baseline organ function). The experts noted that nivolumab would not be appropriate for patients considered to have borderline resectable disease fit for upfront surgery and for whom the goal of neoadjuvant therapy would be to downsize the tumour enough to make surgical resection feasible.

The clinical experts indicated that patients with the highest risk of recurrence (i.e., patients with stage IIIA disease) and a PD-L1 expression level above 50% would likely derive benefit from the treatment, and clinicians may be apt to treat them with this regimen.

According to the clinical experts, patients will be identified by a thoracic surgeon after appropriate review. The experts noted that surgical resectability is usually determined by a thoracic surgeon, and eligibility depends on multiple factors, including a patient’s lung function (measured with pulmonary lung function tests). The clinical experts indicated that the process of determining tumour resectability for patients with early-stage NSCLC is, to a certain extent, subjective. They noted that, ideally, tumour scans are reviewed by a thoracic tumour board, but added that the process may not always be feasible. Patients should undergo baseline staging with a PET scan, MRI brain scan, and mediastinal lymph node sampling. Driver mutations (EGFR or ALK) are important but may not be routinely assessed in all centres in patients with early-stage disease; however, the experts noted that patients with unknown EGFR and ALK mutational status should not be excluded from receiving the treatment. The clinical experts added that underdiagnosis and misdiagnosis are not issues in this setting. Further, there are projections that current screening strategies in Canada may increase the number of patients with early-stage disease who are asymptomatic and are candidates for curative-intent surgery.

Assessing Response to Treatment

The clinical experts noted that patient response to treatment is assessed with preoperative CT scans done after the completion of neoadjuvant systemic therapy, pathologic response, and OS. According to the clinical experts, the interpretation of restaging results can be difficult, given that some patients who receive neoadjuvant checkpoint inhibitors tend to exhibit pseudoprogression, especially in the lymph nodes. The clinical experts noted that any areas of possible progressive disease would be verified with tissue sampling, when feasible, before it is determined that a patient is no longer eligible for surgery because of disease progression.

According to the clinical experts, follow-up after completion of curative-intent surgery is not standardized in current practice, given the lack of definitive literature suggesting the most appropriate timing interval for serial radiography. The clinical experts noted that, in practice, response assessments for patients include surveillance CT scans (typically every 6 months for 2 years, then yearly to 5 years after therapy), and that this would not change because of the use of neoadjuvant nivolumab. In addition, follow-up procedures currently in place would not be affected in patients treated with neoadjuvant chemotherapy and nivolumab; they are already in place for patients who have undergone curative-intent surgery. A clinically meaningful response would be an improvement in OS.

Discontinuing Treatment

According to the clinical experts, chemotherapy and/or nivolumab could be discontinued at a patient’s request in the event of disease progression during the 3 cycles of neoadjuvant therapy, autoimmune or medically dangerous side effects, or intolerable toxicity.

Prescribing Conditions

According to the clinical experts, nivolumab administration should be monitored by a qualified specialist medical doctor (a medical oncologist or, in very rare cases, a respirologist) with experience in the treatment of lung cancer and the use of immunotherapy checkpoint inhibitors. Hospital outpatient settings in which personnel have experience with immunotherapy checkpoint inhibitors and chemotherapy would be appropriate treatment settings.

Additional Considerations

The clinical experts highlighted the current lack of clinical evidence to support the use of adjuvant nivolumab. The experts added that there is no evidence to support the use of the Health Canada–approved atezolizumab in the adjuvant setting for patients who have received neoadjuvant chemotherapy without nivolumab.

The clinical experts advised against defining eligibility for treatment in terms of staging, as there will be further evolution of these manuals in the near future. The experts noted that in the AJCC 7th edition, T2 tumours are defined as being larger than 3 cm and up to 7 cm. On further subdivision, T2a tumours are defined as being larger than 3 cm and up to 5 cm, and T2b tumours are defined as being larger than 5 cm and up to 7 cm. If a tumour is T2aN0 (node negative), it is classified as stage IB. If a tumour is T2bN0, it is classified as stage IIA. The indication being examined for neoadjuvant nivolumab plus chemotherapy includes patients with node-negative disease and tumours 4 cm or larger, so some stage IB tumours, according to the AJCC 7th edition, would qualify for neoadjuvant nivolumab plus chemotherapy and others would not. In the AJCC 8th edition, T2a tumours have been redefined as being larger than 3 cm and up to 4 cm, T2b tumours are now larger than 4 cm and up to 5 cm, and T3 tumours are now larger than 5 cm and up to 7 cm. The overall staging for these groups has also shifted; in the AJCC 8th edition, T2aN0 tumours remain classified as stage IB, but T2bN0 tumours are now classified as stage IIA and T3N0 tumours are now classified as stage IIB. The key difference is that the cancers included in the CheckMate 816 trial, which used the AJCC 7th edition definition of stage IB (node-negative tumours from 4 cm to 5 cm), would be classified as stage IIA in the AJCC 8th edition.

Patients with N2 nodal disease limited to a single nodal station are generally considered surgical candidates, as long as there is no local invasion that would render a complete surgical resection unfeasible, according to the clinical experts. In the AJCC 7th edition, patients with T2b (> 5 cm to 7 cm), N2, or T3N2 disease were considered stage IIIA, and would have been enrolled in the CheckMate 816 trial if they were candidates for upfront resection. In the AJCC 8th edition, the clinical experts noted that patients with primary tumours larger than 5 cm and up to 7 cm are considered T3, and T3N2 tumours have been upstaged from stage IIIA to stage IIIB. Further, tumours that were classified as T3 in the AJCC 7th edition (> 7 cm or with invasion of the diaphragm) are now classified as T4 in the AJCC 8th edition, and T4N2 tumours have been upstaged from stage IIIA to stage IIIB. According to the clinical experts, this means that there are patients with stage IIIB disease who are resectable according to the AJCC 8th edition who would have been considered stage IIIA in the AJCC 7th edition and thus eligible for neoadjuvant chemotherapy plus nivolumab.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Two clinician groups, the OH-CCO Lung Cancer DAC and LCC submitted 2 separate inputs. The OH-CCO’s DAC provides guidance on drug-related issues in support of CCO’s mandate and collected information from 3 clinicians during a DAC meeting. LCC, a national charity and the only organization in Canada solely focused on lung cancer (education, advocacy, research), gathered information from published clinical data and 12 lung cancer medical oncologists from across Canada.

Unmet Needs

According to the OH-CCO group, despite current treatments, a number of patients experience a recurrence quickly and do not survive. Therefore, neoadjuvant nivolumab would be an additional option for patients with resectable NSCLC. LCC cited several advantages of neoadjuvant approaches: limiting the risk of systemic dissemination of the cancer; tumour downsizing (leading to decreased postoperative complications [e.g., pain, infection], decreased performance status, improved surgical outcomes, and improved recovery times); the possibility of easier, safer, and more efficacious surgeries; improving patient capacity to receive postoperative therapies; providing the opportunity for smoking cessation, physical therapy, and medical evaluations for surgery, helping to manage the surgical wait list; and improving the ability to provide prognosis and risk-stratification after surgery.

Place in Therapy

According to the OH-CCO clinicians, neoadjuvant nivolumab would be an additional option for patients with resectable NSCLC and could potentially replace adjuvant chemotherapy in some patients. Similarly, LCC clinicians said that neoadjuvant nivolumab therapy would eliminate the need for postoperative, prolonged, and more expensive therapies (chemotherapy, radiation, immunotherapy). LCC clinicians said it is not clear whether all eligible patients would choose neoadjuvant nivolumab therapy, such as patients with stage II, node-negative disease considered for upfront surgery with optional adjuvant therapies, those at high risk of chemotherapy-associated or immunotherapy-associated complications, and those preferring upfront surgery.

Patient Population

The OH-CCO clinicians said that patients who meet the clinical trial inclusion criteria (i.e., those with resectable stage IIA to stage IIIB NSCLC [AJCC 8th edition] and/or those eligible for chemotherapy) would be best suited for treatment with nivolumab. The LCC clinicians said that neoadjuvant therapy may be favoured for patients with stage IIIA and/or PD-L1-positive disease, based on the favourable results in these strata shown in CheckMate 816 study. However, the LCC group said that a discussion with every eligible patient appears warranted, and that treating all eligible patients with a neoadjuvant would be favoured to decrease the treatment burden after surgery (e.g., postoperative chemotherapy and/or atezolizumab). According to the LCC clinicians, the least suitable patients would be those with a contraindication to chemotherapy and/or immunotherapy, such as those with renal failure, heart failure, severe hearing loss, severe neuropathy, an organ transplant, active and symptomatic autoimmune disease (e.g., patients with Crohn disease on immunosuppressive therapy or those with multiple sclerosis), and an ECOG PS of 2 to 4. The LCC group added that a history of autoimmune disease or autoimmune disease that is clinically silent (e.g., immune thyroiditis) or well controlled without active immunosuppression is not a major contraindication. Last, according to the LCC input, the use of neoadjuvant immunotherapy in patients with EGFR, ALK, ROS1, RET, or NTRK alterations needs further investigation and/or will have to be addressed on a case-by-case basis, as these groups have not been specifically addressed in clinical trials.

Assessing Response to Treatment

The OH-CCO clinician group stated that outcomes such as clinical assessment (to ensure no progression), surgery, and pathological assessment can be used to determine response to nivolumab. The LCC clinician group said that an additional CT scan would be needed after neoadjuvant therapy to evaluate a patient’s eligibility for surgery. According to LCC clinicians, currently there is no clinical, biologic, or imaging tool that can be used to identify patients who will have a pCR on pathological assessment after neoadjuvant treatment and can be excluded from surgical treatment. At present, patients are followed with standard postoperative care, the LCC clinicians reported. However, they anticipate that in the future, as more experience is gained with neoadjuvant approaches, risk-adapted follow-up strategies will be possible, based on, for example, postoperative monitoring of circulating tumour DNA in combination with other clinical and pathologic features of the cancer.

Discontinuing Treatment

The OH-CCO clinicians said that intolerable toxicity and clinically obvious disease progression are factors to consider when deciding whether to discontinue nivolumab treatment. The LCC clinicians stated that clinical and biologic evaluations are performed at every cycle of therapy, as they are for patients undergoing chemotherapy and/or immunotherapy in the advanced disease setting, per standard practice in oncology.

Prescribing Conditions

The OH-CCO clinicians noted that a specialist, ideally as part of a multidisciplinary team, is required in a hospital outpatient clinic to diagnose, treat, and monitor patients receiving nivolumab. The LCC clinicians also stated that, ideally, a multidisciplinary cancer tumour board, consisting of (nonexclusively) respirologists, radiologists, pathologists, thoracic surgeons, medical oncologists, and radiation oncologists, should discuss a multimodal treatment approach for patients who are usually referred to oncologic thoracic surgeons affiliated with major cancer centres. The LCC clinicians added that the delivery of care should be planned according to local structures; ideally, systemic therapies will be administered as close to a patient’s home as possible while patients are continuously monitored by the cancer centre to coordinate neoadjuvant therapies with posttreatment imaging, preoperative evaluations, and the surgical admission itself.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

Drug program implementation questions

Clinical expert response

Relevant comparators

The comparator is appropriate, because if patients were to receive neoadjuvant chemotherapy, it would be platinum-doublet chemotherapy. Neoadjuvant platinum-doublet chemotherapy has an efficacy similar to that of the current standard of care in Canada (adjuvant chemotherapy). Most patients will not receive any treatment in the neoadjuvant setting.

In the CheckMate 816 trial, chemotherapy with vinorelbine and cisplatin, gemcitabine and cisplatin, pemetrexed and cisplatin, or paclitaxel and carboplatin for up to 3 cycles (9 weeks) was implemented. These regimens are some of the chemotherapy options available for neoadjuvant chemotherapy. What chemotherapy regimens are appropriate for neoadjuvant use in combination with nivolumab?

The clinical experts noted that docetaxel and vinorelbine were only allowed in the chemotherapy arm of the CheckMate 816 trial but not the nivolumab arm. It would be appropriate to apply the chemotherapy drugs used in the nivolumab plus chemotherapy arm to patients in real-world practice.

Considerations for initiation of therapy

In the CheckMate 816 trial, participants were excluded if they had known EGFR mutations or ALK translocation. The funding request does not reference EGFR mutation or ALK translocation status

Does PD-L1 status have to be established for a patient to be eligible for nivolumab in combination with neoadjuvant chemotherapy for resectable NSCLC?

According to the clinical experts, nivolumab will be available to all patients, regardless of their PD-L1 expression level.

There are no immunotherapy drugs currently funded in the neoadjuvant NSCLC setting at this time, and this is the first immunotherapy drug to be reviewed.

In other solid tumours, patients are eligible for a downstream PD-1 or PDL-1 inhibitor, provided that disease recurrence (whether locoregional or distant) occurs 6 months or more after the last dose of the neoadjuvant PD-1 or PD-L1 inhibitor. If nivolumab is funded in this setting, will jurisdictions permit a downstream PD-1 or PDL-1 inhibitor used in a manner consistent with other tumour sites?

For pERC consideration.

Considerations for discontinuation of therapy

If patients cannot tolerate chemotherapy, are they able to continue with nivolumab?

Is there a minimum number of chemotherapy cycles that must be given concurrently with nivolumab?

The clinical experts explained that patients would likely go straight to surgery if they remain eligible; however, if the adverse event was attributable to chemotherapy only, then the patients may receive the remainder of the treatment with nivolumab monotherapy.

A second expert noted that treatment discontinuation procedures in practice will likely follow those implemented in the CheckMate 816 trial protocol. The expert explained that in the CheckMate 816 trial, if either chemotherapy or nivolumab needed a dose delay, both were delayed until the patient met resumption criteria for both chemotherapy and nivolumab. If an adverse event could be clearly attributed to either the chemotherapy or nivolumab, which meant that that particular drug had to be discontinued, patients were allowed to continue with the other.

In the event that the treating physician or patient chooses to stop both and proceed with surgery before 3 cycles are complete, it was considered appropriate, but having to stop chemotherapy should not mean that the patient cannot continue to a maximum of 3 cycles of nivolumab, or vice versa.

Considerations for prescribing of therapy

PAG would like to inform pERC that jurisdictions will implement weight-based dosing up to a cap, similar to other immunotherapy policies (i.e., nivolumab 4.5 mg/kg up to 360 mg every 3 weeks).

For pERC consideration.

Generalizability

Should patients with ECOG PS of 2 or greater be eligible for nivolumab in this indication?

Both clinical experts agreed that patients with an ECOG PS of 0 or 1 will benefit from the treatment. One expert noted that patients with an ECOG PS of 2 may be considered, although these patients will be few.

The clinical experts emphasized the need for patients to have a robust performance status before being eligible to receive the treatment, given that patients with less clinical reserve will be susceptible to adverse events that may render them ineligible for curative-intent surgery.

There is a time-limited need to allow patients currently on platinum-based doublet chemotherapy to add nivolumab. What time frame is appropriate to add nivolumab for patients actively on treatment (chemotherapy)?

Both experts agreed that the time-limited need to allow patients currently on platinum-based doublet chemotherapy to add nivolumab will not be an issue in current practice, given the lack of use of neoadjuvant chemotherapy in current clinical practice in Canada. In the event that patients are actively on neoadjuvant treatment with chemotherapy, the experts suggested the addition of nivolumab to any of the remaining cycles of neoadjuvant therapy.

Care provision issues

Nivolumab is already prepared and administered at facilities throughout Canada. Health care professionals have extensive experience with it. Preparation and administration time for nivolumab are reasonable and would not be expected to significantly increase health system resources.

For pERC consideration.

System and economic issues

Nivolumab use as an additional drug in this patient population would have a considerable impact on a budget, compared with chemotherapy alone.

For pERC consideration.

Nivolumab is used for many other indications at this time; it is anticipated that vial sharing or dose rounding will be possible (especially in larger treatment centres).

For pERC consideration.

ALK = anaplastic lymphoma kinase; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGFR = epidermal growth factor receptor; NSCLC = non–small cell lung cancer PD-1 = programmed cell death 1 protein; PD-L1 = programmed cell death 1 ligand 1; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH for nivolumab are summarized in Table 5.

Clinical Evidence

The clinical evidence included in the review of nivolumab is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the Systematic Review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of nivolumab (360 mg administered intravenously), in combination with platinum-doublet chemotherapy every 3 weeks for up to 3 cycles, for the neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease).

Methods

Studies selected for inclusion in the Systematic Review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Table 6: Inclusion Criteria for the Systematic Review

Criteria

Description

Patient population

Adults 18 years and older with resectable NSCLC (tumours ≥ 4 cm or node-positive disease)

Subgroups:

  • PD-L1 expression level (< 1%, ≥ 1%, 1% to 49%, ≥ 50%)

  • Disease stage (stage IB to II vs. stage IIIA vs. other)

  • ECOG PS (0 vs. 1 vs. 2)

  • Histology (squamous vs. nonsquamous)

  • Presence of ALK, EGFR, or ROS1 mutations

Intervention

Nivolumab 360 mg (intravenously) in combination with platinum-doublet chemotherapy intravenously every 3 weeks for up to 3 cycles

Comparators

  • Adjuvant platinum-doublet chemotherapy

  • Platinum-doublet chemotherapy + atezolizumab (patients with PD-L1 expression ≥ 50% PD-L1)a

  • Surgery

  • Neoadjuvant chemotherapy (platinum doublets such as cisplatin + vinorelbine and carboplatin + paclitaxel)

  • Chemoradiation followed by durvalumab

  • Radiation

Outcomes

Efficacy outcomes:

  • OS

  • EFS

    • time to any progression

    • time to locoregional recurrence

    • time to distant metastasis

  • HRQoL

  • pCR or MPR

  • Overall time in operating room

  • Surgically resectable disease

  • Duration of hospital stay

Harms outcomes:

  • AEs

  • SAEs

  • WDAEs

  • Mortality

  • Notable harms or harms of special interest

    • immune-mediated adverse events, such as diarrhea and/or colitis, hepatitis, pneumonitis, nephritis and renal dysfunction, rash, hypersensitivity and/or infusion reactions, and endocrine complications (adrenal insufficiency, hypophysitis, hypothyroidism and/or thyroiditis, hyperthyroidism, and diabetes mellitus)

Study design

Published and unpublished phase III and IV RCTs

E = adverse event; ALK = anaplastic lymphoma kinase; ECOG PS = Eastern Cooperative Group Performance Status; EFS = event-free survival; EGFR = epidermal growth factor receptor; HRQoL = health-related quality of life; MPR = major pathologic response; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathologic complete response; PD-L1 = programmed cell death 1 ligand 1; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event; vs. = versus.

aIdentified by clinical experts as a relevant comparator, but not currently publicly funded in Canada

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.32

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974– via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Patient Headings) and keywords. The main search concepts were Opdivo (nivolumab) and non–small cell lung cancer. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

CADTH-developed search filters were applied to limit retrieval to RCTS or controlled clinical trials. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on September 29, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on February 8, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.33 Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Findings From the Literature

A total of 640 studies were identified from the literature for inclusion in the Systematic Review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Description of Study

CheckMate 816 is an ongoing, open-label, randomized, phase III trial assessing the efficacy and safety of nivolumab (3 mg/kg every 2 weeks for up to 3 cycles) in combination with ipilimumab (single 1 mg/kg dose), nivolumab (360 mg flat dose) in combination with platinum-based chemotherapy every 3 weeks for 3 cycles, and platinum-chemotherapy alone as a neoadjuvant treatment in adults 18 years and older with resectable (stage IB [≥ 4 cm], stage II, and resectable stage IIIA) NSCLC.15 Disease staging at screening was based on the AJCC/UICC TNM 7th edition.15 After completion of neoadjuvant treatment, all patients who remained operative candidates underwent definitive surgery for NSCLC within 6 weeks. Patients were also allowed to receive adjuvant chemotherapy with or without radiation after definitive surgery, per institutional standard, at the discretion of the investigator.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Of the 640 citations identified, 637 were excluded, and 3 electronic literature and 2 grey literature potentially relevant full-text reports were retrieved for scrutiny. Two reports presenting data from 1 unique study were included in the review.

Table 7: Details of Included Study

Detail

CheckMate 816

Designs and populations

Study design

Ongoing, randomized, open-label, phase III trial

Locations

111 sites, 14 countries (North America [including Canada], Europe, Asia, and Rest of the world)

Study duration

Ongoing

Data cut-off date

Interim analyses:

  • pCR: September 16, 2020

  • IA1 EFS, first interim OS analysis: October 20, 2021

Randomized (N)

  • 773 patients enrolled

  • 505 randomized (n = 179 in the nivolumab plus chemotherapy arm (arm C) and 179 in the chemotherapy arm (arm B)

Inclusion criteria

  • Adults 18 years and older or at the age of majority

  • Patients with an ECOG PS of 0 or 1

  • Patients with histologically confirmed stage IB (≥ 4 cm), stage II, or stage IIIA (N2) NSCLC (per the 7th International Association for the Study of Lung Cancer) with disease considered to be resectable

  • Measurable disease according to RECIST 1.1

  • Patients must have a tumour tissue sample available for PD-L1 IHC testing

  • Absence of major associated pathologies that increase surgery risk to an unacceptable level

  • Pulmonary function capacity (e.g., FVC, FEV1, TLC, FRC, and DLco) that is capable of tolerating the proposed lung resection, according to the surgeon

Exclusion criteria

  • Presence of locally advanced unresectable (regardless of stage) or metastatic disease (stage IV)

  • Patients with known EGFR mutations or ALK translocation

  • Patients with brain metastases, including all patients with stage II or higher disease

  • Patients with grade 2 or higher peripheral neuropathy

  • Patients with an active, known, or suspected autoimmune disease (except type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders [such as vitiligo, psoriasis, or alopecia] not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger)

  • Patients with a condition requiring systemic treatment with either corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medications in the 14 days before randomization

  • Known history of positive test for HIV or known AIDS

  • Patients with large-cell neuroendocrine carcinoma tumour histology

  • Prior administration of chemotherapy or any other cancer therapy for early-stage NSCLC

  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody or any other antibody targeting T-cell coregulatory pathways

Drugs

Intervention

Nivolumab: Nivolumab 360 mg (flat dose) IV, every 3 weeks for up to 3 cycles

Chemotherapy: Investigator’s choice of cisplatin (75 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles) or carboplatin (AUC 5 or 6 on day 1 of a 3-week cycle for up to 3 cycles) in combination with gemcitabine (1,000 mg/m2 or 1,250 mg/m2 on days 1 and 8 of a 3-week cycle for up to 3 cycles) for squamous histology, or with pemetrexed (500 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles) for nonsquamous histology, or carboplatin (AUC 5 or 6 on day 1 of a 3-week cycle for up to 3 cycles) + paclitaxel (175 mg/m2 or 200 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles) for any histology.

Comparator(s)

Chemotherapy: Investigator’s choice of cisplatin (75 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles) or carboplatin (AUC 5 or 6 on day 1 of a 3-week cycle for up to 3 cycles) in combination with vinorelbine (25 mg/m2 or 30 mg/m2 on days 1 and 8 of a 3-week cycle for up to 3 cycles), docetaxel (60 mg/m2 or 75 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles), gemcitabine (1,000 mg/m2 or 1,250 mg/m2 on days 1 and 8 of a 3-week cycle for up to 3 cycles) (for squamous histology only), or pemetrexed (500 mg/m2 on day 1 of a 3-week cycle for up to 3 cycles) (for nonsquamous histology only), or carboplatin (AUC 5 or 6) + paclitaxel (175 mg/m2 or 200 mg/m2) on day 1 of a 3-week cycle for up to 3 cycles)

Duration

Phase

  Screening phase

28 days

  Open-label treatment

3 cycles (9 weeks)

  Follow-up

  • visit 1 at 30 days

  • visit 2 after about 100 days, and then every 3 months for 2 years, every 6 months for 3 years, and every 52 weeks for 5 years until disease recurrence or progressed disease

Outcomes

Primary end point

  • EFS by BICR

  • pCR by BIPR

Secondary and exploratory end points

Secondary:

  • OS

  • MPR by BIPR

  • TTDM

Exploratory:

  • EFS2

  • clinical response rate by BICR

  • CR rate

  • MPR rate

  • HRQoL (EQ-5D-3L [utility index and VAS scores])

  • pharmacokinetics

  • biomarkers

  • feasibility of surgery, perioperative and postoperative complications

  • safety and tolerability (AE, SAE, immune-related AEs, deaths, and laboratory abnormalities)

  • pCR rate, MPR rate, cRR, EFS, TTDM, OS, feasibility of surgery, rate of perioperative and postoperative complications (within 90 days of surgery), safety, and tolerability

Publications

Forde et al. (2022)34

Provencio et al. (2022)35

AE = adverse event; ALK = anaplastic lymphoma kinase; AUC = area under the plasma drug concentration-time curve; BICR = blinded independent central review; BIPR = blinded independent pathologic review; CR = complete response; CTLA-4 = cytotoxic T-lymphocyte-associated protein-4; DLco = diffusing capacity; ECOG PS = Eastern Cooperative Group Performance Status; EFS = event-free survival; EFS2 = event-free survival on the next line of therapy; EGFR = epidermal growth factor receptor; EQ-5D-3L = 3-Level EQ-5D; FEV1 = forced expiratory volume in 1 second; FRC = functional residual capacity; FVC = forced vital capacity; HRQoL = health-related quality of life; IA1 = first interim analysis; IHC = immunohistochemistry; MPR = major pathologic response; N = node; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathologic complete response; PD-1 = programmed cell death 1 protein; PD-L1 = programmed cell death 1 ligand 1; RECIST = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; TTDM = time to death or distant metastases; VAS = visual analogue scale.

Source: Clinical Study Report.15

Coprimary end points investigated in the trial were pCR assessed by BIPR and EFS assessed by BICR. Secondary end points included OS, TTDM, and MPR. Safety, tolerability, and HRQoL were exploratory outcomes.15 All BICR and BIPR reviews of radiology scans and tumour and/or lymph node tissue for progression and disease recurrence were completed by a third-party vendor using prespecified guidelines (RECIST 1.1). Any investigator-assessed radiographic progression per RECIST 1.1 guidelines to confirm progression or recurrence was confirmed by BICR, per RECIST 1.1 guidelines.

The CheckMate 816 trial was initially designed as a 2-arm trial in which patients were randomized in a 1:1 ratio to 1 of 2 trial arms: nivolumab plus ipilimumab or chemotherapy. An update to the protocol (protocol revision 2) introduced a third arm, nivolumab plus chemotherapy, thereby allowing patients to be subsequently randomized in a 1:1:1 scheme to any treatment arm. A third update to the protocol (protocol revision 3) discontinued the randomization of patients to the nivolumab plus ipilimumab arm. Subsequently, patients enrolled in the study were randomized to either nivolumab plus chemotherapy or to chemotherapy in a 1:1 ratio and stratified by 3 factors:

Patients who were already randomized to the nivolumab plus ipilimumab arm stayed in the study and continued scheduled study procedures. Study objectives in the CheckMate 816 trial were updated to focus on the comparison between nivolumab plus chemotherapy and chemotherapy for patients who were concurrently randomized. This CADTH review focuses on findings reported in the nivolumab plus chemotherapy and chemotherapy arms.

Patient enrolment began in March 2017 and the last patient was randomized on December 11, 2019. A total of 773 patients were enrolled at 111 sites in 14 countries (North America [including Canada], Europe, Asia, and the rest of the world). In total, 505 patients were randomized, 358 of whom were placed in the nivolumab plus chemotherapy arm (n = 179) or the chemotherapy arm (n = 179).15

The primary data cut-off date for the prespecified final pCR analysis was September 16, 2020, and the data cut-off date for IA1 EFS was October 20, 2021. By the October 20, 2021, data cut-off date, all treated patients had been off neoadjuvant study treatment for more than 18 months; 93.8% and 84.7% of treated patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively, had completed the course of neoadjuvant therapy.15 Figure 2 presents the design flow of the CheckMate 816 trial.

At Screening

Baseline screening assessments were performed in the 28 days before randomization. PET-CT with contrast was assessed at baseline and a separate CT with contrast of the chest, abdomen, and other suspected areas (as well as the PET-CT) was required if the CT component of a PET-CT was not of sufficient diagnostic quality for RECIST 1.1 measurements. Patients with suspected brain metastases, including those with stage II disease or higher were evaluated with MRI/CT of the brain before and after contrast procedures. Tumour assessments were performed using the RECIST 1.1 guidelines.12

Figure 2: Study Design of the CheckMate 816 Trial

The study design flow of the CheckMate 816 trial. Patients were randomized in a 1:1:1 scheme to 1 of 3 treatment arms (nivolumab plus ipilimumab, neoadjuvant chemotherapy, or nivolumab plus chemotherapy).

cRR = clinical response rate; EFS = event-free survival; EFS2 = event-free survival on the next line of therapy; HCP = health care provider; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathologic complete response; PD = disease progression; PD-L1 = programmed cell death 1 ligand 1; ; PK = pharmacokinetic; PRO = patient-reported outcome; Q12W = every 12 weeks; Q2W = every 2 weeks; Q3W = every 3 weeks; Q6 mos = every 6 months; RT = radiotherapy; RT = radiotherapy; SOC = standard of care; TTDM = time to death or distant metastases; tx = treatment; WT = wild-type.

Source: Clinical Study Report.15

Postoperative Assessments

Preoperative PET-CT with contrast was obtained in the 14 days before surgery. Postoperative assessments with CT with contrast of the chest, including the adrenal glands, and CT or MRI of other additional suspected or known sites of disease were performed. The first tumour assessment took place 12 weeks (± 7 days) after definitive surgery, per RECIST 1.1, and then every 12 weeks (± 7 days) for 2 years (104 weeks), every 6 months (24 weeks ± 7 days) for 3 years, and every year (52 weeks ± 7 days) for 5 years or until disease recurrence or progression confirmed by BICR.

The same imaging methods used at baseline were recommended for postoperative procedures.12

First tumour assessments were performed 12 weeks (± 7 days) following tumour restaging in patients who did not receive definitive surgery and who had no tumour progression, as confirmed by BICR. Subsequent tumour assessments were performed for these patients using methods similar to those implemented for patients who had received definitive surgery and at the same frequency.

In the event that a planned initiation of subsequent anticancer therapy was within 12 weeks of restaging, tumour assessments were repeated before the administration of subsequent anticancer therapy.12 Postoperative radiation was administered per institutional standard of care.

The survival follow-up phase began 3 months after postneoadjuvant follow-up visit 2. Participants were followed every 3 months for survival. Survival follow-up visits could be performed with phone contact or an office visit.

Investigators at all participating sites were trained to perform radiology imaging in accordance with the study’s image acquisition guidelines before scanning the first patient.12

Loss to Follow-Up

Loss to follow-up was adequately defined in the protocol and measures were taken to account for missing data based on prespecified criteria.15

Populations

Inclusion and Exclusion Criteria

Patients 18 years and older with histologically confirmed stage IB (≥ 4 cm), stage II, or stage IIIA NSCLC (per TNM 7th edition) with resectable disease were included in the study. Patients underwent PET-CT, including contrast scans from the base of the skull to the upper thighs, to confirm disease stage. Patients were also required to undergo a CT scan with contrast of the chest, abdomen, and other suspected areas of disease (as well as the PET-CT) if the CT component of the PET-CT was not of sufficient diagnostic quality for RECIST 1.1 measurements. All suspicious mediastinal lymph nodes, including those that were pathologically enlarged or fluorodeoxyglucose avid on PET-CT required further pathologic sampling before randomization. Brain MRI or a CT of the head was required for patients with stage II or stage III disease or any patient with suspicion of brain metastases. Patients were expected to have an ECOG PS of 0 or 1 and measurable disease according to RECIST 1.1.15

Patients who had received prior chemotherapy or any other cancer therapy for early-stage NSCLC, patients with distant active brain metastases, and patients with an active, known, or suspected autoimmune disease were excluded. Patients with locally advanced, unresectable or metastatic disease and patients with known EGFR mutations or ALK translocation were also excluded.15

Baseline Characteristics

Most patients randomized to the nivolumab plus chemotherapy and chemotherapy arms were male (71.5% and 70.9%, respectively) and about half were white (49.7% and 44.7%, respectively) and about half were Asian (48.0% and 52.0%, respectively). In total, 48.6% and 53.1% of patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively had squamous tumour histology; 63.1% and 64.2%, respectively, had stage IIIA disease, and 89.4% and 88.3%, respectively, were current or former smokers. PD-L1 expression in the nivolumab plus chemotherapy and chemotherapy arms was less than 1% in 43.6% and 43.0% of patients, respectively, 1% or more in 49.7% and 49.7% of patients, respectively, 1% to 49% in 28.5% and 26.3% of patients, respectively, 50% or more in 21.2% and 23.5% of patients, respectively, and not evaluable in 6.7% and 7.3% of patients, respectively. The sponsor noted that there was a small discrepancy in disease stage between the case report form and Interactive Response Technology system, which affected 8.4% of patients in the nivolumab plus chemotherapy arm and 7.8% of patients in the chemotherapy arm.15

Table 8: Summary of Baseline Characteristics — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy

n = 179

Chemotherapy

n = 179

Age (years)

   Mean

64.1

63.6

   Median (range)

64.0 (41 to 82)

65.0 (34 to 84)

Age categorization (years), n (%)

   < 65

93 (52.0)

83 (46.4)

   ≥ 65

86 (48.0)

96 (53.6)

   ≥ 65 and < 75

75 (41.9)

83 (46.4)

   ≥ 75 and < 85

11 (6.1)

13 (7.3)

Sex, n (%)

   Male

128 (71.5)

127 (70.9)

   Female

51 (28.5)

52 (29.1)

Race, n (%)

   White

89 (49.7)

80 (44.7)

   Black or African American

4 (2.2)

3 (1.7)

   Asian

86 (48.0)

93 (52.0)

   Other

0

3 (1.7)

Geographic region, n (%)

   North America

41 (22.9)

50 (27.9)

   Europe

41 (22.9)

25 (14.0)

   Asia

85 (47.5)

92 (51.4)

   Rest of the world

12 (6.7)

12 (6.7)

Disease stage at study entry (CRF), n (%)a

   Stage IA

0

1 (0.6)

   Stage IB

10 (5.6)

8 (4.5)

   Stage IIA

30 (16.8)

32 (17.9)

   Stage IIB

25 (14.0)

22 (12.3)

   Stage IIIA

113 (63.1)

115 (64.2)

   Stage IIIB

0

0

   Stage IV

1 (0.6)

1 (0.6)

Cell type at study entry, n (%)

   Squamous cell carcinoma

87 (48.6)

95 (53.1)

   Nonsquamous cell carcinoma

92 (51.4)

84 (46.9)

   Adenocarcinoma

86 (48.0)

84 (46.9)

   Large-cell carcinoma

2 (1.1)

0

   Other

4 (2.2)

0

Tobacco use, n (%)

   Never smoker

19 (10.6)

20 (11.2)

   Current or former

160 (89.4)

158 (88.3)

Baseline ECOG PS, n (%)

   0

124 (69.3)

117 (65.4)

   1

55 (30.7)

62 (34.6)

   > 1

0

0

Baseline weight (kg)

   Mean (SD)

71.21 (15.80)

68.55 (13.9)

   Median (range)

68.10 (40.4 to 147.9)

67.20 (35.7 to 114.6)

Time from current diagnosis to randomization (months)

   Mean (SD)

1.27 (0.89)

1.24 (0.72)

   Median (range)

1.05 (0.0 to 9.1)

1.08 (0.0 to 3.7)

Time from current diagnosis to randomization, n (%)

   < 1 months

85 (47.5)

82 (45.8)

   1 to < 2 months

68 (38.0)

72 (40.2)

   2 to < 3 months

23 (12.8)

18 (10.1)

   3 to < 4 months

2 (1.1)

7 (3.9)

   4 to < 5 months

0

0

   ≥ 5 months

1 (0.6)

0

PD-L1 expression level (clinical database), n (%)

   < 1%

78 (43.6)

77 (43.0)

   ≥ 1%

89 (49.7)

89 (49.7)

   1% to 49%

51 (28.5)

47 (26.3)

   ≥ 50%

38 (21.2)

42 (23.5)

   Not evaluable

12 (6.7)

13 (7.3)

CRF = case report form; ECOG PS = Eastern Cooperative Oncology Group Performance Status; PD-L1 = programmed cell death 1 ligand 1; SD = standard deviation.

aTNM 7th edition used for classification.

Source: Clinical Study Report.15

Interventions
Nivolumab Plus Chemotherapy (Arm C)

Nivolumab: Nivolumab 360 mg (flat dose), intravenously, every 3 weeks for up to 3 cycles.

Chemotherapy: Investigator choice of platinum-based doublet chemotherapy (intravenously).

Patients who were unable to tolerate cisplatin were properly documented. The investigator obtained approval from the medical monitor before using a carboplatin-containing regimen, except when the regimen was carboplatin plus paclitaxel.15

Chemotherapy (Arm B)

Investigator choice of platinum-based doublet chemotherapy (intravenously):

For patients who were unable to tolerate cisplatin, the reasons were documented. The investigator obtained approval from the medical monitor before using a carboplatin-containing regimen, except when the regimen was carboplatin plus paclitaxel.15

Note that 2 chemotherapy treatments allowed in the chemotherapy arm (cisplatin plus docetaxel and cisplatin plus vinorelbine) were not allowed in the nivolumab plus chemotherapy arm because, at the time nivolumab plus chemotherapy was added to the protocol, safety data were not available for nivolumab in combination with these chemotherapy backbones. The remaining chemotherapy options were the same for the chemotherapy and nivolumab plus chemotherapy arms.15

Dose Modification: Dose reductions were permitted for platinum-doublet chemotherapy, according to the trial’s protocol. Any dose reductions implemented were permanent and were not re-escalated in subsequent cycles. Dose reductions for each drug in the chemotherapy regimen was independently adjusted in accordance with a prespecified schedule. Patients experiencing toxicity that required a dose reduction after 2 previous dose reductions for any 1 drug in the regimen were discontinued from the drug. Dose modifications were allowed for hematological toxicities due to platinum-doublet therapy, based on nadir blood counts (assessed per local standards) from the proceeding drug administration. Growth factors were permitted after cycle 1 to assist hematologic recovery. Dose reductions were not permitted for nivolumab or ipilimumab.15

Dose Delay: Dose delays were permitted for all treatments in the trial; any dose delay of more than 7 days was skipped, and treatment resumed for the patient at the next scheduled dose (provided that criteria for re-treatment were met). Nivolumab and platinum-doublet chemotherapy were delayed in the event of AEs, and patients were re-evaluated weekly and treatment was resumed if they met re-treatment criteria.15

Treatment Discontinuation: Patients were allowed to discontinue treatment for the following reasons.

Treatment was also discontinued in the event that a patient became pregnant. Patients who discontinued their assigned study treatment prematurely were not allowed to receive subsequent neoadjuvant therapy and proceeded to receive surgery within the study’s indicated timelines.15

After definitive surgery, patients in each arm could receive up to 4 cycles of adjuvant chemotherapy, per institutional standard, at the discretion of the investigator. Investigators chose from the following treatments:

Treatment 1:

Treatment 2:

Treatment 3 (for squamous histology):

Treatment 4 (nonsquamous histology only):

Concomitant Medications

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review is provided in Table 9 and subsequently summarized. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

Outcome measure

End point

Definition

Included in the hierarchical multiple testing procedure

OS

Secondary

Defined as the time between the date of randomization and the date of death from any cause. OS was censored on the last date a patient was known to be alive.

Yes

EFS

Primary

Defined as the length of time from randomization to any of the following events:

  • any progression of disease precluding surgery

  • progression or recurrence of disease (based on BICR assessment, per RECIST 1.1) after surgery

  • death from any cause.

Patients who did not undergo surgery, but for reasons other than progression, were considered to have an event at RECIST 1.1 progression (based on BICR) or death.

Yes

pCR

Primary

Defined as the number of randomized patients with an absence of residual tumour in lung resected tissue and lymph nodes, as evaluated by BIPR, divided by the number of randomized patients in each treatment arm.

Randomized patients who were no longer eligible for surgery, who received alternative anticancer therapy before surgery, who discontinued the study (e.g., withdrew consent) before surgery, or who otherwise did not have an evaluable BIPR result available were counted as nonresponders.

Yes

HRQoL

Exploratory

Patients’ overall health status and health utility were measured with the EQ-5D-3L VAS and utility index, respectively.

No

TTDM

Secondary

Defined as the time between the date of randomization and the first date of distant metastasis, or the date of death in the absence of distant metastasis. A distant metastasis was defined as any new lesion outside of the thorax as assessed by BICR and RECIST 1.1. Patients who had not developed distant metastasis or who had died at the time of the analysis were censored on the date of their last evaluable tumour assessment.

No

MPR

Secondary

Defined as the number of randomized patients with residual tumour of 10% or less in lung and lymph nodes (per BIPR), divided by the number of randomized patients in each treatment arm. Viable in situ carcinomas were not included in the MPR calculation.

No

EFS2

Exploratory

Defined as the time from randomization to objectively documented progression, per investigator assessment, after the next line of therapy or to death from any cause, whichever occurs first.

No

Feasibility of surgery

Exploratory

Delayed or cancelled surgery, duration of surgery, length of hospital stay, surgical approach (including completeness of surgery), incidence of AEs or SAEs associated with surgery out to 90 days after surgery.

No

Safety

Exploratory

AE, SAEs, immune-related AEs, death, and laboratory abnormalities.

No

AE = adverse event; BICR = blinded independent central review; BIPR = blinded independent pathologic review; EFS = event-free survival; EFS2 = event-free survival on the next line of therapy; EQ-5D-3L = 3-Level EQ-5D; HRQoL = health-related quality of life; MPR = major pathologic response; OS = overall survival; pCR = pathologic complete response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; TTDM = time to death or distant metastasis’ VAS = visual analogue scale.

Assessment of Outcomes

Radiologic tumour assessments were reviewed by a BICR from a third-party radiology vendor. Both the investigator and independent radiologists assessed whether each patient met RECIST 1.1 for progression or disease recurrence. All investigator-assessed radiographic progressions and all recurrences were confirmed by BICR, per RECIST 1.1 guidelines. Participants whose disease progression or recurrence was not confirmed by central review continued tumour assessments (when clinically feasible) in accordance with protocol-specified schedules. Subsequent tumour assessments were submitted to a third-party radiology vendor for subsequent review and, if applicable, patients were discontinued from the study when both the investigator and independent radiologists assessed that the participant met RECIST 1.1 for progression or recurrence.

A BIPR was implemented for the central review of tumour scans, for tumour and/or lymph node samples, and for the confirmation of end points. Personnel at participating sites were trained before enrolment of the first study participant. Sections of tumours were used for central pathology review to assess pCR and MPR. Any tumour, tumour bed, or lymph node specimens reviewed locally were submitted for central pathology review.

All participants (in either treatment arm) who remained operative candidates after completion of neoadjuvant treatment (up to 3 cycles) underwent definitive surgery for NSCLC within 6 weeks.

Lymph node levels were sampled at the time of definitive surgery:

Tumour and lymph node samples were collected from definitive surgical resection, and sampling of fresh tumour tissue in RNAlater was mandatory for biomarker studies (as applicable, depending on the size of the residual tumour) on the day of surgery. The remainder of the specimens were processed for histopathologic analysis, performed within 72 hours of the procedure. Sections of the fresh tumour samples collected were used to assess pCR and MPR.12 Disease recurrence, change in tumour measurements, and tumour response were assessed by BICR, per RECIST 1.1. After definitive surgery, patients in each arm could receive adjuvant chemotherapy with or without radiation, per institutional standard, at the discretion of the investigator.

Health-Related Quality of Life

EQ-5D-3L is a generic preference-based HRQoL instrument that has been applied to a wide range of health conditions and treatments.36,37 One part of the EQ-5D-3L is a descriptive system that classifies respondents (12 years and older) into 1 of 243 distinct health states. The descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 possible levels, with 1 indicating no problems, 2 indicating some problems, and 3 indicating extreme problems. Respondents are asked to choose 1 level that reflects their own health state for each of the 5 dimensions. A scoring function can be used to assign a value (i.e., EQ- 5D-3L index score) to each self-reported health state, based on a set of population-based preference weights.36,37 The other part of EQ-5D-3L is a vertical, calibrated EQ VAS that has end points labelled 0, indicating the worst imaginable health state, and 100, indicating the best imaginable health state. A detailed discussion and critical appraisal of the EQ-5D-3L questionnaire are available in Appendix 3.

Participants were asked to complete the EQ-5D-3L before any clinical activities were performed during on-treatment clinic visits, at postneoadjuvant visits 1 and 2, and at designated visits or during phone calls during the survival follow-up phase. A standardized script was used to facilitate telephone administration of the EQ-5D-3L.

Harms Outcome

Safety parameters evaluated included frequency of death, SAEs, AEs leading to discontinuation or dose modification, overall AEs, AEs of special clinical interest that are potentially associated with the use of nivolumab or ipilimumab (i.e., select AEs, immune-mediated AEs), clinical laboratory assessments (hematology, serum chemistry, and liver and thyroid function tests), and vital sign measurements.12

Statistical Analysis

Sample-Size and Power Calculation: The sample size of the CheckMate 816 trial was calculated based on EFS (primary end point) and accounted for multiple primary end point comparisons (pCR and EFS), with an initial alpha allocation of 0.01 and 0.04, respectively.12

The overall type I error (alpha) was controlled using the following procedure for nivolumab plus chemotherapy versus chemotherapy (alpha and P values are 2-sided):

The primary end point of pCR rate was tested at a 1% alpha level, using a fallback method:

EFS and OS were tested at a planned interim analysis, and both have a planned final analysis. Stopping boundaries were calculated for each end point individually, according to the observed number of events, using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries corresponding to an overall alpha of 4% or 5%. Given that the EFS and OS end points were tested using a group sequential approach, an overall hierarchical testing approach was used in which each end point would have its own specific Lan-DeMets alpha spending function with O’Brien-Fleming boundaries.12 The sponsor estimated that about 500 patients would be randomized in the study.12 The randomization of about 350 patients was planned for the 2 arms (175 patients each in the nivolumab plus chemotherapy and chemotherapy arms).

Primary Outcome Analyses
Pathologic Complete Response

A formal analysis for pCR took place after 350 patients who had been randomized into the nivolumab plus chemotherapy and chemotherapy arms from the start of the 1:1:1 randomization and had undergone surgery (approximately 30 months after the 1:1:1 randomization was initiated).12

The sponsor assumed that 350 patients would be needed to provide more than 90% power to detect an odds ratio of 3.857 with a 2-sided type I error rate of 1% if a pCR rate of 10% were to occur in the chemotherapy arm (arm B) and a pCR rate of 30% were to occur in the nivolumab plus chemotherapy arm (arm C).12

The pCR rate was computed for each treatment arm, along with the exact 95% CI, using the Clopper-Pearson method. The numerator was the number of randomized patients who achieved a pCR in both the tumour and the lymph nodes, as assessed by BIPR. The denominator was the number of all patients randomized to the nivolumab plus chemotherapy and chemotherapy arms. Patients who were no longer eligible for surgery, who were on an alternative anticancer therapy before surgery, who discontinued before surgery, or who did not have pCR results available were counted as nonresponders, ensuring a robust pCR definition. pCR was compared in the nivolumab plus chemotherapy and chemotherapy arms using the stratified Cochran Mantel-Haenszel test with a 2-sided 1% alpha level.12

Event-Free Survival

A formal EFS analysis took place after 148 events had occurred in the nivolumab plus chemotherapy arm and the chemotherapy arm after the start of the 1:1:1 randomization scheme (54 months after the 1:1:1 randomization scheme was initiated). The superiority hypothesis was tested in the EFS interim analysis.

In the event that pCR was significant, the 1% alpha allocated to pCR was reallocated to EFS, which was then tested at an overall 5% alpha level. The interim boundary was derived from the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries.12

A stratified log-rank test, with stratification factors per Interactive Response Technology (PD-L1 expression [≥ 1% versus < 1%, not evaluable, indeterminate], disease stage [stage IB or II versus stage IIIA], and gender or sex), and a 2-sided P value was used to assess EFS between the nivolumab plus chemotherapy arms and chemotherapy. A Lan-DeMets alpha spending function with an O’Brien and Fleming type of boundary was used to determine the nominal significance levels for the interim and final analyses. The HR and the corresponding (adjusted alpha) CIs were estimated for the nivolumab plus chemotherapy and chemotherapy arms using a stratified Cox proportional hazards model with the randomized arm as a single covariate.12

The EFS curves for each randomized arm were estimated using the KM product-limit method. The median and 2-sided 95% CI for EFS in each treatment arm was computed using the log-log transformation method. In addition, EFS rates at different time points were derived from KM estimates on the EFS curve for each randomized arm. Associated 2-sided 95% CIs were calculated using the Greenwood formula (using a log-log transformation).12

The sponsor assumed that the occurrence of 185 EFS events among the 358 randomized patients would ensure that an overall 2-sided 5% significance level sequential test procedure with 2 interim analyses — after 148 events (80% of events required for final analysis) and after 167 events (90% of events required for final analysis) — would have 82% power, assuming an HR of 0.65 between the 2 arms. IA1 EFS was event driven (at least 148 events expected by data cut-off date of October 20, 2021). The stopping boundaries at the interim and final EFS analyses were derived from the exact number of events using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries.12 Figure 3 presents the schematic presentation of the planned analyses in the CheckMate 816 trial. Table 10 presents a summary of scheduled analyses in the CheckMate 816 trial.

Table 10: Scheduled Analyses, Criteria, and Projected Timelines for Formal Analyses of pCR and EFS

Scheduled analysis

Criteria and population

Projected timeline

Formal analysis

pCR analysis

When patients in the nivolumab plus chemotherapy and chemotherapy arms have an opportunity for surgery

30 months after 1:1:1 randomization (36 months from FPFV)

pCR comparison between the nivolumab plus chemotherapy and chemotherapy arms, with an alpha of 0.01

Interim EFS analysis

First interim OS analysisa

148 EFS events in the nivolumab plus chemotherapy and chemotherapy arms after the start of 1:1:1 randomizationb

54 months after 1:1:1 randomization (60 months from FPFV)

The stopping boundaries were based on Lan-DeMets alpha spending function with O’Brien-Fleming boundaries

EFS comparison arms: The nominal P value cut-off for the nivolumab plus chemotherapy and chemotherapy arms is 0.019 if the EFS comparison alpha is 0.04, and 0.024 if the EFS comparison alpha is 0.05

OS comparison of nivolumab plus chemotherapy and chemotherapy (if EFS is significant): The nominal P value cut-off is 0.007 if the EFS comparison alpha is 0.04, and 0.010 if the EFS comparison alpha is 0.05

Final EFS analysis

Second interim OS analysisa

185 EFS events in the nivolumab plus chemotherapy and chemotherapy arms after the start of 1:1:1 randomizationb

69 months after 1:1:1 randomization (75 months from FPFV)

The stopping boundaries is based on Lan-DeMets alpha spending function

with O’Brien-Fleming boundaries

EFS comparison arms:

The nominal P value cut-off for the nivolumab plus chemotherapy and chemotherapy arms is 0.035 if the EFS comparison alpha is 0.04, and 0.043 if the EFS comparison alpha is 0.05

OS comparison of nivolumab plus chemotherapy and chemotherapy (if EFS is significant)

The nominal P value cut-off is 0.018 if the EFS comparison alpha is 0.04, and 0.023 if the EFS comparison alpha is 0.05

Final OS analysis

185 OS events in the nivolumab plus chemotherapy and chemotherapy arms after the start of 1:1:1 randomization

87 months after 1:1:1 randomization (93 months from FPFV)

OS comparison of nivolumab plus chemotherapy and chemotherapy (if EFS is significant)

The stopping boundaries are based on Lan-DeMets alpha spending function with O’Brien-Fleming boundaries

The nominal P value cut-off is 0.034 if the EFS comparison alpha is 0.04, and 0.042 if the EFS comparison alpha is 0.05

EFS = event-free survival; FPFV = first patient’s first visit; OS = overall survival; pCR = pathologic complete response.

aIf EFS reaches significance at the interim analysis of EFS but not OS, only the interim analysis of OS will be conducted; EFS will not be formally re-tested.

bIf EFS reaches significance at the interim analysis of EFS but not OS, interim OS analyses will be triggered by the number of OS events.

Source: Sponsor’s submission.12

Figure 3: Schematic Representation of the Planned Analyses Time Points

Figure shows the initial allocation for each hypothesis. The boxes show the outcome analyzed and the corresponding censoring rule. The dashed arrows show the alpha reallocation in pCR, the solid arrows show the EFS comparison significance and the corresponding significance level, and the dotted arrows show comparisons that are not significant at the corresponding significance level.

EFS = event-free survival; FA = final analysis; IA1 = first interim analysis; IA2 = second interim analysis; IA3 = third interim analysis; mo = months; OS = overall survival; pCR = pathologic complete response; t = time point.

Note: EFS and OS were tested using their own O’Brien-Fleming alpha spending functions.

* Analysis occurred at the September 16, 2020, data cut-off date.

** Analysis occurred at the October 20, 2021, data cut-off date.

Source: Sponsor submission.12

Censoring Rules for EFS (Primary Definition)
Censoring Rules for EFS (Secondary Definition)
Sensitivity Analyses

Sensitivity analyses were conducted in the nivolumab plus chemotherapy and chemotherapy arms for the primary end point of EFS. The P values from these sensitivity analyses were presented for descriptive purposes only and were not adjusted for multiplicity.

The following sensitivity analyses were considered:

Subgroup Analyses: Subgroup analyses were conducted for pCR and EFS for the following baseline characteristics12:

Handling Missing Data

The sponsor outlined several methods to account for missing data for safety outcomes, missing death dates, missing data for date of progression or recurrence, missing dates for definitive surgery start date and definitive surgery end date, as follows:12

For death dates, the following conventions were used for imputing partial dates:

Secondary Outcome Analyses
Overall Survival

The sponsor assumed that 185 OS events among the 358 randomized patients would ensure that an overall 2-sided 5% significance level sequential test procedure with 3 interim analyses — after approximately 101, 128, and 161 events (55%, 69%, and 87% of events required for final analysis, respectively) — would have 82% power, assuming an exponential distribution, with a median OS time of 54 months in the chemotherapy arm and 83 months in the nivolumab plus chemotherapy arm (corresponding to a target HR of 0.65). The sponsor anticipated that OS analyses would take place after about 48 months (IA1 EFS), 58 months (EFS interim analysis 2), 73 months (EFS final analysis), and 86 months (OS, final analysis) after the start of 1:1:1 randomization. The trigger for the timing of these interim analyses was the number of EFS events.12

In the event that EFS became significant before OS, the planned formal remaining OS analyses would be triggered by the number of OS events (approximately 128 OS events [69% information fraction] or 1 year after IA1 EFS, whichever occurred first for interim analysis 2, and 161 OS events or 4 years after last patient’s randomization, whichever occurred first for OS interim analysis 3).12

To account for a potential slowdown in event rates in the longer term, which could prevent OS analysis from being performed in a reasonable time window, the sponsor planned that in the event that the 185th event failed to occur 5 years after randomization of the last participant, the final OS analysis would be conducted at that time. The final analysis boundary would then be recalculated using the actual updated final number of events.12

Time to Death or Distant Metastases

TTDM, based on BICR assessments, was compared between the nivolumab plus chemotherapy and chemotherapy arms using the same methods as described for EFS.12

Major Pathologic Response

MPR rates were computed in each treatment group, along with the exact 95% CI, using Clopper-Pearson method. An estimate of the difference and the odds ratio in MPR rates between concurrent arms B and C and corresponding 95% CIs were calculated the using Cochran-Mantel-Haenszel methodology and adjusted by stratification factors.12

EFS on Next Line of Therapy

EFS2 was estimated using KM techniques, and graphically presented. A 2-sided 95% CI for the median in each treatment group were computed using a log-log transformation method. Events rates at fixed time points (e.g., 6 months, 12 months, depending on the minimum follow-up) were presented along with their associated 95% CIs. Estimates were derived from the KM estimate and corresponding CIs were based on the Greenwood formula for variance derivation and on log-log transformation applied to the survivor function.

Analysis Populations

Efficacy analysis population: The ITT population consisted of all randomized participants in the nivolumab plus chemotherapy and chemotherapy arms (which included all patients concurrently randomized to nivolumab plus chemotherapy or chemotherapy as of the 1:1:1 randomization and after revised protocol 2).

Safety analyses population: The primary analysis population consisted of all participants concurrently randomized to the nivolumab plus chemotherapy arm or chemotherapy arm at the 1:1:1 randomization who received at least 1 dose of any study medication in the neoadjuvant setting and was used to assess drug exposure and safety in the nivolumab plus chemotherapy and chemotherapy arms.

Protocol Amendments

Protocol revision 1 (March 3, 2017): This revision incorporated changes from amendment 2 and administrative letters 1 and 2. It clarified the use of TNM 7th edition in the study; adjusted dosing details of the chemotherapy drugs to include the dose approved by the local prescribing information and the standard-of-care infusion time for each country; clarified lymph node samples at screening and definitive surgery; clarified the tissue sample process for calculation of the primary end point; and clarified requirements for PET-CT scans and broadened the window for scans before surgery.15

Protocol revision 2 (July 6, 2017): This revision added the third arm of nivolumab plus chemotherapy; increased the sample size to 642 to accommodate the new treatment arm; changed the primary objective to dual primary objectives of pCR and EFS and changed a secondary objective to MPR based on health authority feedback; and increased the prescreening tissue requirement to 15 slides, updated contrast requirements for brain MRI scans, expanded the window for pulmonary function tests to within 6 weeks of randomization, and included updates to synopsis, rationale or background information, and study personnel.15

Protocol revision 3 (September 21, 2018): This revision stopped enrolment in the nivolumab plus ipilimumab arm, so the primary population concurrently randomized patients to the nivolumab plus chemotherapy and chemotherapy arms based on external clinical data on PD-1 expression and chemotherapy; clarified the definition of EFS, excluded patients with large-cell neuroendocrine carcinoma tumour histology, and added a platinum-doublet chemotherapy regimen (paclitaxel plus carboplatin); updated dose modification for docetaxel; added TTDM as a secondary end point; clarified tumour assessments for patients who did not proceed to definitive surgery; updated the statistical analysis plan, rationale, background information, and trial schematic; and clarified pulmonary function parameters, the time relationship between adjuvant radiotherapy and tumour imaging assessments, and the time window of cycle 1 day 1 end-of-infusion pharmacokinetic sampling.15

Protocol revision 4 (June 25, 2019): This revision updated the postsurgery collection of serum and plasma-soluble factors; added the concomitant administration of substances that are tubularly secreted (e.g., probenecid) and could potentially result in the delayed clearance of pemetrexed; added hypothesis testing for OS; and clarified the analysis population for pCR, added an exploratory end point of EFS on the next line of therapy, and added instructions for BICR.15

Protocol revision 5 (September 18, 2019): This revision made modifications to the pCR analysis population and projected timelines; updated the surgical-approach end point; updated censoring rules for TTDM; removed optional biopsy at disease progression in China; and updated the management algorithms to include myocarditis.15

Protocol revision 6 (July 14, 2020): This revision clarified an EFS event to be any progression that precluded surgery and clarified that RECIST 1.1 progression and/or recurrence, per BICR, should be applied after surgery or for patients who did not undergo surgery; corrected the number of patients; removed the first of 2 IA of EFS (60% events) and updated alpha spending based on the remaining single interim and final analyses of EFS; and clarified that the actual timing of analyses may differ from projected timing.15

Protocol revision 7 (August 18, 2021): This revision added an interim analysis of EFS and added a calendar-based rule for the final analysis of EFS, with a corresponding OS interim analysis (if EFS was significant).15

Results

Patient Disposition

Table 11 presents patient disposition data from the CheckMate 816 trial at the October 20, 2021, data cut-off date (EFS IA1). In total, 773 patients were enrolled, and 505 patients were randomized: 358 to nivolumab plus chemotherapy (n = 179) or chemotherapy (n = 179). After neoadjuvant treatment, 149 (83.2%) patients in the nivolumab plus chemotherapy arm and 135 (75.4%) in the chemotherapy arm underwent definitive surgery; 28 (15.6%) patients in the nivolumab plus chemotherapy arm and 37 (20.7%) in the chemotherapy arm did not undergo surgery for the following reasons:15

The proportion of patients who did not complete the neoadjuvant treatment period because of study drug toxicity was similar in the nivolumab plus chemotherapy and chemotherapy arms (5.7% and 6.8%, respectively). The proportion of patients who did not complete the neoadjuvant treatment period because of disease progression was low in the nivolumab plus chemotherapy and chemotherapy arms (0.6% and 1.1%, respectively). The minimum follow-up was 21.0 months, and the median follow-up was 29.5 months.15 Table 12 presents the patients who received definitive surgery in the CheckMate 816 trial.

Table 11: Patient Disposition

Disposition

Nivolumab plus chemotherapy

Chemotherapy

Total

Enrolled, n

773

Randomized, n (%)

179 (100.0)

179 (100.0)

505 (65.2)

Not randomized, n (%)

0

0

268 (34.7)

Reason for not being randomized

   AE

1 (0.1)

   Withdrawal of consent

26 (3.4)

   No longer meeting study requirement

227 (29.4)

   Other

14 (1.8)

   Treated

176 (98.3)

176 (98.3)

495 (98.0)

   Not treateda

3 (1.7)

3 (1.7)

10 (2.0)

Reason for not being treated

   AE unrelated

1 (0.6)

0

1 (0.2)

   Withdrawal of consent

0

2 (1.1)

3 (0.6)

   No longer meeting study criteria

2 (1.1)

1 (0.6)

6 (1.2)

Status (%)

   Continuing in the neoadjuvant treatment period

0

0

0

   Not continuing in the neoadjuvant treatment period

176 (100.0)

176 (100.0)

495 (100)

Reason for not continuing in the neoadjuvant treatment period

   Completed neoadjuvant treatment

165 (93.8)

149 (84.7)

443 (89.5)

   Disease progression

1 (0.6)

2 (1.1)

6 (1.2)

   Study drug toxicity

10 (5.7)

12 (6.8)

30 (6.1)

   Death

0

0

1 (0.2)

   AE unrelated to study drug

0

3 (1.7)

3 (0.6)

   Patient request to discontinue study treatment

0

5 (2.8)

7 (1.4)

   Withdrawal of consent

0

4 (2.3)

4 (0.8)

   No longer meeting study criteria

0

1 (0.6)

1 (0.2)

   Continuing in the study

175 (99.4)

172 (97.7)

489 (98.8)

   Not continuing in the study

1 (0.6)

4 (2.3)

6 (1.2)

Reason for not continuing in the study

   Death

0

1 (0.6)

2 (0.4)

   Withdrawal of consent

1 (0.6)

3 (1.7)

4 (0.8)

AE = adverse event.

aPercentages based on patients randomized.

Source: Clinical Study Report.15

Table 12: Patients Who Received Definitive Surgery — All Randomized Patients

Characteristics

Nivolumab plus chemotherapy

n = 179

Chemotherapy

n = 179

Definitive surgery

   Patients with clinical downstaging,a n (%)

55 (30.7)

42 (23.5)

   Patients with definitive surgery, n (%)

149 (83.2)

135 (75.4)

   Patients with definitive surgery not reported n (%)

2 (1.1)

7 (3.9)

Patients with cancelled definitive surgery, n (%)

28 (15.6)

37 (20.7)

   Reason for cancelled surgeryb

   AE

2 (7.1)

1 (2.7)

   Disease progression

12 (42.9)

17 (45.9)

   Other

14 (50.0)

19 (51.4)

   Patient refused surgery

7

5

   Patient not suitable for surgery

2

2

   Respiratory function not adequate

2

2

   Patient randomized but not treated

1

   Patient status did not allow neoadjuvant treatment

1

   Patient had financial difficulties

1

   Patient withdrew consent

0

2

   CR

0

1

Patients with delayed surgery,b,c n (%)

31 (20.8)

24 (17.8)

   Reason for delayed surgeryd,e

   AE

6 (19.4)

9 (37.5)

   Administrative reason

17 (54.8)

8 (33.3)

   Other

8 (25.8)

7 (29.2)

Duration of surgery (minutes)

   n

122

120

   Mean (SD)

203.9 (95.9)

221.3 (94.4)

   Median (range)

185.0 (25 to 560)

213.5 (46 to 486)

Length of hospital stay (days)

   n

142

127

   Mean (SD)

11.6 (8.3)

12.8 (10.1)

   Median (range)

10.0 (1 to 51)

10.0 (1 to 67)

Surgery outcome,c n (%)

   R0 (negative margin)

124 (83.2)

105 (77.8)

   R1 (microscopic positive margin)

16 (10.7)

21 (15.6)

   R2 (macroscopic positive margin)

5 (3.4)

4 (3.0)

   Unknown

4 (2.7)

5 (3.7)

On-study or last assessment before subsequent anticancer therapy, n (%)

   Received subsequent anticancer therapyf

12 (6.7)

18 (10.1)

   Received subsequent systemic therapy

6 (3.4)

9 (5.0)

   Received subsequent radiotherapyg

5 (2.8)

9 (5.0)

   Received subsequent surgery

1 (0.6)

0

On study

97 (54.2)

66 (36.9)

   Still on neoadjuvant treatment

0

0

   Still on adjuvant treatment

0

0

   In follow-up

97 (54.2)

66 (36.9)

AE = adverse event; CR = complete response; SD = standard deviation.

Notes: Patients in arm B randomized in the initial protocol are included in the total.

The data cut-off date was October 20, 2021.

aPatients with clinical downstaging have a lower disease stage before surgery than at baseline.

bDenominator based on the number of patients with cancelled surgery.

cDenominator based on the number of patients with surgery.

dDenominator based on the number of patients with delayed surgery.

eTime from last neoadjuvant dose to surgery > 6 weeks.

fIncludes patients, regardless of treatment status, who received subsequent anticancer therapy (outside of protocol-specified adjuvant therapy) without a prior reported EFS event. Those patients were censored at the last tumour assessment before or on the start date of subsequent anticancer therapy.

gRadiotherapy other than protocol-defined adjuvant radiotherapy.

Source: Clinical Study Report.15

Protocol Deviations

Important protocol deviations that were considered to potentially affect the interpretability of study results were reported in 2% of patients in the study (1.1% in the nivolumab plus chemotherapy arm and 2.2% in the chemotherapy arm). In total, 3 patients (1 in the nivolumab plus chemotherapy arm and 2 in the chemotherapy arm) received concurrent cancer therapy. Important protocol deviations in the 2 arms are presented in Table 44 in Appendix 3.

Exposure to Study Treatments

The proportion of patients who received all 3 doses of nivolumab or chemotherapy in the 2 treatment arms in the CheckMate 816 trial are presented in the Table 45 and Table 46 in Appendix 3, and are as follows:

The proportion of all treated patients in the 2 treatment arms who received 90% or more of the planned dose intensity during the neoadjuvant period was as follows:

Interruptions, Delays, Reductions, and Omissions of Neoadjuvant Study Therapy

Dose delays were permitted in all treated patients in the nivolumab plus chemotherapy and chemotherapy arms. Dose reductions were permitted for chemotherapy drugs only, and interruptions of infusions or infusion rate reductions were infrequent. There was a higher proportion of dose omissions for gemcitabine and vinorelbine, which are dosed twice per cycle, than for other chemotherapy drugs.15

Table 13: Interruptions, Delays, Reductions, and Omissions of Neoadjuvant Study Therapy — All Randomized Patients

Detail

Nivolumab plus chemotherapy

Chemotherapy

Dose delays, n/N (%)

   Nivolumab

44/176 (25)

NA

   Carboplatin

7/51 (13.7)

7/42 (16.7)

   Cisplatin

31/136 (22.8)

44/143 (30.8)

   Gemcitabine

28/66 (42.4)

22/49 (44.9)

   Paclitaxel

5/28 (17.9)

2/22 (9.1)

   Pemetrexed

15/83 (18.1)

19/63 (30.2)

   Docetaxel

6/29 (20.7)

   Vinorelbine

10/14 (71.4)

Dose reductions, n/N (%)

   Carboplatin

11/51 (21.6)

13/42 (31.0)

   Cisplatin

14/136 (10.3)

17/143 (11.9)

   Gemcitabine

12/66 (18.2)

8/49 (16.3)

   Paclitaxel

4/28 (14.3)

7/22 (31.8)

   Pemetrexed

1/83 (1.2)

3/63 (4.8)

   Docetaxel

5/29 (17.2)

   Vinorelbine

1/14 (7.1)

Dose omissions, n/N (%)

   Nivolumab

5/176 (2.8)

NA

   Carboplatin

1/51 (2.0)

1/42 (2.4)

   Cisplatin

5/136 (3.7)

6/143 (4.2)

   Gemcitabine

18/66 (27.3)

8/49 (16.3)

   Paclitaxel

1/28 (3.6)

0/22 (0)

   Pemetrexed

2/83 (2.4)

3/63 (4.8)

   Docetaxel

0/29 (0)

   Vinorelbine

7/14 (50)

Infusion interruptions, n/N (%)

   Nivolumab

5/176 (2.8)

   Gemcitabine

1/66 (1.5)

1/49 (2.0)

   Cisplatin

1/136 (0.7)

1/143 (0.7)

   Carboplatin

0/51 (0)

1/42 (2.4)

   Paclitaxel

4/28 (14.3)

4/22 (18.2)

   Pemetrexed

0/83 (0)

0/63 (0)

   Docetaxel

1/29 (3.4)

   Vinorelbine

0/14 (0)

NA = not applicable.

Source: Clinical Study Report.15

Concomitant Medications

In total, all patients in the nivolumab plus chemotherapy arm and 99.4% in the chemotherapy arm received concomitant medications during the trial.12 Table 14 presents the anatomic class of concomitant therapies permitted in the CheckMate 816 trial.

Subsequent Anticancer Therapy

Table 15 presents subsequent anticancer therapies administered to patients in the CheckMate 816 trial. In total, 38 (21.2%) patients in the nivolumab plus chemotherapy arm and 78 (43.6%) in the chemotherapy arm received subsequent cancer therapy (local and/or systemic therapy) started on or after the first study drug dose was administered (i.e., started on or after the date of randomization, if not treated) and not part of the on-protocol adjuvant study therapy (systemic and radiotherapy).12

Table 14: Concomitant Medications Permitted — All Treated Patients

Anatomic Therapeutic Chemical class generic name

Nivolumab plus chemotherapy

(n = 176)

Chemotherapy

(n = 176)

Total patients using concomitant medication, n (%)

176 (100.0)

175 (99.4)

Alimentary tract and metabolism, n (%)

173 (93.3)

172 (97.7)

Antidiarrhea, intestinal antiinflammation, antiinfection, n (%)

15 (8.5)

21 (11.9)

Antiemetic and antinauseant, n (%)

163 (92.6)

165 (93.8)

Antispasmodic, anticholinergic, propulsive, n (%)

57 (32.4)

65 (36.9)

Bile and liver therapy, n (%)

7 (4.0)

20 (11.4)

Diabetes therapy, n (%)

44 (25.0)

30 (17.0)

Digestive, including enzymes, n (%)

7 (4.0)

2 (1.1)

Laxative, n (%)

94 (53.4)

94 (53.4)

Mineral supplement, n (%)

82 (46.6)

81 (46.0)

Other alimentary tract, metabolism product, n (%)

11 (6.3)

7 (4.0)

Stomatological preparations, n (%)

13 (7.4)

8 (4.5)

Vitamin, n (%)

64 (36.4)

76 (43.2)

Antineoplastic and immunomodulating drug, n (%)

37 (21.0)

56 (31.8)

Blood and blood forming organ, n (%)

165 (93.8)

158 (89.8)

Antihemorrhagic, n (%)

18 (10.2)

20 (11.4)

Antithrombic drug, n (%)

72 (40.9)

77 (43.8)

Other hematological drug, n (%)

8 (4.5)

13 (7.4)

Plasma substitute and perfusion solution, n (%)

121 (68.8)

117 (66.5)

Serum lipid-reducing drug, n (%)

46 (26.1)

49 (27.8)

Cardiovascular system, n (%)

131 (74.4)

128 (72.7)

Dermatological, n (%)

52 (29.5)

46 (26.1)

General antiinfective for systemic use, n (%)

106 (60.2)

113 (64.2)

Genitourinary system and sex hormone, n (%)

25 (14.2)

22 (12.5)

Musculoskeletal system, n (%)

52 (29.5)

57 (32.4)

Sensory organ, n (%)

9 (5.1)

11 (6.3)

Systemic hormonal preparation, excluding sex hormones, n (%)

153 (86.9)

156 (88.6)

Various, n (%)

80 (45.5)

81 (46.0)

Unassigned, n (%)

1 (0.6)

0

Source: Sponsor submission.12

Table 15: Subsequent Cancer Therapy — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy

(n = 179)

Chemotherapy

(n = 179)

Patients with any subsequent therapy, n (%)

38 (21.2)

78 (43.6)

Patients who received subsequent radiotherapy, n (%)

20 (11.2)

38 (21.2)

Patients who received subsequent surgery, n (%)

3 (1.7)

6 (3.4)

Patients who received subsequent systemic therapy, n (%)

31 (17.3)

65 (36.3)

Immunotherapy

10 (5.6)

42 (23.5)

   Anti-PD-1

6 (3.4)

32 (17.9)

   Anti PD-1

0

1 (0.6)

   Nivolumab

2 (1.1)

8 (4.5)

   Pembrolizumab

4 (2.2)

22 (12.3)

   Sintilimab

0

1 (0.6)

   Toripalimab

0

1 (0.6)

   Anti-PD-L1

4 (2.2)

14 (7.8)

   Atezolizumab

2 (1.1)

8 (4.5)

   Durvalumab

2 (1.1)

6 (3.4)

   Anti-CTLA4

0

0

   Ipilimumab

0

0

Targeted therapy

13 (7.3)

21 (11.7)

   ALK and/or EGFR tyrosine kinase inhibitors

4 (2.2)

9 (5.0)

   Afatinib

0

1 (0.6)

   Alectinib

0

2 (1.1)

   Brigatinib

1 (0.6)

0

   Crizotinib

1 (0.6)

1 (0.6)

   Erlotinib

1 (0.6)

0

   Gefitinib

0

3 (1.7)

   Icotinib

1 (0.6)

0

   Osimertinib

1 (0.6)

4 (2.2)

   VEGFR inhibitors

10 (5.6)

12 (6.7)

   Anlotinib

3 (1.7)

4 (2.2)

   Bevacizumab

2 (1.1)

4 (2.2)

   Endostar

1 (0.6)

0

   Endostatin

1 (0.6)

2 (1.1)

   Ramucirumab

3 (1.7)

2 (1.1)

   Simvastatin

0

1 (0.6)

   Other targeted therapy

0

3 (1.7)

   Capmatinib

0

1 (0.6)

   Entrectinib

0

1 (0.6)

   Regorafenib

0

1 (0.6)

   Temsirolimus

0

0

Other systemic cancer therapy: chemotherapy, n (%)

27 (15.1)

40 (22.3)

   Carboplatin

12 (6.7)

20 (11.2)

   Cisplatin

6 (3.4)

10 (5.6)

   Docetaxel

8 (4.5)

9 (5.0)

   Etoposide

3 (1.7)

1 (0.6)

   Gemcitabine

6 (3.4)

4 (2.2)

   Tegafur, gimeracil, oteracil

1 (0.6)

0

   Lobaplatin

1 (0.6)

0

   Nedaplatin

1 (0.6)

3 (1.7)

   Paclitaxel

14 (7.8)

18 (10.1)

   Pemetrexed

1 (0.6)

7 (3.9)

   Taxane

0

0

   Tegafur

0

3 (1.7)

   Vinorelbine

6 (3.4)

5 (2.8)

Other systemic cancer therapy, n (%)

0

6 (3.4)

   Herbs

0

5 (2.8)

   MLN0128

0

0

   Pamidronate

0

1 (0.6)

   Spleen extract

0

1 (0.6)

ALK = anaplastic lymphoma kinase; CTLA-4 = cytotoxic T-lymphocyte-associated protein-4; EGFR = epidermal growth factor receptor; PD-1 = programmed cell death 1 protein; PD-L1 = programmed cell death 1 ligand 1; VEGFR = vascular endothelial growth factor receptors.

Notes: Patient may have received more than 1 type of subsequent therapy. Subsequent therapy was defined as therapy started on or after the first dosing date (randomization date if patient never treated) outside of the protocol-specified adjuvant therapy. The reported medication Avastin was coded as simvastatin by error in the locked database. It should have been bevacizumab.

The data cut-off date was October 20, 2021.

Source: Sponsor submission.12

Adjuvant Therapy

Optional adjuvant chemotherapy or radiotherapy was allowed following surgery per protocol (per the investigator’s judgment). Table 16 presents the number of patients who received adjuvant therapy in the CheckMate 816 trial.

Table 16: Adjuvant Treatment — All Treated Patients

Characteristic

Nivolumab plus chemotherapy

(n = 176)

Chemotherapy

(n = 176)

Patients receiving adjuvant systemic therapy, n (%)

26 (14.8)

44 (25.0)

Patients receiving adjuvant radiotherapy, n (%)

14 (8.0)

17 (9.7)

Patients receiving adjuvant radiotherapy without systemic adjuvant, n (%)

9 (5.1)

12 (6.8)

Patients receiving any adjuvant therapy, n (%)

35 (19.9)

56 (31.8)

Source: Clinical Study Report.15

Efficacy

Only efficacy outcomes and analyses of subgroups identified in the CADTH review protocol are reported here.

Overall Survival

OS was formally tested at the October 20, 2021, data cut-off date (IA1 EFS), based on the hierarchical statistical testing rules for EFS and OS outlined in the statistical analysis plan.15

Median OS was not reached in either the nivolumab plus chemotherapy arm or the chemotherapy arm. The HR for death was 0.57 (99.67% CI, 0.30 to 1.07). The P value for OS (P = 0.008) did not cross the prespecified statistical significance boundary (0.0033). A second OS test is planned after 128 OS events have occurred (or 1 year after the IA1 EFS data cut-off date).15 Figure 4 presents the KM curves of OS at the data cut-off date.

Figure 4: OS — All Randomized Patients

This figure shows the OS curves of the total number of at-risk patients from 0 to 48 months in the nivolumab plus chemotherapy and chemotherapy arms. Both curves cross at 15 months and remain diverged until month 48.

CI = confidence interval; mo = months; No. = number; NR = not reported; OS = overall survival.

Note: The data cut-off date was October 20, 2021.

Source: Forde et al. (2022).34

Event-Free Survival

Table 17 presents EFS findings at the IA1 data cut-off date (October 20, 2021) and Figure 5 presents the KM curves for the nivolumab plus chemotherapy and chemotherapy arms.

In total, 64 of 179 (35.8%) EFS events occurred in the nivolumab plus chemotherapy arm, and the median EFS was 31.57 months (95% CI, 30.16 to not available months). In the chemotherapy arm, 87 of 179 (48.6%) EFS events occurred, and the median EFS was 20.80 months (95% CI, 14.03 to 26.71 months). The estimated HR was 0.63 (97.38% CI, 0.43 to 0.91), with a P value of 0.0052 based on stratified log-rank test, which was statistically significant according to a prespecified threshold of 0.0262.15

The Cox model analyses based on baseline stratification factors (PD-L1 expression level [≥ 1% versus < 1%], disease stage [IB to II versus stage IIIA], and sex) had an HR of 0.64 (95% CI, 0.46 to 0.89); the estimated HR based on the unstratified Cox model was 0.63 (95% CI, 0.45 to 0.87). Additional sensitivity analyses that accounted for missing tumour assessments before EFS events had an estimated an HR of 0.66 (95% CI, 0.47 to 0.92).15.

Table 17: EFS per BICR — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy (n = 179)

Chemotherapy (n = 179)

Number of patients censored, n (%)

115 (64.2)

92 (51.4)

Number of events (%)

64 (35.8)

87 (48.6)

  Median EFS (95% CI), monthsa

31.57 (30.16 to NA)

20.80 (14.03 to 26.71)

  HR (97.38% CI)b

0.63 (0.43 to 0.91); P = 0.0052c

EFS rates (95% CI), %a

  At 6 months

85.6 (79.3 to 90.1)

81.9 (75.1 to 87.0)

  At 12 months

76.1 (68.8 to 81.9)

63.4 (55.3 to 70.4)

  At 18 months

68.3 (60.4 to 74.9)

53.1 (44.9 to 60.7)

  At 24 months

63.8 (55.7 to 70.9)

45.3 (37.0 to 53.2)

Type of event n (%)

  Progression precluding surgeryd

12 (6.7)

16 (8.9)

  Progression and/or recurrence after surgerye

39 (21.8)

56 (31.3)

  Locoregional

24 (13.4)

28 (15.6)

  Distant

14 (7.8)

25 (14.0)

  Both locoregional and distant

1 (0.6)

3 (1.7)

  Progression without surgerye

2 (1.1)

3 (1.7)

  Locoregional

2 (1.1)

1 (0.6)

  Distant

0

1 (0.6)

  Both locoregional and distant

0

1 (0.6)

  Death

11 (6.1)

12 (6.7)

BICR = blinded independent central review; CI = confidence interval; EFS = event-free survival; HR = hazard ratio; NA = not available.

Note: The data cut-off date was October 20, 2021.

aBased on KM estimates.

bHR of arm C to concurrent arm B from a Cox model stratified by PD-L1 expression level (≥ 1% vs. < 1%, not evaluable, indeterminate), disease stage (IB or II vs. stage IIIA), and sex (male vs. female) as entered into the Interactive Response Technology.

cLog-rank test stratified by the same factors as in the Cox proportional hazards model. The P value threshold for statistical significance was 0.0262.

dProgression not necessarily meeting RECIST 1.1.

eProgression and/or recurrence, per RECIST 1.1.

Source: Clinical Study Report.15

Figure 5: EFS per BICR — All Randomized Patients

This figure presents EFS KM curves of the total number of at-risk patients in the nivolumab plus chemotherapy and chemotherapy arms from 0 to 42 months. Both curves diverge at month 3 and remain separated at month 42.

BICR = blinded independent central review; Chemo = chemotherapy; CI = confidence interval; Conc. = concurrent; EFS = event-free survival; HR = hazard ratio; KM = Kaplan-Meier; N.A. = not available; Nivo = nivolumab.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Subgroup Analyses

Although there were inconsistencies across identified subgroups in terms of benefit, overall, a positive EFS benefit was observed in the nivolumab plus chemotherapy arm compared with chemotherapy. Increasing benefit was reported for nivolumab plus chemotherapy over chemotherapy across the PD-L1 subgroup, with a higher magnitude of benefit reported in patients with a PD-L1 expression level of at least 50% (HR = 0.24; 95% CI, 0.10 to 0.61) than in those with a PD-L1 expression level of 1% to 49% (HR = 0.58; 95% CI, 0.30 to 1.12), of at least 1% (HR = 0.41; 95% CI, 0.24 to 0.70), and of more than 1% (HR = 0.85; 95% CI, 0.54 to 1.32). Similarly, benefit was observed in the nivolumab plus chemotherapy arm in the disease-stage subgroup, with a higher magnitude of benefit reported for patients with stage IIIA disease (HR = 0.54; 95% CI, 0.37 to 0.80) than for those with stage IB or II disease (HR = 0.87; 95% CI, 0.48 to 1.53). A benefit was also observed in the histology subgroup — the HR for patients with nonsquamous disease was 0.50 (95% CI, 0.32 to 0.79) — and in the performance-status subgroup, in which the magnitude of benefit was higher in patients with an ECOG PS of 0 (HR = 0.61, 95% CI, 0.41 to 0.91) than in those with an ECOG PS of 1 (HR = 0.71; 95% CI, 0.41 to 1.21).

A subgroup analysis conducted to evaluate EFS by pCR status showed an EFS HR for pCR versus no pCR of 0.13 (95% CI, 0.05 to 0.37) in the nivolumab plus chemotherapy arm. No results were presented for the chemotherapy arm because of the small number of patients who achieved a pCR.

Of note, multiplicity adjustments to account for a type I error were not conducted during the subgroup analyses; as such, the subgroup findings are considered exploratory. Table 47 in Appendix 4 presents EFS findings in the subgroups identified in the CADTH review protocol.

Pathologic Complete Response and Major Pathologic Response

pCR analyses were conducted at the September 16, 2020, data cut-off date. The pCR rate, per BIPR, was 24.0% (43 of 179 patients; 95% CI, 18.0% to 31.0%) in the nivolumab plus chemotherapy arm compared to 2.2% (4 of 179 patients; 95% CI, 0.6% to 5.6%) in the chemotherapy arm. The difference in MPR between the 2 arms was 27.9% (95% CI, 19.6% to 36.1%). Table 18 presents the pCR and MPR rates obtained at the September 8, 2020, data cut-off date.

The pCR rate in the sensitivity analysis was 30.5% (43 of 141 patients; 95% CI, 23.0% to 38.8%) in the nivolumab plus chemotherapy arm and 3.2% (4 of 126 patients; 95% CI, 0.9% to 7.9%) in the chemotherapy arm.

Table 18: pCR — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy

(n = 179)

Chemotherapy

(n = 179)

pCR

   Responders, n (%)

43 (24.0)

4 (2.2)

   95% CIa

(18.0 to 31.0)

(0.6 to 5.6)

   Difference (95% CI), %b,c

21.6 (15.1 to 28.2)

MPR

   Responders, n (%)f

66 (36.9)

16 (8.9)

   95% CIa

(29.8 to 44.4)

(5.2 to 14.1)

   Difference, (95% CI), %b,c

27.9 (19.6 to 36.1)

CI = confidence interval; MPR = major pathologic response; pCR = pathologic complete response.

Note: The data cut-off date was September 16, 2020.

aCI based on the Clopper-Pearson method.

bStrata-adjusted difference (arm C – concurrent arm B) based on the Cochran-Mantel-Haenszel method of weighting.

cStratified by PD-L1 expression level (≥ 1% vs. < 1%, unevaluable, indeterminate), disease stage (stage IB to II vs. stage IIIA), and sex (male vs. female) as entered into the Interactive Response Technology.

Source: Clinical Study Report.15

Subgroup Analyses

The pCR rates observed in the CADTH specified-protocol subgroups favoured nivolumab plus chemotherapy over chemotherapy. A numerically higher difference between treatments was observed in the subgroup of patients with a PD-L1 expression level of at least 50% (difference = 40.0%; 95% CI, 21.7% to 55.9%) than in the other PD-L1 subgroups. Differences were also observed in the disease-stage subgroup, with a difference between treatments of 20.0% for stage IIIA disease (95% CI, 12.8% to 28.4%) and of 24.4% (95% CI, 11.6% to 36.6%) for stage IB to II disease; in the histology subgroup, with a difference between treatments of 2.1% (95% CI, 11.0% to 31.4%) for squamous cell disease and of 22.8% (95% CI, 14.2% to 32.4%) for nonsquamous cell disease; and in the performance-status subgroup, with a difference between treatments of 24.9% (16.7% to 33.4%) for an ECOG PS of 0 and of 15% (95% CI, 3.8% to 33.4%) for an ECOG PS of 1. Table 48 of Appendix 4 presents the pCR obtained in subgroups at the September 8, 2020, data cut-off date.

Time to Death or Distance Metastasis

The median TTDM was not reached in the nivolumab plus chemotherapy arm at the October 28, 2021, data cut-off date. The estimated HR was 0.53 (95% CI, 0.36 to 0.77), as presented in Table 19.

Table 19: TTDM — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy (n = 179)

Chemotherapy (n = 179)

Events, n (%)

45 (25.1)

75 (41.9)

Median (95% CI), montha

Not reached (36.60 to NA)

26.71 (22.41 to NA)

HR (95% CI)b

0.53 (0.36 to 0.77)

TDDM rates (95% CI)

At 12 months

85.7 (79.4 to 90.2)

76.0 (68.8 to 81.8)

At 24 months

75.8 (68.3 to 81.7)

57.1 (48.8 to 64.6)

CI = confidence interval; HR = hazard ratio; NA = not available; TTDM = time to death or distance metastasis.

Note: The data cut-off date was October 20, 2021.

aBased on KM estimates.

bHR for arm C to concurrent arm B from a Cox model stratified by PD-L1 expression level (≥ 1% vs. < 1%, not evaluable, indeterminate), disease stage (IB or II vs. stage IIIA), and sex (male vs. female) as entered into the Interactive Response Technology.

Source: Clinical Study Report.15

Health-Related Quality of Life

Patients completed the EQ-5D-3L questionnaire at baseline, before on-treatment clinic visits, at postneoadjuvant visits 1 and 2, and at designated time points during the survival follow-up phase. Completion rates of questionnaires were reported for both study arms and are presented in Table 49 in Appendix 4.

EQ-5D index scores (based on the UK time trade-off value set) were collected for both study arms. Mean change from baseline in EQ-5D VAS and EQ-5D index during the neoadjuvant treatment phase were minimal and similar to baseline levels in the 2 treatment arms (Table 20 and Table 21). Figure 6 and Figure 7 presents mean changes in EQ-5D-3L utility index scores and VAS from baseline.12

Table 20: Summary of the Utility Index Score — All Randomized Patients

Nominal time point

Nivolumab plus chemotherapy (N = 179)

Chemotherapy (N = 179)

N

Mean (SD)

95% CI

Median

Q1, Q3

N

Mean (SD)

95% CI

Median

Q1, Q3

Baseline

169

0.89 (0.13)

0.87 to 0.91

1.0

0.80 to 1.0

171

0.89 (0.16)

0.86 to 0.91

1.0

0.80 to 1.0

Week 3

NA

NA

Change from baseline

NA

NA

Week 4

168

0.91 (0.15)

0.89 to 0.93

1.0

0.82 to 1.0

158

0.89 (0.17)

0.86 to 0.91

1.0

0.80 to 1.0

Change from baseline

163

0.02 (0.16)

–0.01 to 0.04

0.0

0 to 0.07

153

0.00 (0.17)

–0.02 to 0.03

0.0

0.00 to 0.05

Week 5

NA

NA

Change from baseline

NA

NA

Week 7

151

0.89 (0.18)

0.86 to 0.92

1.0

0.80 to1.0

145

0.89 (0.17)

0.86 to 0.92

1.0

0.80 to 1.0

Change from baseline

148

–0.01 (0.18)

–0.04 to 0.02

0.0

0.0 to 0.04

141

–0.01 (0.18)

–0.03 to 0.03

0.0

0.00 to 0.00

Postneoadjuvant visit 1

156

0.88 (0.18)

0.86 to 0.91

1.0

0.80 to 1.0

146

0.86 (0.20)

0.83 to 0.80

1.0

0.80 to 1.0

Change from baseline

152

–0.01 (0.18)

–0.04 to 0.02

0.0

–0.04 to 0.02

143

–0.02 (0.21)

–0.06 to 0.01

0.0

–0.09 to 0.0

Postneoadjuvant visit 2

134

0.81 (0.25)

0.77 to 0.85

0.82

0.73 to 1.0

132

0.80 (0.24)

0.76 to 0.84

0.80

0.73 to 1.0

Change from baseline

131

–0.09 (0.20)

–0.12 to –0.05

0.0

–0.20 to 0.0

129

–0.09 (0.23)

–0.13 to –0.05

–0.036, 0.0

–0.20 to 0.0

CI = confidence interval; NA = not available; Q1 = first quartile; Q3 = third quartile; SD = standard deviation.

Note: The data cut-off date was October 20, 2021.

Source: Sponsor submission.12

Table 21: Summary of Overall Self-Rated Health Status on EQ VAS— All Randomized Patients

Nominal time point

Nivolumab plus chemotherapy

N = 179

Chemotherapy

N = 179

N

Mean (SD)

95% CI

Median

Q1, Q3

N

Mean (SD)

95% CI

Median

Q1, Q3

Baseline

169

83.1 (15.8)

80.7 to 85.5

90.0

80.0 to 90.0

170

82.4 (14.2)

80.3 to 84.6

85.5

77.0 to 90.0

Week 3

NA

NA

Change from baseline

NA

NA

Week 4

168

83.0 (13.5)

81.0 to 85.1

85.0

80.0 to 90.0

159

81.0 (13.4)

78.9 to 83.1

80.0

70.0 to 90.0

Change from baseline

163

–0.2 (12.1)

–2.0 to 1.7

0.0

–5.0 to 5.0

153

–1.2 (13.1)

–3.3 to 0.9

0.0

–10.0 to 5.0

Week 5

NA

NA

NA

Change from baseline

NA

NA

NA

Week 7

152

81.8 (15.1)

79.4 to 84.2

85.0

80.0 to 90.0

145

82.0 (13.2)

79.8 to 84.2

84.0

75.0 to 90.0

Change from baseline

148

–1.3 (13.8)

–3.5 to 1.0

0.0

–5.0 to 5.0

141

–0.7 (12.6)

–2.8 to 1.4

0.0

–5.0 to 5.0

Postneo­adjuvant visit 1

156

83.3 (13.1)

81.2 to 85.3

87.0

80.0 to 90.0

146

80.5 (14.9)

78.1 to 83.0

80.0

70.0 to 90.0

Change from baseline

152

–0.2 (13.9)

–2.4 to 2.1

0.0

–8.0 to 5.0

142

–1.0 (15.4)

–3.5 to 1.6

0.0

–10.0 to 5.0

Postneoadjuvant visit 2

134

81.2 (14.8)

78.7 to 83.7

84.5

80.0 to 90.0

133

79.0 (17.1)

76.0 to 81.9

80.0

70.0 to 90.0

Change from baseline

131

–2.5 (16.5)

–5.4 to 0.3

0.0

–10.0 to 5.0

129

–2.5 (17.3)

–5.5 to 0.5

0.0

–10.0 to 6.0

CI = confidence interval; NA = not available; Q1 = first quartile; Q3 = third quartile; SD = standard deviation.

Note: The data cut-off date was October 20, 2021.

Source: Sponsor submission.12

Table 22: EFS2 — All Randomized Patients

Characteristic

Nivolumab plus chemotherapy (n = 179)

Chemotherapy (n = 179)

Number of events (%)

42 (23.5)

70 (39.1)

Median (95% CI), monthsa

Not reached (NA to NA)

Not reached (27.40 to NA)

HR (95% CI)b

0.54 (0.37 to 0.80)

Type of events (%)

Disease progression after subsequent next-line systemic anticancer therapy

15 (8.4)

29 (16.2)

Start of second subsequent next-line systemic anticancer therapy death

0

4 (2.2)

Death

27 (15.1)

37 (20.7)

Number of patients censored (%)

137 (76.5)

109 (60.9)

No subsequent next-line systemic anticancer therapy and alive

127 (70.9)

93 (52.0)

Next-line systemic therapy but no progression and no second next-line therapy and alive

10 (5.6)

16 (8.9)

CI = confidence interval; EFS2 = event-free survival on the next- line of therapy; HR = hazard ratio; NA = not available.

aBased on KM estimates.

bHR of arm C to concurrent arm B from a Cox Model stratified by: PD-L1 expression level (≥ 1% vs. < 1%, not evaluable, indeterminate), disease stage (IB or II vs. stage IIIA), and sex (male vs. female) as entered into the Interactive Response Technology.

Source: Clinical Study Report.15

Figure 6: Mean Change in EQ-5D-3L Utility Index Score from Baseline — All Randomized Patients

Plot diagram of mean change from baseline to weeks 1, 2, 3, 4, 5, 6, and 7 in EQ-5D-3L utility index score for nivolumab plus ipilimumab, nivolumab plus chemotherapy, and chemotherapy. Overlaps in SDs are seen for nivolumab plus chemotherapy and chemotherapy at week 4 and week 7.

EQ-5D-3L = 3-Level EQ-5D; SD = standard deviation.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Figure 7: Mean Changes in Overall Self-Rated Health Status on EQ VAS From Baseline — All Randomized Patients

Plot diagram of mean change from baseline to weeks 1, 2, 3, 4, 5, 6, and 7 in self-rated health status on EQ VAS for nivolumab plus ipilimumab, nivolumab plus chemotherapy, and chemotherapy. There are overlaps in SDs observed in the nivolumab plus chemotherapy and chemotherapy arms at week 4 and week 7.

EQ VAS = EQ visual analogue scale.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Figure 8: EFS2 — All Randomized Patients

Figure presents EFS KM curves of the total number of at-risk patients in the nivolumab plus chemotherapy and chemotherapy arms from 0 to 48 months for EFS2. Both curves diverge at month 12 and remain separated at month 42.

Chemo = chemotherapy; CI = confidence interval; Conc. = concurrent; EFS = event-free survival; EFS2 = event-free survival on the next line of therapy; KM = Kaplan-Meier; N.A. = not available; Nivo = nivolumab.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Event-Free Survival on the Next Line of Therapy

By the October 20, 2021, data cut-off date, median EFS2, per investigator, was not reached in either the nivolumab plus chemotherapy or chemotherapy arm. The estimated HR was 0.54 (95% CI, 0.37 to 0.80). Table 22 presents EFS2 data and Figure 8 presents the KM curves for the nivolumab plus chemotherapy and chemotherapy arms.

Harms

Only harms identified in the CADTH review protocol are reported here. Safety data were reported for all treated patients randomized into the nivolumab plus chemotherapy and chemotherapy arms by the October 20, 2021, data cut-off date.

Adverse Events

Overall, 163 (92.6%) patients treated in the nivolumab plus chemotherapy arm and 171 (97.2%) in the chemotherapy arm reported at least 1 AE in the CheckMate 816 trial. The most frequently reported AEs in the nivolumab plus chemotherapy arm were nausea (38.1%), constipation (33.5%), anemia (29.0%), decreased appetite (20.5%), fatigue (16.5%), and neutropenia (16.5%), and in the chemotherapy arm were nausea (44.9%), constipation (32.4%), anemia (26.7%), decreased appetite (23.3%), and decreased neutrophil count (21.0%). AEs of grade 3 or 4 were reported in 40.9% (n = 72) and 43.8% (n = 77) of patients, respectively, in the nivolumab plus chemotherapy and chemotherapy arms.15 Table 23 presents details of the most frequently reported AEs of grade 3 or 4 in the 2 study arms of the CheckMate 816 trial.

Serious Adverse Events

SAEs of any grade were reported in 30 (17.0%) patients in the nivolumab plus chemotherapy arm and 24 (13.6%) patients in the chemotherapy arm. SAEs of grades 3 or 4 were reported in 19 (10.8%) patients in the nivolumab plus chemotherapy arm and 17 (9.7%) patients in the chemotherapy arm. The most commonly reported SAEs in the nivolumab plus chemotherapy arm were vomiting (2.3%), pneumonia (2.3%), embolism (1.1%), and febrile neutropenia (1.1%), and in the chemotherapy arm were febrile neutropenia (2.8%), pneumonia (1.7%), neutropenia (1.1%), and diarrhea (1.1%).15

Dose Delay or Reduction Due to AEs

AEs leading to a dose delay or reduction were reported in 53 (30.1%) and 66 (37.5%) treated patients, respectively, in the nivolumab plus chemotherapy and chemotherapy arms.15 The most common AEs leading to a dose delay or reduction are presented in Table 23.

Discontinuations Due to AEs

AEs leading to the discontinuation of study treatments were reported in 18 (10.2%) patients in the nivolumab plus chemotherapy arm and 20 (11.4%) in the chemotherapy arm. Grade 3 or 4 AEs leading to the discontinuation of at least 1 study drug were reported in 10 (5.7%) patients in the nivolumab plus chemotherapy arm and 7 (4.0%) patients in the chemotherapy arm. The most frequently reported AEs of any grade leading to discontinuation in the nivolumab plus chemotherapy arm were anaphylactic reaction (1.7%), decreased neutrophil count (1.1%), and fatigue (1.1%), and in the chemotherapy arm were neutropenia (2.3%), decreased neutrophil count (1.1%), increased blood creatinine (1.1%), and pneumonia (1.1%).15

Mortality

By the October 20, 2021, data cut-off date, 35 (19.9%) patients had died in the nivolumab plus chemotherapy arm and 59 (33.5%) patients had died in the chemotherapy arm (Table 24). There were no deaths due to study drug toxicity (per investigator) in the nivolumab plus chemotherapy arm, but 3 deaths due to study drug toxicity (per investigator) in the chemotherapy arm (caused by pancytopenia, diarrhea, and acute kidney injury [all 3 reported in 1 patient]; enterocolitis infection; and lung infection and/or pneumonia). Among the 149 patients who underwent surgery after treatment with nivolumab plus chemotherapy, 5 (3.4%) died within 90 days of surgery, most commonly from intraoperative hemorrhage, esophageal perforation, pneumonia, cardiopulmonary arrest due to pulmonary embolism, or aortic rupture. Among the 135 patients who underwent surgery after chemotherapy, 2 (1.5%) patients died within 90 days from an AE or SAE associated with pneumonia.15

Notable Harms

AEs of special interest, specifically immune-related AEs, are presented in Table 23.

Table 23: Summary of Safety With Neoadjuvant Treatment — All Treated Patients

Safety parameters

Nivolumab plus chemotherapy

(n = 176)

Chemotherapy

(n = 176)

Any grade

Grade 3 or 4

Any grade

Grade 3 or 4

All-causality AEs, n (%)

163 (92.6)

72 (40.9)

171 (97.2)

77 (43.8)

≥ 10% of all treated patients in any treatment arm, by PT, n (%)

GI disorders

102 (58.0)

4 (2.3)

124 (70.5)

9 (5.1)

   Nausea

67 (38.1)

1 (0.6)

79 (44.9)

2 (1.1)

   Constipation

59 (33.5)

0

57 (32.4)

2 (1.1)

   Vomiting

19 (10.8)

2 (1.1)

22 (12.5)

1 (0.6)

   Diarrhea

16 (9.1)

1 (0.6)

24 (13.6)

4 (2.3)

General disorders and administration-site conditions, n (%)

85 (48.3)

5 (2.8)

78 (44.3)

4 (2.3)

   Fatigue

29 (16.5)

2 (1.1)

22 (12.5)

1 (0.6)

   Malaise

26 (14.8)

1 (0.6)

25 (14.2)

1 (0.6)

   Asthenia

16 (9.1)

2 (1.1)

19 (10.8)

1 (0.6)

Blood and lymphatic system disorders, n (%)

76 (43.2)

26 (14.8)

74 (42.0)

36 (20.5)

   Anemia

51 (29.0)

7 (4.0)

47 (26.7)

9 (5.1)

   Neutropenia

29 (16.5)

16 (9.1)

31 (17.6)

21 (11.9)

Investigations, n (%)

66 (37.5)

22 (12.5)

77 (43.8)

25 (14.2)

   Decreased neutrophil count

26 (14.8)

13 (7.4)

37 (21.0)

19 (10.8)

   Decreased WBC count

13 (7.4)

3 (1.7)

19 (10.8)

6 (3.4)

Skin and subcutaneous tissue disorders, n (%)

58 (33.0)

4 (2.3)

37 (21.0)

0

   Rash

24 (13.6)

1 (0.6)

5 (2.8)

0

   Alopecia

19 (10.8)

0

26 (14.8)

0

Metabolism and nutrition disorders, n (%)

63 (35.8)

9 (5.1)

64 (36.4)

10 (5.7)

   Decreased appetite

36 (20.5)

2 (1.1)

41 (23.3)

4 (2.3)

Respiratory, thoracic, and mediastinal disorders, n (%)

54 (30.7)

1 (0.6)

51 (29.0)

2 (1.1)

   Hiccups

18 (10.2)

0

26 (14.8)

0

≥ 20% of patients in any treatment arm, by PT, n (%)

   Nausea

67 (38.1)

1 (0.6)

79 (44.9)

2 (1.1)

   Constipation

59 (33.5)

0

57 (32.4)

2 (1.1)

   Anemia

51 (29.0)

7 (4.0)

47 (26.7)

9 (5.1)

   Decreased appetite

36 (20.5)

2 (1.1)

41 (23.3)

4 (2.3)

   Decreased neutrophil count

26 (14.8)

13 (7.4)

37 (21.0)

19 (10.8)

All-causality select AEs, by category, n (%)

   Endocrine

11 (6.3)

0

0

0

   GI

16 (9.1)

1 (0.6)

25 (14.2)

4 (2.3)

   Hepatic

15 (8.5)

1 (0.6)

22 (12.5)

4 (2.3)

   Pulmonary

2 (1.1)

0

0

0

   Renal

16 (9.1)

1 (0.6)

21 (11.9)

0

   Skin

43 (24.4)

4 (2.3)

20 (11.4)

1 (0.6)

   Hypersensitivity and/or infusion reactions

12 (6.8)

4 (2.3)

6 (3.4)

2 (1.1)

All-causality SAEs, n (%)

30 (17.0)

19 (10.8)

24 (13.6)

17 (9.7)

   ≥ 1% of patients in any treatment arm, by PT

   Vomiting

4 (2.3)

2 (1.1)

0

0

   Pneumonia

4 (2.3)

1 (0.6)

3 (1.7)

2 (1.1)

   Febrile neutropenia

2 (1.1)

2 (1.1)

5 (2.8)

5 (2.8)

   Embolism

2 (1.1)

1 (0.6)

0

0

   Neutropenia

0

0

2 (1.1)

2 (1.1)

   Diarrhea

0

0

2 (1.1)

2 (1.1)

All-causality AEs leading to discontinuation, n (%)

18 (10.2)

10 (5.7)

20 (11.4)

7 (4.0)

   ≥ 1% of patients in any treatment arm, by PT

   Anaphylactic reaction

3 (1.7)

3 (1.7)

0

0

   Decreased neutrophil count

2 (1.1)

2 (1.1)

2 (1.1)

0

   Fatigue

2 (1.1)

1 (0.6)

0

0

   Increased blood creatinine

1 (0.6)

0

2 (1.1)

0

   Neutropenia

1 (0.6)

0

4 (2.3)

3 (1.7)

   Pneumonia

0

0

2 (1.1)

1 (0.6)

Aes leading to dose delay or reduction, n (%)

53 (30.1)

28 (15.9)

66 (37.5)

33 (18.8)

   ≥ 5% of patients in any treatment arm, by PT

   Neutropenia

13 (7.4)

7 (4.0)

17 (9.7)

10 (5.7)

   Anemia

11 (6.3)

3 (1.7)

8 (4.5)

0

   Decreased neutrophil count

16 (9.1)

8 (4.5)

22 (12.5)

13 (7.4)

All-causality AEs leading to surgical delay, n (%)

6 (3.4)

2 (1.1)

9 (5.1)

4 (2.3)

All-causality AEs leading to surgery cancellation, n (%)

2 (1.1)

0

1 (0.6)

0

All-causality imAEs within 100 days of last dose, treated with immune-modulating medication, by category, n (%)

   Diarrhea and/or colitis

0

0

0

0

   Hepatitis

0

0

0

0

   Pneumonitis

2 (1.1)

0

1 (0.6)

1 (0.6)

   Nephritis and/or renal dysfunction

0

0

0

0

   Rash

15 (8.5)

3 (1.7)

1 (0.6)

0

   Hypersensitivity and/or infusion reactions

2 (1.1)

0

0

0

All-causality endocrine imAEs within 100 days of last dose, with or without immune-modulating medication, by category, n (%)

   Adrenal insufficiency

2 (1.1)

2 (1.1)

0

0

   Hypophysitis

1 (0.6)

1 (0.6)

0

0

   Hypothyroidism and/or thyroiditis

4 (2.3)

0

0

0

   Hyperthyroidism

7 (4.0)

0

0

0

   Diabetes mellitus

2 (1.1)

0

0

0

AE = adverse event; GI = gastrointestinal; imAE = immune-mediated adverse event; PT = preferred term, SAE = serious adverse event; WBC = white blood cell.

Note: The data cut-off date was October 20, 2021.

Source: Clinical Study Report.15

Table 24: Summary of Death — All Treated Patients

Safety parameter

Nivolumab plus chemotherapy

(n = 176)

Chemotherapy

(n = 176)

Deaths, n (%)

35 (19.9)

59 (33.5)

Primary reason for death, n (%)

   Disease

24 (13.6)

45 (25.6)

   Study drug toxicitya

0

3 (1.7)

   Unknown

2 (1.1)

5 (2.8)

   Otherb

9 (5.1)

6 (3.4)

   Patients who died within 100 days of last neoadjuvant dose, n (%)

9 (5.1)

4 (2.3)

   Primary reason for death, n (%)

   Disease

3 (1.7)

1 (0.6)

   Study drug toxicity

0

3 (1.7)

   Unknown

0

0

   Other

6 (3.4)

0

Notes: Only AEs that led to death within 24 hours were documented as grade 5. Events leading to death > 24 hours after onset are reported as the worst grade before death.

Data cut-off of October 20, 2021.

aThe causes of death, per investigator, in the chemotherapy arm were as follows: pancytopenia, diarrhea, and acute kidney injury (all 3 reported in 1 patient); enterocolitis infection; and lung infection and/or pneumonia.

bThe verbatim terms reported for other reasons for death and were consistent with events expected in the study population. None were considered to be related to study drug (per the investigator).

Source: Clinical Study Report.15

Critical Appraisal

Internal Validity

CheckMate 816 is an ongoing, randomized, open-label, phase III trial. Initially, patients were randomized using an Interactive Response Technology in a 1:1 ratio into 1 of 2 treatment arms, and treatment allocation was concealed. Baseline characteristics in the 2 arms of interest were balanced, suggesting that randomization was successful. The methods of randomization, treatment allocation, and stratification factors were considered appropriate. Disease stage and PD-L1 expression level were considered prognostic factors for NSCLC, and sex was considered a significant factor in the assessment of outcomes for immunotherapy.

The treatment effect for the 2 coprimary end points (EFS and pCR) was estimated during a prespecified interim analysis, adjusted using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries that accounted for the actual number of events at an overall alpha of 4% or 5%. Overall, the estimated treatment effect of the coprimary end points was based on interim analyses. There is uncertainty about the magnitude of the treatment effect, given that interim analyses have a tendency to overestimate treatment effect.38-40

OS estimated by the HR for death was statistically nonsignificant, based on the preplanned interim analysis stopping rule (P = 0.008 against a prespecified level of significance at the interim analysis of 0.0033). Although the results showed a promising trend toward a significant treatment effect for OS, the final analysis may be needed to confirm the findings, particularly the exact estimate of the difference in median survival, which was not estimable at the date cut-off date.

Performance and assessment biases due to the open-label design of the trial were considered unlikely, given that radiologic assessments of CT scans for EFS and pathologic review of tumour sections were completed by a blinded independent review team, based on prespecified and validated RECIST 1.1 guidelines. Further, an independent pathology review team assessed images and tumour or lymph node samples for pCR and MPR, which minimizes performance bias.

The proportion of patients exposed to 3 doses of chemotherapy drugs was slightly higher in the nivolumab plus chemotherapy arm than in the chemotherapy arm, which could bias the findings in favour of nivolumab plus chemotherapy (70.6% versus 66.7% for carboplatin; 84.6% versus 79.7% for cisplatin; 85.7% versus 81.8% for paclitaxel; 92.8% versus 84.1% for pemetrexed; and 72.3% versus 75.5% for gemcitabine). In addition, patients in the nivolumab plus chemotherapy arm did not receive docetaxel or vinorelbine because the safety profile of these drugs used in combination with nivolumab had not been established before the establishment of the study arm. The impact of docetaxel and vinorelbine in the estimated effect between treatment arms was considered likely to be negligible. There were also slight differences in the cumulative dose intensity (which also accounted for dose delays and reductions during the trial) in the nivolumab plus chemotherapy and chemotherapy arms for some chemotherapy drugs (46.2% versus 63.3% for gemcitabine [important]; 60.7% versus 81.8% for paclitaxel; and 85.5% versus 79.4% for pemetrexed), which may introduce bias in either direction in the nivolumab plus chemotherapy arm (it may have affected the proportion of patients that became eligible for surgery).

More patients in the chemotherapy arm than in the nivolumab plus chemotherapy arm received any subsequent therapy (n = 78 versus 38 [43.6% versus 21.2%]), received subsequent systemic anticancer therapy (n = 65 versus 31 [36.3% versus 17.3%]), and received subsequent immunotherapy (n = 42 versus 10 [23.5% versus 5.6%]). The use of subsequent anticancer therapy may bias EFS and OS outcomes in the 2 groups. Further, the proportion of patients who received subsequent adjuvant therapy (optional) after surgery was higher in the chemotherapy arm than in the nivolumab plus chemotherapy arm (n = 56 versus 35 [31.8% versus 19.9%]). The use of subsequent adjuvant therapy may bias EFS and OS findings in favour of the chemotherapy arm, which may have led to the improved OS and EFS reflected in the KM curves estimates. The sponsor-presented analyses that did not apply censoring at subsequent anticancer therapy use showed an HR of 0.63 (97.38% CI, 0.44 to 0.89), consistent with the primary analysis (HR = 0.63; 97.38% CI, 0.44 to 0.89; P = 0.0027 [descriptive]). The sponsor also performed additional analyses that adjusted for the use of adjuvant chemotherapy (as a time-dependent covariate), which favoured nivolumab plus chemotherapy over chemotherapy alone (adjusted HR = 0.65; 95% CI, 0.47 to 0.90). There is a potential risk of bias from the use of systemic anticancer therapy and adjuvant chemotherapy; however, the bias was in the outcomes was considered low.

The methods used to address missing data in the trial were considered conservative and may have had an impact on the assessment of efficacy outcomes. The extent of bias may favour of nivolumab plus chemotherapy over chemotherapy for OS and EFS outcomes, given that there were more patients in the chemotherapy arm who did not undergo definitive surgery.

All efficacy end points were adequately described in the sponsor-submitted statistical analysis plan, and censoring rules, hierarchical hypothesis testing, and stopping rules were provided for the primary outcomes, including OS, investigated in the CheckMate 816 trial. Crossing over from 1 study arm to the other was not permitted during the trial, which preserved the treatment differences observed in the randomized arms for EFS and OS. A Cox proportional hazards model, which relies on the assumption of proportional hazards in both treatment groups, was used to assess OS and EFS survival curves. Visual assessment of the KM curve for EFS did not suggest a violation of the proportional hazards assumption, as the curves did not cross; however, visual assessment of the OS curves did suggest a violation of the proportional hazards assumption. In addition, no assessment of the proportional hazards assumption was provided for EFS and OS; therefore, it is uncertain whether the sponsor addressed potential violations in their analyses.

The EQ-5D-3L questionnaire is a generic instrument that has been used to measure patient-reported outcomes and treatments across different health conditions, including cancers.36,37 However, there is limited evidence available on its validity, reliability, and responsiveness to change in patients with NSCLC. In general, the estimated MID for EQ-5D-3L index scores for patients with lung cancer was 0.06 in the US and 0.08 in the UK, using an anchor-based method.41 The MID for EQ VAS scores identified in literature was 7 to 12, and was estimated using the ECOG PS method.41 Utility index and VAS scores obtained from the EQ-5D-3L questionnaire at different time points (baseline, week 4, week 7, postadjuvant visit 1, and postadjuvant visit 2) were used to assess the general health status of patients enrolled in the trial. Missing data for HRQoL were considered missing at specific time points in the analysis. Multiplicity adjustments were not conducted to account for the type I error rate, so the findings were considered exploratory, and no conclusions could be drawn.

Several changes were made to the study protocol, which were adequately reported. These frequent amendments occurred after the study was initiated to reflect the high degree of uncertainty in the objectives when the study was designed. Sample-size calculations and other efficacy outcomes were updated in the statistical analysis plan to reflect the amendments.

All protocol deviations in the 2 study arms of the trial were adequately reported. Relevant protocol deviations were slightly higher in the chemotherapy arm than in the nivolumab plus chemotherapy arm (1.1% versus 2.2%). The most common protocol deviations were incorrect disease staging at baseline and on-treatment deviations related to concurrent cancer therapy.

There was a low risk of selective reporting, as all the outcomes prespecified in the protocol were reported. Interim analysis for pCR and EFS on the first line of therapy were prespecified in the protocol, including the trigger factors and stopping rules. The approaches used to preserve the alpha and the power in the interim analyses were outlined adequately in the statistical analysis plan and were considered to be appropriate. Efficacy analyses were conducted using the ITT population (patients randomized in the 1:1:1 randomization scheme in revised protocol 2 and in the 1:1 randomization scheme in revised protocol 3 [i.e., patients concurrently randomized in the nivolumab plus chemotherapy and chemotherapy arm]), which maintained randomization and minimized the risk of bias that could be introduced when comparing groups that differ in prognostic factors.

External Validity

The sponsor’s reimbursement request aligns with the Health Canada indication: in combination with platinum-doublet chemotherapy for the neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease). The CheckMate 816 study only included patients with an ECOG PS of 0 or 1. The magnitude of benefit of nivolumab plus chemotherapy in patients with an ECOG PS of 2 or higher is uncertain. The experts highlighted the need for patients to have a robust performance status before receiving nivolumab plus chemotherapy to mitigate the risk of treatment-related toxicity, which can occur during treatment and preclude patients from receiving surgery. Thus, patients with an ECOG PS of 0 or 1 are more likely to receive the treatment than those with an ECOG PS of 2 and higher. Further, they are less likely to have other comorbidities unrelated to the cancer that would place them at higher risk for AEs.

There were differences identified in baseline characteristics between the CheckMate 816 trial population and the patient population in Canada. The mean age of patients enrolled in the CheckMate 816 trial was younger (by 10 years) than in the NSCLC population in Canada. Further, more patients with stage IIIA disease than with stage IB or stage II disease were enrolled in the trial, which, according to the experts, is uncommon in Canadian practice. As highlighted by the experts, patients eligible for surgical resection in practice are at an earlier disease stage than those eligible in the trial (the majority of patients enrolled in the trial had stage IIIA disease). The study included only patients with an ECOG PS of 0 or 1 but, according to the experts, more patients with an ECOG PS of 2 or 3 are seen in current practice than in the trial. It was also noted by the experts that a higher proportion of patients with a PD-L1 expression level of at least 50% would be expected in practice than in the CheckMate 816 trial (in practice, the proportion of patients with a PD-L1 expression level of less than 1%, 1% to 49%, and 50% or more, according to the clinical experts, is about one-third for each category. These differences were considered unlikely to affect the generalizability of the CheckMate 816 trial findings to the Canadian population, according to the clinical experts.

The dosing of nivolumab in the reimbursement request aligns with the Health Canada indication.

Dose adjustments were allowed for chemotherapy drugs but not for nivolumab in the trial, which aligns with the Health Canada indication. The experts indicated that the flat-dose approach for nivolumab, as implemented in the CheckMate 816 trial, would be used in practice because of the convenience to patients and pharmacists, and to reduce drug wastage.

The clinical experts indicated that the current standard of care in Canada for resectable NSCLC is upfront surgery with curative intent, followed by adjuvant chemotherapy. Therefore, there is uncertainty in the magnitude of benefit derived from using nivolumab plus chemotherapy in the neoadjuvant setting for patients with resectable NSCLC in the absence of a comparator arm that included surgery followed by adjuvant chemotherapy or comparative studies that evaluate the relative effects of the treatment against surgery followed by adjuvant chemotherapy. Regardless, the clinical experts noted that the magnitude of benefit in EFS for nivolumab plus chemotherapy, as estimated by the postsurgery HR, was clinically meaningful compared to current outcomes observed in patients who receive upfront surgery in current practice.

The clinical experts agreed that the chemotherapy treatments and dosing schedules implemented in the CheckMate 816 trial align with treatments used in the adjuvant setting for NSCLC in Canada. Dose delays and dose discontinuations are anticipated for chemotherapy treatments, according to the experts; however, the experts mentioned that no dose adjustments would be performed for nivolumab, and that there is currently no evidence to support the use of nivolumab in the adjuvant setting for patients with resected NSCLC.

Of note, the specific chemotherapy drugs to be used in combination with nivolumab were not specified in the indication. It is uncertain whether the addition of nivolumab to chemotherapy drugs not included in the nivolumab plus chemotherapy arm of the trial (e.g., docetaxel and vinorelbine) or in the Canadian product monograph will result in benefits similar to those seen with the chemotherapy drugs used in the CheckMate 816 trial. There is therefore uncertainty about the generalizability of the findings to real-world practice with respect to the use of chemotherapies not included in the trial.

Efficacy outcomes investigated in the CheckMate 816 trial were considered to be appropriate by the clinical experts and were considered to be important to patients and clinicians and reflective of outcomes assessed in real-world practice. There is limited evidence on the correlation of EFS as a surrogate outcome for OS with its validation for use in the neoadjuvant setting for NSCLC by regulatory agencies. The clinical experts indicated that EFS was presumably used in the CheckMate 816 trial to incorporate progression that precluded surgery and surgical mortality following neoadjuvant treatment as meaningful end points. pCR has not been validated as a surrogate outcome for OS by Health Canada. The clinical experts cited studies that have reported a correlation between pCR and MPR with OS in neoadjuvant trials for NSCLC following the use of chemotherapy; however, there is limited literature on the correlation of pCR and MPR in trials with targeted therapy or immunotherapy.11

There were more follow-up procedures implemented in the CheckMate 816 trial than would be seen in real-world practice. Patients underwent more frequent assessments in the CheckMate 816 trial than are likely reflective of real-world practice. The clinical experts noted that patients in Canada are followed according to thoracic guidelines (i.e., every 6 months in the first year and annually thereafter, which may differ by practice and may depend on how late patients are in their follow-up schedule). The diagnostic methods and efficacy measurements implemented in the CheckMate 816 trial were considered appropriate by the experts. The assessment methods implemented in the trial were considered to be more reflective of academic than practice settings by the clinical experts, which may not be reflective of current Canadian practice guidelines, as patients would not be excluded from treatment if some of the procedures applied in the trial were not conducted. The clinical experts did not identify any major deviations in the diagnostic methods or assessment procedures that might have had an impact on eligibility criteria or that might have had an influence on the generalizability of the trial findings to current patient population in Canada.

Concomitant medications administered to patients in the trial were considered appropriate by the clinical experts. No significant discrepancies were identified that would have an impact on the trial outcomes or that would deviate from medications administered in real-world practice. Subsequent anticancer therapies administered during the trial were also considered appropriate.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and critically appraise available indirect evidence comparing nivolumab plus platinum-doublet chemotherapy with other relevant treatments in patients with resectable, nonmetastatic NSCLC.

A focused literature search for ITCs dealing with NSCLC was run in MEDLINE All (1946–) on September 29, 2022. No search limits were applied. Titles, abstracts, and full-text articles were screened for inclusion based on the population, intervention, comparator, and outcome criteria outlined in the protocol for the CADTH review. No eligible ITCs were identified from the CADTH literature search.

Description of Indirect Comparison

The sponsor provided an NMA16 that assessed the efficacy and safety of neoadjuvant nivolumab plus chemotherapy relative to other relevant treatments, including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone in patients diagnosed with resectable, nonmetastatic NSCLC.

Methods of Sponsor-Submitted ITC

Objectives

The objective of the sponsor-submitted ITC was to evaluate the efficacy and safety of neoadjuvant nivolumab plus chemotherapy relative to other relevant treatments, including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone in patients with resectable, nonmetastatic NSCLC.

Study-Selection Methods

Based on the prespecified eligibility criteria outlined in Table 25, the sponsor conducted an SLR42 to identify studies investigating the efficacy and safety of current treatments for patients diagnosed with resectable, nonmetastatic NSCLC. The literature searches, last updated on April 1, 2022, were conducted in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. The study screening and selection process was conducted by 2 independent reviewers, and disagreement was resolved by consultation with a third reviewer. Data were extracted by 1 reviewer and verified by a second reviewer. Risk-of-bias assessment was carried out on the recommendations from the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal and Highly Specialised Technologies Evaluation: User Guide for Company Evidence Submission Template.43 From the evidence base created from the SLR, the sponsor identified studies that were eligible for an ITC based on a set of additional criteria, listed in Table 25.

ITC Analysis Methods

An NMA using the Bayesian approach was conducted, and reporting of the NMA generally followed guidance for the PRISMA (Table 26).

For each outcome examined in the NMA, random-effects and fixed-effects models were run. The random-effects model was considered by the sponsor to be the default model. However, the fixed-effects model was selected by the sponsor for all analyses in the NMA because of the sparseness of the network, which was not able to estimate the between-study SD with enough precision. Deviance information criterion was also used to determine model fit, with a lower deviance information criterion indicating a relative improvement in model fit. The sponsor was not able to assess consistency between the direct and indirect evidence because of a lack of closed loops in the network. Convergence was assessed by the monitoring of plots.

The primary outcomes of interest were EFS and OS. Secondary outcomes of interest included TTLRR, TTDM, pCR, and safety outcomes. Of note, the OS data from the sponsor-conducted CheckMate 816 trial was based on an immature data cut-off date.

In addition to the stage-agnostic network, which included studies regardless of the staging of the patient population, the network for each outcome was stratified by tumour staging (i.e., stage IB or II, stage IIIA, and stage IIIA N2). The base-case analysis for each outcome in the NMA synthesized evidence from patients who were deemed candidates for surgery and received third-generation platinum-based doublet chemotherapy. Sensitivity analyses were also carried out for each outcome whenever data were available. These sensitivity analyses involved second-generation platinum-based chemotherapies, the population of resected patients, data stratified by PD-L1 expression level (i.e., ≥ 1% versus < 1%), and data from the ITT population of the CheckMate 816 trial instead the subpopulations of the CheckMate 816 trial (i.e., stage IB or II, stage IIIA, and stage IIIA N2) used in the base-case stage-specific networks.

Results of Sponsor-Submitted NMA

Summary of Included Studies

Of the 59 RCTs identified from the SLR,42 23 met the inclusion criteria (Table 25) for the sponsor-submitted NMA.16 Of those, 8 were included in the base-case analyses, 5 additional RCTs were included in the sensitivity analyses involving second-generation chemotherapies, and 4 additional RCTs were included in the sensitivity analyses expanded to capture patients who had undergone resection. With respect to the 6 RCTs that met the NMA inclusion criteria but were not analyzed in the NMA, the sponsor claimed that 2 RCTs (i.e., 1 evaluating postadjuvant atezolizumab and 1 evaluating postadjuvant pembrolizumab) would be included in exploratory analyses in a separate report. However, the sponsor confirmed later that, to date, the exploratory analyses were not available. The remaining 4 RCTs were not involved in any analysis as they included patients who had undergone complete resection and investigated a second-generation chemotherapy or the combination of tegafur plus uracil, which was relevant only to the population in Japan.

Table 27, Table 28, and Table 29 present study characteristics, patient characteristics, and tumour staging information, respectively, for the RCTs included in the base-case analyses in the sponsor-submitted NMA. Of note, the inclusion and exclusion criteria for the patient populations in the 8 included RCTs were not explicitly stated in the NMA report. In addition, according to the clinical experts consulted by CADTH, the proportion of male participants in the included RCTs was higher than would be seen in real-world clinical practice. Furthermore, no information on the modalities used to stage the tumour was provided.

Table 25: Study-Selection Criteria and Methods for SLR and ITCs

Characteristic

Sponsor-submitted SLR

Sponsor-submitted ITC

Population

  • Adults with resectable (stage I to stage IIIA) nmNSCLC

  • Exclusions: patients with EGFR and/or ALK mutation

  • Studies enrolling adults with resectablea nmNSCLC (stage IB to stage IIIAb)

  • Sensitivity analysis only: studies in which eligibility was assessed after surgical resection and in which patients were restricted to adults with nmNSCLC with resection

Intervention and/or comparators

  • Surgery + chemotherapy (with or without radiotherapy)

  • Surgery + targeted therapy (with or without radiotherapy)

  • Surgery + immunotherapy (with or without radiotherapy)

  • Surgery + BSC and/or no treatment (with or without radiotherapy)

  • Chemotherapies allowed:

    • platinum-based chemotherapy or mix of platinum-based chemotherapiesc

    • oral fluorouracil therapies (i.e., S-1 and UFT in monotherapy or combination therapy)

    • monochemotherapy (e.g., docetaxel)

    • nonplatinum-based combination chemotherapies

  • Targeted therapies allowed:

    • bevacizumab-based chemotherapy

    • gefitinib and erlotinibd

  • Immunotherapies allowed:

    • nivolumab

    • durvalumab

    • pembrolizumab

    • atezolizumab

  • Exclusions:

    • platinum-based adjuvant chemotherapy that includes at least 1 first-generation therapye (e.g., cyclophosphamide, doxorubicin)

    • experimental drugs (e.g., pazopanib, panitumumab)

  • Studies comparing 2 or more of the following regimens:

    • neoadjuvant nivolumab in combination with chemotherapy (third-generation platinum doubletf)g

    • eoadjuvant chemotherapy (third-generation platinum doubletf)g

    • neoadjuvant chemoradiotherapy (third-generation platinum doublet,f delivered concurrently or sequentially with radiotherapy)g

    • adjuvant chemotherapy (third-generation platinum doubletf)

    • surgery alone

  • Sensitivity analysis only: eligible platinum chemotherapies are expanded to include second-generation platinum combinationsh and UFT monotherapy

  • Exploratory analysis only: trials investigating adjuvant or postadjuvant atezolizumab or pembrolizumab will be included in a separate exploratory ITC

  • Studies not comparing 2 or more of the aforementioned regimens will be excluded (e.g., neoadjuvant chemotherapy vs. another neoadjuvant chemotherapy)

  • Regimens not considered to be relevant comparators include S-1 monotherapy, S-1 in combination with chemotherapy, UFT in combination with chemotherapy, bevacizumab-based therapy, gefitinib, third- or second-generation chemotherapies used as monotherapy, and chemotherapy involving a first-generation drugi

Outcome

  • Response:

    • radiographic or clinical response (CR, PR, stable disease, and PD)

    • pathologic response (pCR or MPR)

  • Survival outcomes:

    • OS, PFS, EFS, RFS, and DFS

  • Adverse events

  • HRQoL

  • Studies reporting at least 1 of the following outcomes will be retained:

    • survival outcomes (OS, PFS, EFS, RFS, DFS) reported as relative treatment effects using a time-to-event end point and/or providing Kaplan-Meier plots

    • pathologic response (pCR, MPR) to neoadjuvant therapy reported in at least 2 study arms

    • locoregional recurrence or distant metastases reported in at least 2 study armsj

Study design

  • Interventional studies (RCTs)

  • Observational studies (retrospective or prospective) with the objective of determining the effectiveness of relevant therapies and designed to adjust for confounders (e.g., propensity score matching, adjustment for covariates)

RCTs

Restriction

  • English

  • For observational studies, publication date was restricted to 2008 to 2019

Same as for the SLR

Search strategy

  • Main search was conducted in MEDLINE, Embase, and CENTRAL; the most recent search was on April 1, 2022

  • Epidemiology targeted search was conducted in Embase and MEDLINE; the most recent search was on May 13, 2022

  • Conferences were searched in Embase

  • Unpublished studies were also searched

Same as for the SLR

Selection process

  • Articles were screened and selected independently by 2 reviewers, and disagreement was settled by discussion or consultation with a third reviewer; the judgment of the third reviewer was considered final

Same as for the SLR

Data-extraction process

  • Data extracted by 1 reviewer and verified by a second reviewer

Same as for the SLR

Quality assessment

Assessed based on recommendations from the NICE Single Technology Appraisal and Highly Specialised Technologies Evaluation: User Guide For Company Evidence Submission Template43

Same as for the SLR

ALK = anaplastic lymphoma kinase; BSC = best supportive care; CR = complete response; DFS = disease-free survival; EFS = event-free survival; EGFR = epidermal growth factor receptor; HRQoL = health-related quality of life; ITC = indirect treatment comparison; MPR = major pathologic response; NICE = National Institute for Health and Care Excellence; nmNSCLC = nonmetastatic non–small cell lung cancer; OS = overall survival; pCR = pathologic complete response; PD = progressive disease; PFS = progression-free survival; PR = partial response; RCT = randomized controlled trial; RFS = recurrence-free survival; S-1 = tegafur, gimeracil, and oteracil; SLR = systematic literature review; UFT = tegafur and uracil.

aBased on study designs in which patients were enrolled before surgery with the intention of surgical resection.

bIn trials that include other stages (i.e., stage IA or stage IIIB), no more than 20% of the trial population could represent stages that were not of interest, otherwise such trials were ineligible. Of note, although the CheckMate 816 population was restricted to patients with stage IB disease and tumour sizes ≥ 4 cm, this criterion was not applied to the population, intervention, control, and outcomes study design (PICOS), as this was not consistently reported across trials.

cTo address the objectives of treatment patterns, patients receiving BSC or no treatment at all are included.

dTargeted therapies include oncogene-targeted therapies, such as tyrosine kinase inhibitors and drugs like bevacizumab.

eFirst-generation-based chemotherapies were included if they were used in the neoadjuvant setting.

fCisplatin or carboplatin in combination with gemcitabine, vinorelbine, paclitaxel, docetaxel, or pemetrexed. Note that if a trial arm included a mix of treatments (e.g., third- and second-generation platinum-based chemotherapies), at least 80% of the patients in the trial had to have received third-generation platinum-based chemotherapies for the study to be included in the base-case analysis).

gIn studies involving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (including, for example, neoadjuvant chemotherapy and surgery), the additional administration of postsurgical chemotherapy and/or radiotherapy was permitted. Postsurgical chemotherapy and/or radiotherapy could differ across treatment arms if administered to only a subset of patients (e.g., postsurgical chemotherapy given to patients who responded to neoadjuvant chemotherapy, or chemotherapy and/or radiotherapy given to patients with an R1 or R2 resection). However, if protocol-defined chemotherapy and/or radiotherapy was administered to all patients, irrespective of surgical outcome or response to initial therapy, the same postsurgical regimen must have been used in all relevant trial arms being compared, otherwise such trials were ineligible.

hCisplatin or carboplatin in combination with the following second-generation therapies: ifosfamide, mitomycin, vindesine, vinblastine, and etoposide. Note that if a trial included a mix of treatments (e.g., second- and first-generation platinum-based chemotherapies), at least 80% of the patients in the trial had to have received second- or third-generation platinum-based chemotherapies for the study to be included in the sensitivity analysis). All other trials (e.g., trials enrolling > 20% of patients who received first-generation platinum-based chemotherapies) were excluded.

iFirst-generation chemotherapies include methotrexate, cyclophosphamide, vincristine, and doxorubicin.

jLocoregional recurrences and distant metastases were not included in the PICOS of the SLR that informed the NMA (although these data were extracted, when available); however, given their relevance to the cost-effectiveness analysis, these outcomes were included in the NMA PICOS.

Sources: Sponsor SLR and ITC report.16,42

Table 26: ITC Analysis Methods

Variable

Sponsor-submitted ITC

ITC methods

  • An NMA was conducted based on the Bayesian approach, in alignment with methodological recommendations from NICE44

  • The NMA was reported according to PRISMA guidance17

  • Both random-effects and fixed-effects models were run

  • • All analyses were performed using R version 4.0.2 and WinBUGS version 1.4.3

Priors

Vague priors were used for all parameters except the prior distribution of the between-study SD in the random-effects model. An informative prior was considered if the evidence base was insufficient to estimate the vague prior’s posterior distribution with enough precision to deem the results informative. Informed priors were defined based on the posterior of the between-study SD obtained from a vague prior from the largest available network across all base-case and sensitivity analyses conducted.

Assessment of model fit

  • DIC was used to indicate relative model fit. A lower DIC indicates a relative improvement in model fit.

  • The random-effects model was considered to be the preferred and default model, based on an assumption of heterogeneity in treatment-effect size across RCTs, provided it converged and that the between-study SDs could be estimated, based on either an uninformative prior (the a priori choice) or an informed prior (the alternative choice). However, the fixed-effects model was selected by the sponsor for all analyses in the NMA, owing to the sparseness of the network, which was not able to estimate the between-study SD with enough precision.

Assessment of consistency

Not performed because of a lack of closed loops in the network.

Assessment of convergence

For each model, analyses were based on 3 chains, and a total of 100,000 simulations were run for each chain. The 20,000 of those determined to be burn-in simulations (i.e., simulations before convergence of the model) were discarded. The number of simulations was increased when the chains were slow to converge. Convergence was assessed by the monitoring of plots.

Outcomes

  • EFS (which included the following author-reported end points: DFS, RFS, PFS)

  • OS

  • pCR

  • TTLRR

  • TTDM

Base-case analysis

Analyses of patients deemed to be candidates for surgery and who received third-generation platinum-based doublet chemotherapies

Subgroup analysis

  • Stage-agnostic population (i.e., for the target population: stage IB to stage IIIA)

  • Stage IB to II population

  • Stage IIIA population

  • Stage IIIA N2 population

Sensitivity analysis

  • Analyses of patients deemed to be candidates for surgery and who received third- or second-generation chemotherapies

  • Analysis of patients deemed to be candidates for surgery or who already underwent tumour resection and received third-generation chemotherapies

  • Analyses of stage-agnostic patients deemed to be candidates for surgery and who received third-generation chemotherapies, and stratified by PD-L1 expression level (≥ 1% and < 1%)

  • Analyses using the ITT population of the CheckMate 816 trial in stage-specific networks in the base-case analyses instead of the subpopulations (i.e., stage IB to II, stage III, stage IIA N2) of the trial

Methods for pairwise meta-analysis

Pairwise meta-analysis was conducted using the frequentist approach with the R package “meta” which used the inverse variance approach for pooling and the DerSimonian-Laird method for estimating between-study variance

DFS = disease-free survival; DIC = deviance information criterion; EFS = event-free survival; ITC = indirect treatment comparison; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; OS = overall survival; pCR = pathologic complete response; PD-L1 = programmed cell death 1 ligand 1; PFS = progression-free survival; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RFS = relapse-free survival; SD = standard deviation; TTDM = time to death or distant metastases; TTLRR = time to locoregional recurrence.

Source: Sponsor ITC Report.16

Table 27: Study Characteristics for Base-Case Analysis in the Sponsor-Submitted NMA

Study

Total N

Intervention and/or comparator

Phase

Blinding method

Median follow-up, years (IQR)

Notes

CheckMate 81634

358

Neoadjuvant chemotherapy, neoadjuvant nivolumab in combination with chemotherapy

III

Open-label

2.5 (NR)

NATCH45

619

Surgery alone, neoadjuvant chemotherapy, adjuvant chemotherapy

III

Open-label

4.2 (NR)

CHEST46

270

Neoadjuvant chemotherapy, surgery alone

III

NR

2.6 to 3.3

Stopped early due to positive results

SWOG S990047

337

Neoadjuvant chemotherapy, surgery alone

III

Open-label

5.3 (NR)

Li (2009)48

56

Neoadjuvant chemotherapy, surgery alone

III

Open-label

3.2 (NR)

Prematurely terminated due to slow accrual

IFCT 010149

46

Neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, neoadjuvant chemoradiotherapya

II

Open-label

2.6 (NR)

Prematurely terminated due to slow accrual

WJTOG 990350

60

Neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy

III

NR

5.1 (NR)

Prematurely terminated due to slow accrual

SAKK 16/0051

232

Neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy

III

Open-label

4.4 (NR)

IQR = interquartile range; NMA = network meta-analysis; NR = not reported.

aIFCT 0101 involved 2 different regimens of induction chemoradiotherapy, which included a third cytotoxic drug (i.e., cisplatin and vinorelbine, carboplatin and paclitaxel).

Source: Sponsor ITC Report.16

Table 28: Patient Characteristics for the Studies Included in the Base-Case Analysis in the Sponsor-Submitted NMA

Study

Regimen

Sample size

Median age (years)

Male (%)

Asian (%)

ECOG PS

Histology (%)

0 (%)

1 (%)

SC

NSC

CheckMate 81634

Neoadjuvant chemotherapy

179

65

71

52

65

35

53

47

Neoadjuvant nivolumab in combination with chemotherapy

179

64

72

48

69

31

49

51

NATCH45

Surgery

210

64

88

NR

49a

50a

50

50b

Neoadjuvant chemotherapy

199

65

88

NR

44a

54a

54

46b

Adjuvant chemotherapy

210

64

86

NR

45

53

49

51b

CHEST46

Neoadjuvant chemotherapy

129

61

78

NR

74

26

37

63b

Surgery

141

63

89

NR

70

30

45

55b

SWOG S990047

Neoadjuvant chemotherapy

169

65

64

< 1

66

34

34

66b

Surgery

168

64

68

< 1

63

37

42

58b

Li (2009)48

Neoadjuvant chemotherapy

28

56

68

100

36

64

36

64b

Surgery

28

62

61

100

29

71

29

71b

IFCT 010149

Neoadjuvant chemotherapy

14

56

64

NR

71

29

57

43b

Neoadjuvant chemoradiotherapy

17

88

NR

82

18

41

59b

Neoadjuvant chemoradiotherapy

15

87

NR

73

27

60

40b

WJTOG 990350

Neoadjuvant chemotherapy

29

57

66

100

NR

NR

28

72b

Neoadjuvant chemoradiotherapy

31

58

68

100

NR

NR

16

84b

SAKK 16/0051

Neoadjuvant chemoradiotherapy

117

60

67

NR

71

29

36

64b

Neoadjuvant chemotherapy

115

59

67

NR

69

31

31

69b

ECOG PS = Eastern Cooperative Oncology Group Performance Status; NMA = network meta-analysis; NR = not reported; NSC = nonsquamous cell; SC = squamous cell.

aNATCH was the only study that included patients with an ECOG PS of 2 (although the number was < 1%).

bThe sponsor inferred nonsquamous cell histology from the proportion of patients with squamous cell histology.

Source: Sponsor ITC Report.16

Table 29: Staging Information for the Studies Included in the Base-Case Analysis in the Sponsor-Submitted NMA

Study

Eligible stage

TNM staging system

Clinical stage (%)a

Nodal status (%)

IA

IB

IIA

IIB

IIIA

N0

N1

N2

CheckMate 81634

IB (TS > 4 cm) to IIIA

AJCC 7th

< 1

5

17

13

64

NR

NR

NR

NATCH45

IA (TS > 2 cm) to II (T3N1)

AJCC 6th

11

64

1

22

1

85

15

0

CHEST46

IB to II (T3N1)

AJCC 5th

2

47

4

44

3

49

51

0

SWOG S990047

IB to II (T3N1)

AJCC 5th

0

68 (IB to IIA)

33 (IIB to IIIA)

NR

NR

0

Li (2009)48

IIIA

ISS (1997)

0

0

0

0

100

0

23

77

IFCT 010149

IIIA N2

ISS (1997)

0

0

0

0

100

0

0

100

WJTOG 990350

IIIA N2

AJCC 6th

0

0

0

0

100

0

0

100

SAKK 16/0051

IIIA N2

AJCC 6th

0

0

0

0

100

0

0

100

AJCC = American Joint Committee on Cancer; ISS = International Staging System; N = number of nearby lymph nodes that have cancer; NMA = network meta-analysis; NR = not reported; TMN = tumour, node, and metastasis; TS = tumour size.

aThese data may not add to 100% due to rounding.

Source: Sponsor ITC Report.16

In terms of the risk of bias in the 8 RCTs included in the base-case analysis, the sponsor reported that 2 studies46,49 had a high risk of bias in baseline similarity and all had a high risk of bias in blinding. In addition, the sponsor determined that some included studies failed to provide adequate information on the method of randomization and allocation concealment46-50 and the imbalanced drop out rates.48,49

Several potential sources of heterogeneity were noted in the 8 studies included in the base-case analysis in the sponsor-submitted NMA, including differences in the proportion of male participants (range, 61% to 89%), regimen characteristics (e.g., cisplatin-based versus carboplatin-based regimens, 2 versus 3 treatment cycles, concurrent versus sequential radiotherapy), squamous histology (range, 16% to 60%), and tumour staging (IB to IIIA).

Efficacy Results of the Sponsor-Submitted ITC

As mentioned previously, the sponsor ran both the random-effects model and the fixed-effects model for each outcome in the NMA, and considered the random-effects model to be the default. However, the fixed-effects model was selected by the sponsor for all analyses in the NMA because of the sparseness of the network, which was not able to estimate the between-study SD with enough precision.

Moreover, in this section, we present the stage-agnostic and stage-specific results from the base-case analyses (i.e., analyses of patients deemed to be candidates for surgery and who received third-generation platinum-based doublet chemotherapy) and sensitivity analyses, including analyses of patients deemed to be candidates for surgery and who received third- or second-generation chemotherapies, analyses of patients deemed to be candidates for surgery or who had already undergone tumour resection and third-generation chemotherapy, as well as analyses of patients with stage-agnostic disease deemed to be candidates for surgery who had received third-generation chemotherapies and were stratified by PD-L1 expression level (≥ 1% versus < 1%).

Event-Free Survival

The evidence networks for EFS in the base-case analyses in the sponsor-submitted NMA are displayed in Figure 9, Figure 10, Figure 11, and Figure 12.

Stage-agnostic and stage-specific network estimates for EFS HRs are shown in Table 30. In the base-case analyses, for the 1,978 patients with stage-agnostic disease, neoadjuvant nivolumab in combination with chemotherapy led to a significantly lower risk of an event (i.e., EFS HR < 1 and CrI excluding 1) than neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone. For the 284 patients with the stage IIIA NSCLC, those who received neoadjuvant nivolumab in combination with chemotherapy had a significantly lower risk of an event than those who received neoadjuvant chemotherapy or surgery alone. For the 566 patients with stage IIIA N2 NSCLC, there was a significantly lower risk of an event in those receiving neoadjuvant nivolumab in combination with chemotherapy than in those receiving neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy. However, for patients with stage IB to II NSCLC, there was no significant difference in EFS between neoadjuvant nivolumab plus chemotherapy and neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone.

Results of stage-agnostic and stage-specific networks from the sensitivity analyses were generally consistent with those from the base-case analyses, except in the stage-agnostic network of the sensitivity analyses that involved patients with a PD-L1 expression level below 1%, there were no significant differences in EFS between neoadjuvant nivolumab plus chemotherapy and neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone.

Figure 9: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (EFS for Patients With Stage-Agnostic Disease)

The evidence network for efivent-free survival among patients with stage-agnostic disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone were connected in the network.

adjCT = adjuvant chemotherapy; EFS = event-free survival; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery.

Source: Sponsor ITC Report.16

Figure 10: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (EFS for Patients With Stage IB to II Disease)

The evidence network for event-free survival among patients with stage IB-II disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone were connected in the network.

adjCT = adjuvant chemotherapy; EFS = event-free survival; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery.

Source: Sponsor ITC Report.16

Figure 11: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (EFS for Patients With Stage IIIA Disease)

The evidence network for event-free survival among patients with stage IIIA disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and surgery alone were connected in the network.

EFS = event-free survival; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery.

Source: Sponsor ITC Report.16

Figure 12: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (EFS for Patients With Stage IIIA N2 Disease)

The evidence network for event-free survival among patients with stage IIIA N2 disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy were connected in the network.

EFS = event-free survival; N = number of nearby lymph nodes that have cancer; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis.

Source: Sponsor ITC Report.16

Table 30: Redacted

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Note: This table has been redacted at the request of the sponsor.

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Overall Survival

As data for OS were not mature in the sponsor-conducted CheckMate 816 trial, only the stage-agnostic network for the base-case analysis was available in the sponsor-submitted NMA (Figure 13), and the network estimates are presented in Table 31. Neoadjuvant nivolumab in combination with chemotherapy significantly reduced the risk of death, compared with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone. No significant difference was observed between neoadjuvant plus chemotherapy and neoadjuvant chemoradiotherapy.

Figure 13: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (OS for Patients With Stage-Agnostic Disease)

The evidence network for overall survival among patients with stage-agnostic disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone were connected in the network.

adjCT = adjuvant chemotherapy; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; OS = overall survival; S = surgery.

Source: Sponsor ITC Report.16

Table 31: Redacted

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Note: This table has been redacted at the request of the sponsor.

Time to Locoregional Recurrence

The evidence networks for TTLRR in the base-case analyses in the sponsor-submitted NMA are presented in Figure 14, Figure 15, Figure 16, and Figure 17.

Network estimates of TTLRR HRs are presented in Table 32. Neoadjuvant nivolumab in combination with chemotherapy only had a significantly lower risk of locoregional recurrence than neoadjuvant chemotherapy in patients with stage IIIA and stage IIIA N2 disease in the base-case analyses.

Figure 14: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTLRR for Patients With Stage-Agnostic Disease)

The evidence network for time to locoregional recurrence among patients with stage-agnostic disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and surgery alone were connected in the network.

neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery; TTLRR = time to locoregional recurrence.

Source: Sponsor ITC Report.16

Figure 15: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTLRR for Patients With Stage IB to II Disease)

The evidence network for time to locoregional recurrence among patients with stage IB-II disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and surgery alone were connected in the network.

neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery; TTLRR = time to locoregional recurrence.

Source: Sponsor ITC Report.16

Figure 16: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTLRR for Patients With Stage IIIA Disease)

The evidence network for time to locoregional recurrence among patients with stage IIIA disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemotherapy were connected in the network.

neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; TTLRR = time to locoregional recurrence.

Source: Sponsor ITC Report.16

Figure 17: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTLRR for Patients With Stage IIIA N2 Disease)

The evidence network for time to locoregional recurrence among patients with stage IIIA N2 disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy were connected in the network.

N = number of nearby lymph nodes that have cancer; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; TTLRR = time to locoregional recurrence.

Source: Sponsor ITC Report.16

Table 32: Redacted

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Time to Death or Distant Metastases

The evidence networks for TTDM in the base-case analyses in the sponsor-submitted NMA are displayed in Figure 18, Figure 19, Figure 20, and Figure 21.

Network estimates for TTDM HRs are shown in Table 33. Neoadjuvant nivolumab in combination with chemotherapy significantly reduced the risk of distant metastases compared with neoadjuvant chemotherapy and surgery alone in patients with stage-agnostic disease in base-case analyses and sensitivity analyses. In addition, there were significant differences in TTDM between neoadjuvant nivolumab in combination with chemotherapy and adjuvant chemotherapy in the sensitivity analysis expanded to include patients who had undergone resection, as well as between neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemoradiotherapy in the sensitivity analysis stratified by a PD-L1 expression level of at least 1%.

Figure 18: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTDM for Patients With Stage-Agnostic Disease)

The evidence network for time to distant metastases among patients who are stage agnostic in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and surgery alone were connected in the network.

neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery; TTDM = time to death or distant metastases.

Source: Sponsor ITC Report.16

Figure 19: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTDM for Patients With Stage IB to II Disease)

The evidence network for time to distant metastases among patients with stage IB-II disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and surgery alone were connected in the network.

neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; S = surgery; TTDM = time to distant death or metastases.

Source: Sponsor ITC Report.16

Figure 20: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTDM for Patients With Stage IIIA Disease)

The evidence network for time to distant metastases among patients with stage IIIA disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemotherapy were connected in the network.

neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; TTDM = time to death or distant metastases.

Source: Sponsor ITC Report.16

Figure 21: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (TTDM for Patients With Stage IIIA N2 Disease)

The evidence network for time to distant metastases among patients with stage IIIA N2 disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy alone were connected in the network.

N = number of nearby lymph nodes that have cancer; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; TTDM = time to death or distant metastases.

Source: Sponsor ITC Report.16

Table 33: Redacted

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Pathologic Complete Response

The evidence networks for pCR in the base-case analyses in the sponsor-submitted NMA are displayed in Figure 22 and Figure 23.

Network estimates for pCR ORs are shown in Table 34. Patients who received neoadjuvant nivolumab in combination with chemotherapy were more likely to have a pCR of statistical significance than those who received neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy in all available analyses, except in the sensitivity analysis of patients with a PD-L1 expression level below 1%, in which the effect estimate favoured neoadjuvant nivolumab in combination with chemotherapy over neoadjuvant chemoradiotherapy but without statistical significance.

Figure 22: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (pCR for Patients With Stage-Agnostic and Patients With Stage IIIA N2 Disease)

The evidence network for pathological complete response among patients with stage-agnostic or IIIA N2 disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy were connected in the network.

N = number of nearby lymph nodes that have cancer; neoCRT = neoadjuvant chemoradiotherapy; neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; pCR = pathologic complete response.

Source: Sponsor ITC Report.16

Figure 23: Network Diagram for the Base-Case Analysis in the Sponsor-Submitted NMA (pCR for Patients With Stage IB to II and Patients With Stage IIIA Disease)

The evidence network for pathological complete response among patients with stage IB-II or stage IIIA disease in the base-case analysis is shown for the sponsor-submitted ITC. Neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemotherapy were connected in the network.

neoCT = neoadjuvant chemotherapy; neoNIVO-CT = neoadjuvant nivolumab in combination with chemotherapy; NMA = network meta-analysis; pCR = pathologic complete response.

Source: Sponsor ITC Report.16

Table 34: Redacted

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Harms Results of the Sponsor-Submitted ITC

The sponsor-submitted NMA34 was not able to quantitively synthesize evidence on safety outcomes, and provided a brief narrative description only. The reasons given by the sponsor were the sparseness of the data and the differences in treatment regimens across the base-case studies.

Critical Appraisal of the Sponsor-Submitted ITC

Overall, the SLR conducted by the sponsor to identify relevant studies for the NMA was methodologically sound. The sponsor used a comprehensive literature search strategy, performed study selection and data extraction in duplicate, assessed and reported the risk of bias appropriately, described the characteristics of the included studies, and narratively summarized the results in adequate detail. However, it was unclear whether the risk-of-bias assessment was carried out by a single assessor or by multiple assessors. The reporting of the sponsor-submitted NMA generally followed the PRISMA checklist.17 The sponsor explicitly stated the objectives, with reference to the participants, interventions, comparisons, outcomes, and study design of interest, and provided adequate detail in the methods, results, and discussion sections of the NMA.

Wide CrIs in the random-effects model often indicate the existence of a large degree of heterogeneity across studies and/or sparseness in the network. There are several notable sources of heterogeneity in the sponsor-submitted NMA, such as male domination (range, 61% to 89%), large variations in squamous histology (range, 16% to 60%), and tumour staging (IB to IIIA). According to the clinical experts consulted by CADTH, the heterogeneity in tumour staging for patients with stage-agnostic NSCLC was significant. And indeed, the efficacy results of neoadjuvant nivolumab in combination with chemotherapy for EFS by stage, for example, were inconsistent between patients with stage IB to II NSCLC and those with stage IIIA or stage IIIA N2 NSCLC (i.e., statistically significant versus nonsignificant), when compared with neoadjuvant chemotherapy in the base-case analysis. Given the significant differential treatment effects observed between patients with stage IB to II disease and those with stage IIIA or stage IIIA N2 NSCLC, the pooled ITC results from patients with stage-agnostic disease would be deemed significantly biased, and the pooling is inappropriate, methodologically, although neoadjuvant nivolumab in combination with chemotherapy significantly improved EFS compared with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone in patients with stage-agnostic NSCLC. The best practice in an ITC is, whenever possible, to apply a stratified analysis on the significant effect modifier to account for heterogeneity.

For each outcome examined in the NMA, random-effects models and fixed-effects models were run. The random-effects model was considered by the sponsor to be the default model. However, the fixed-effects model was later selected by the sponsor for all analyses in the NMA because of the sparseness of the network, which was not able to estimate between-study SDs with enough precision. Although it was considered appropriate to use the fixed-effects model instead of the random-effects model when the network was sparce, the fixed-effects model is not capable of capturing or accounting for heterogeneity because it assumes that variance is only derived from within-study variances, not from between-study variances.52 Furthermore, the fixed-effects model tends to generate a narrower CrI, which might also bias the results.

Misclassification of tumour stage using different versions of tumour classification criteria (i.e., TNM 5th edition, 6th edition, 7th edition, and the 1997 International Staging System) could have had an impact on the ITC estimation. A study53 that adopted the TNM 7th edition criteria to retrospectively reclassify 145 patients with NSCLC whose tumour stage was originally determined using the TNM 6th edition showed that the TNM 7th edition criteria for lung cancer shifted 49 of 145 patients (33.8%) to a higher or lower stage. In the sponsor-submitted NMA, of the 8 RCTs in the base-case analysis, the CheckMate 816 trial was the only study to use the TNM 7th edition classification; 2 other trials adopted the TNM 5th edition, 3 used the TNM 6th edition, and 2 used the 1997 International Staging System (Table 5). Different staging criteria could lead to the different classification of patients with NSCLC, which would consequently result in differences in prognosis estimation and treatment selection.

In the sponsor-submitted NMA, safety outcomes were only narratively described, as the sponsor considered a quantitative synthesis not feasible because of the sparseness of the data and the differences in treatment regimens across the base-case studies. However, without a quantitative synthesis, a balanced judgment of comparative benefits relative to comparative harms could not be made. In addition, outcomes that are important to patients, such as HRQoL, were not involved in the NMA. Furthermore, the sponsor claimed in correspondence with CADTH that an analysis comparing neoadjuvant nivolumab in combination with chemotherapy with adjuvant atezolizumab was not feasible and was inappropriate because of significant methodological challenges (e.g., significant heterogeneity across the patient populations). Nonetheless, feedback from the clinical experts consulted by CADTH emphasized that adjuvant atezolizumab was an appropriate treatment option for patients with resectable stage IB to stage IIIA NSCLC with a PD-L1 expression level of at least 50%. Therefore, the lack of relevant analyses might have introduced uncertainty into the sponsor’s submitted analysis.

Summary

The sponsor-submitted NMA16 evaluated the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy relative to neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone in patients diagnosed with resectable nonmetastatic NSCLC. The primary efficacy end points used for the NMA estimates were EFS and OS, the latter of which was based on an immature data cut-off in the sponsor-conducted CheckMate 816 trial. Secondary outcomes included TTLRR, TTDM, and pCR. For each outcome, base-case and sensitivity analyses were carried out whenever data were available. The base-case analysis involved patients who were deemed to be candidates for surgery and received third-generation platinum-based doublet chemotherapy. The sensitivity analyses expanded to second-generation platinum-based chemotherapies, patients who had undergone resection, data stratified by PD-L1 expression level (i.e., ≥ 1% versus < 1%), and data from the ITT population of the CheckMate 816 trial instead of the subpopulations from that study (i.e., stage IB to II, stage IIIA, and stage IIIA N2) that were used in the base-case stage-specific networks. Furthermore, for each outcome, in addition to the stage-agnostic network, which included studies regardless of the staging of the patient population, the network was also stratified by tumour staging (i.e., stage IB to II, stage IIIA, and stage IIIA N2). The sponsor-submitted NMA ran the random-effects model by default but selected the fixed-effects model for all analyses in the NMA because of the sparseness of network, which was not able to estimate between-study SDs with enough precision. According to the base-case analysis on EFS, patients with stage IIIA NSCLC receiving neoadjuvant nivolumab in combination with chemotherapy had a significantly lower risk of an event than those receiving neoadjuvant chemotherapy or surgery alone. For patients with stage IIIA N2 NSCLC, the risk of an event in patients receiving neoadjuvant nivolumab in combination with chemotherapy was also significantly lower than the risk of those receiving neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy. However, in patients with stage IB to II NSCLC, the difference in EFS improvement was not significant between neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone. The significant differential treatment effects observed between patients with stage IB to II and patients with stage IIIA or stage IIIA N2 NSCLC suggested that the pooled ITC results from the stage-agnostic population (i.e., stage IB to stage IIIA) were significantly biased and that the pooling was inappropriate, methodologically, although neoadjuvant nivolumab in combination with chemotherapy significantly improved EFS compared with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone in patients with stage-agnostic NSCLC. The sponsor-submitted NMA was not able to quantitively synthesize evidence on safety outcomes, and provided a brief narrative description only, because of the sparseness of the network and the differences in treatment regimens across the base-case studies. Without a quantitative synthesis, a balanced judgment of comparative benefits relative to comparative harms could not be made.

Other Relevant Evidence

This section includes long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

Other Sponsor-Submitted Evidence

As part of the submission for nivolumab, the sponsor provided a systematic review and a meta-analysis describing clinical evidence in patients with nonmetastatic, resectable NSCLC. The objective of this section is to summarize and critically appraise the methods and findings of those submissions.

Description of Study

The sponsor conducted a systematic review and a meta-analysis of available clinical evidence presenting information on the potential of pCR and/or MPR to be used as a surrogate end point for long-term outcomes (EFS, OS) in patients with resectable NSCLC. In total, 82 studies with full text were reviewed and 32 were included in the analyses that presented evidence of an association between OS and/or EFS and pCR and/or MPR, measured as an HR, or had reported KM curves for OS and/or EFS by pCR and/or MPR status, allowing for the reconstruction of HRs.

Methods
Objectives

The objective of the sponsor-submitted meta-analysis was to investigate the potential for pCR and/or MPR as a surrogate end point for long-term outcomes (EFS, OS) in patients with resectable NSCLC. Four objectives were outlined in the sponsor-submitted meta-analysis:

  1. to determine whether treatment effects on the potential surrogate response end points, pCR and MPR, are correlated with treatment effects on the survival-based end points of OS and EFS

  2. to determine whether treatment effects on the composite end point of EFS are correlated with treatment effects on OS

  3. to determine whether survival-based end points (OS and EFS) are associated with the achievement of a pathologic response (pCR or MPR)

  4. to determine treatment effects by estimating the expected improvement in EFS and/or OS to determine the improvement in the proportion of patients who achieved a pCR.

Only results quantifying the association between pCR on OS are presented in this CADTH review report.

Study-Selection Methods

The SLR used to inform the sponsor-submitted meta-analysis was conducted using the prespecified PICO criteria outlined in Table 35 using the PRISMA guidelines. The systematic review included RCTs (which addressed the first objective [i.e., whether OS and EFS are associated with pCR and MPR]), nonrandomized studies, and cohort studies to address the second objective. ITT-derived estimates were extracted from the RCTs that informed the first 2 objectives; for objective 3, studies were restricted to retrospective, observational studies and to patients who had undergone surgery.

Online databases were searched, and a grey literature search of congress proceedings and other available grey literature sites was conducted. Articles were screened by 2 independent reviewers and a second analyst extracted data, which was validated by a second reviewer. The sponsor did not present any methods to assess the risk of bias in the included studies.

Table 35: Study-Selection Criteria and Methods for Sponsor-Submitted Meta-Analysis

Variable

Objectives 1 and 2

Objectives 3 and 4

Population

Adults with resectable, early and locally advanced-stage (I to III) NSCLC

Intervention

Neoadjuvant or perioperative chemotherapy, targeted therapy or immunotherapy (any regimen), or surgery alonea

Neoadjuvant or perioperative chemotherapy (using third-generation chemotherapies), targeted therapy or immunotherapya

Comparator

Neoadjuvant or perioperative chemotherapy, targeted therapy or immunotherapy (any regimen), or surgery alonea

Neoadjuvant or perioperative chemotherapy (using third-generation chemotherapy), targeted therapy or immunotherapya

Outcome

  • pCR

  • MPR

  • OS

  • EFS

  • OS

  • EFS

  • pCR

  • MPR

Study design

RCTs

RCTs, observational studies

Publication characteristics

Database inception to March 11, 2019

Exclusion criteria

Studies focusing on subsegments of the study population:

  • patients with EGFR- or ALK-mutated tumours

  • patients with superior sulcus, chest wall, or brain metastases

  • patients with oligo-recurrence or great vessel invasion

  • older patients, those with a poor performance status, and those with specific comorbidities, such as chronic obstructive pulmonary disease

  • patients receiving interferon, phototherapy, cell therapy, or proton beam therapy

Databases searched

MEDLINE (including MEDLINE in-process and e-publications ahead of print), Embase, and the Cochrane Central Register of Controlled Trials from database inception to March 11, 2019, including conference abstracts (the European Lung Cancer Congress in collaboration with the International Association for the Study of Lung Cancer and the European Society for Medical Oncology, the American Association for Cancer Research, and the American Society of Clinical Oncology).

Selection process

Articles were screened independently by 2 researchers

A third reviewer resolved disagreements in screening

Data-extraction process

One reviewer extracted the data, which was independently validated by a second reviewer

Quality assessment

Not reported

ALK = anaplastic lymphoma kinase; EFS = event-free survival; EGFR = epidermal growth factor receptor; MPR = major pathologic response; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathologic complete response; RCT = randomized controlled trial.

aAny of these therapies can be with or without radiotherapy.

Methods of Sponsor-Submitted Meta-Analysis

Table 36 presents the methods used in the sponsor-submitted meta-analysis.

Patient-level data from the 32 included trials were reconstructed from published KM curves, using the approach described by Guyot et al. (2012).54 An electronic digitizing tool was used to extract the number of patients at risk at time 0 for each group, and HRs were derived from digitized KM curves for trials that did not report HRs but reported KM curves for trial-level and frequentist analyses. Patient-level survival data were also reconstructed from the digitized KM curves for the Bayesian analyses.12

Missing data were imputed as needed. In situations where an HR was reported without an associated CI or standard error, P values were used to calculate (log) standard errors and 95% CIs, following the method described by Altman and Bland (2011).55 Funnel plots were generated and visually inspected for asymmetry to assess publication bias. Standard errors of the effect estimates were graphed against the effect estimate (i.e., HR for OS by pCR, HR for OS by MPR, HR for EFS by pCR, and HR for EFS by MPR). Table 36 presents a summary of the sponsor-submitted meta-analysis methods.12

An assessment for the risk of bias for the studies included in the meta-analysis was not presented.

Table 36: Sponsor-Submitted Meta-Analysis Methods

Variable

Meta-analysis

Methods

For objectives 1 and 2 (correlation of treatment effects): A weighted linear regression model, as suggested by Cortazar et al. (2014)56 was used to capture treatment effect on a survival-based end point vs. treatment effect on response.

To address objective 3 (association between survival-based end points and response, irrespective of treatment): A standard meta-analysis using Bayesian and frequentist frameworks with random effects (which assumes there is some degree of heterogeneity across studies) was performed.

To address objective 4 (estimated trial-level treatment effects on survival): A Bayesian meta-analysis was conducted to predict treatment effects in survival, given the differences observed in treatment response.

Priors

For objective 3: A noninformative inverse gamma prior distribution. The log HR for pCR was modelled assuming a noninformative normal prior distribution with θ1 ~ (0 to 102).

Outcomes

  • pCR

  • MPR

  • OS

  • EFS

Follow-up time points

  • 1-year OS

  • 2-year OS

  • 3-year OS

  • 5-year OS

Sensitivity analyses

Fixed-effect models were run as sensitivity analyses

For objectives 1 and 2, sensitivity analyses were run on different time points for OS and/or EFS

  • 1-year OS

  • 2-year OS

  • 3-year OS

  • 5-year OS

Subgroup analysis

Bayesian hierarchical meta-analyses subgroups:

  • Neoadjuvant treatment type (chemotherapy vs. chemoradiotherapy vs. chemotherapy and/or chemoradiotherapy)

  • pCR definition (ypT0N0 vs. ypT0 vs. 0% viable tumour cells)

  • MPR definition (≤ 10% viable tumour cells vs. other definitions)

  • Time 0 on KM curves (neoadjuvant treatment initiation vs. surgery vs. diagnosis)

  • Neoadjuvant chemotherapy only

  • Resectable population

  Secondary objectives

  • Study design (RCT vs. single-arm trial vs. cohort trial)

  • Geographic region (Asian vs. non-Asian)

  • Population included (resectable vs. resected)

  • Histology (nonsquamous vs. squamous)

  • Stage (stage IIIB vs. nonstage IIIB)

  • Neoadjuvant treatment (chemoradiotherapy vs. chemotherapy)

  • Presence of adjuvant therapy (neoadjuvant vs. periadjuvant)

  • Pathologic response definition (pCR: ypT0N0 vs. ypT0; MPR: ≤ 10% viable tumour cells vs. other)

Survival-based end point definition

  • Quality of HR (author-reported vs. HR reconstruction with life tables vs. HR reconstructions without life tables)

  • Time 0 on KM curves (neoadjuvant treatment initiation vs. surgery)

Methods for pairwise meta-analysis

  • Primary objectives 1 and 2:

    • The results of the regression model were summarized using estimates of the slope, including standard error and the P value. Corresponding R2 and adjusted R2 statistics, along with Pearson correlation coefficients (each with a 95% CI), were calculated.

    • The HRs for OS and EFS and the OR for pCR were analyzed on the natural log scale.

  • Primary objective 3:

    • For the frequentist approach, the between-study variance was captured using the DerSimonian-Laird method. Relative effect estimates were captured as HRs (and 95% CIs and/or standard errors of the log HR) between groups of patients. An overall HR with the corresponding 95% CIs was derived.

    • I2 and Cochran’s Q heterogeneity statistics were applied to measure heterogeneity within the included studies.

    • For the Bayesian approach, the random-effects model was used.

EFS and OS were modelled as piecewise exponentials.

  • Primary objective 4:

    • A Bayesian framework with random-effects model was used to assess trial-level treatment differences between pCR and/or MPR (yes or no to expected treatment benefits) in survival time-to-event end points. Posterior median and 95% probability interval of simulated survival HRs as the predicted survival HR for each incremental difference in pCR rates were reported.

CI = confidence interval; EFS = event-free survival; HR = hazard ratio; KM = Kaplan-Meier; MPR = major pathologic response; OR = odds ratio; OS = overall survival; pCR = pathologic complete response; RCT = randomized control trial.

Source: Sponsor’s submission.12

Results
Summary of Included Studies

Of the 82 studies retrieved for the patient-level analyses sets, 32 were included in the meta-analysis (Table 37) because they reported an association between OS and/or EFS and pCR and/or MPR, measured as an HR or with a KM curve for OS and/or EFS by pCR and/or MPR status, which allowed the reconstruction of HR, when needed.12

Patients received only neoadjuvant chemotherapy in 8 studies, only neoadjuvant chemotherapy plus radiotherapy in 17 studies, and a mix of chemotherapy and chemotherapy plus radiotherapy in 7 studies. Most studies retrieved were retrospective cohort studies. Most studies reported exclusively on patients who had undergone surgical resection (i.e., resected population), rather than including a mix of patients who had undergone surgical resection and who were potentially resectable but did not end up undergoing surgical resection. Table 37 presents study characteristics and characteristics of participants in the trials included in the meta-analysis. Neoadjuvant treatments included platinum-based chemotherapy with or without radiotherapy. The platinum drug used in the trials was cisplatin or carboplatin.12

A summary of specific demographic and baseline patient characteristics from the included trials was not provided, and therefore assessment of heterogeneity related to patients, outcomes, and study design was not possible.

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Table 37: Study and Patient Characteristics in the 32 Included Studies

First author (year)

Study type

Study period

Country

Stage

N

Eligible population

Neoadjuvant systemic treatment

Neoadjuvant chemotherapy

Brandt (2019)

Cohort

2000 to 2015

US

IB to IIIA

184

Resected

Platinum doublet

Cascone (2018)

Other trial

2007 to 2009

US

I to III

47

Potentially resectable

CIS plus TXT

Mouillet (2012)

RCT

1991 to 2006

France

IB to IIB

492

Potentially resectable

PLAT-based chemotherapya

Pataer (2012)

Cohort

2001 to 2006

US

I to IV

358

Resected

Platinum doublet

Qu (2019)

Cohort

2006 to 2014

US

II to III

272

Resected

Platinum doublet

Remark (2016)

Cohort

2008 to 2012

France

III

161

Resected

Platinum doublet

Spaggiari (2016)

Cohort

1998 to 2013

Italy

IIIA

141

Potentially resectable

CIS-based chemotherapy

Stefani (2010)

Cohort

2001 to 2007

France

IIIA to IIIB

175

Resected

Platinum doublet

Neoadjuvant CRT

Appel (2017)

Cohort

2012 to 2016

Israel

IIB to IIIB

52

Resected

Platinum doublet

Arnett (2017)

Cohort

2004 to 2015

US

IIIA

44

Resected

CARB plus TAX

Coroller (2017)

Cohort

2003 to 2013

US

II to III

85

Resected

Not available

Fischer (2008)

Cohort

1999 to 2007

Canada

IIB to IIIB

44

Resected

CIS plus ETO

Haque (2019)

Cohort

2004 to 2015

US

III

1,750

Resected

Not available

Isobe (2012)

Other trial

2001 to 2010

Japan

III

30

Potentially resectable

CARB plus TAX

Kim (2016)

Cohort

1997 to 2013

Korea

IIIA to IIIB

574

Resected

Platinum doublet

Kim (2011)

Cohort

1989 to 2008

US

IB to IIIB

233

Resected

PLAT-based chemotherapyb

Lee (2012)

Cohort

2004 to 2009

Korea

IIIA

205

Resected

CIS plus ETO

Lee (2014)

Cohort

1997 to 2011

Korea

IIIA

355

Potentially resectable

Platinum doublet

Pöttgen (2015)

Cohort

2000 to 2012

Germany

III

157

Potentially resectable

CIS-based chemotherapy

Shintani (2012)

Cohort

1995 to 2008

Japan

IIIA to IIIB

52

Potentially resectable

CIS-based chemotherapyc

Shiraishi (2014)

Cohort

1993 to 2011

Japan

IIB to IIIB

26

Resected

PLAT-based chemotherapyd

Tanaka (2018)

Other trial

2011 to 2013

Japan

IIIA

40

Potentially resectable

CARB plus TAX

van der Meij (2011)

Cohort

2003 to 2009

Netherlands

III

51

Resected

CIS-based chemotherapy

Yamaguchi (2013)

Cohort

2005 to 2011

Japan

IIIA to IIIB

42

Potentially resectable

CIS plus S-1

Yokomise (2007)

RCT

2000 to 2006

Japan

IIIA to IIIB

41

Potentially resectable

CARB plus taxane

Neoadjuvant chemotherapy or CRT

Couñago (2019)

Cohort

2005 to 2014

Spain

IIIA

118

Potentially resectable

Platinum doublet

Kayawake (2019)

Cohort

2005 to 2015

Japan

II to III

145

Resected

CARB-based chemotherapy

Krantz (2018)

Cohort

2006 to 2012

US

IIIA

1,945

Resected

Not available

Li (2009)

Cohort

1998 to 2004

China

IIIA

91

Resected

CIS-based chemotherapy

Martin (2002)

Cohort

1993 to 1999

US

IA to IV

446

Potentially resectable

PLAT-based chemotherapye

Sawabata (2003)

Cohort

1988 to 1999

Japan

IIIA to IIIB

131

Resected

Not available

Schreiner (2019)

Cohort

2008 to 2017

Germany

IIIA to IIIB

55

Resected

CIS plus ETO

CARB = carboplatin; CIS = cisplatin; CRT = chemoradiotherapy; ETO = etoposide; PLAT = platinum; RCT = randomized controlled trial; S-1 = tegafur, gimeracil, and oteracil; TAX = paclitaxel; TXT = docetaxel.

Note: Platinum doublets consisted of carboplatin or cisplatin in combination with vinorelbine, gemcitabine, etoposide, paclitaxel, docetaxel, or pemetrexed. Chemotherapy, unless specified as old chemotherapy, consisted of vinorelbine, gemcitabine, etoposide, paclitaxel, docetaxel, or pemetrexed.

aMouillet et al. (2012) pooled results from 2 trials. In trial 1, neoadjuvant therapy consisted of cisplatin, ifosfamide, and mitomycin, whereas in trial 2, it consisted of platinum doublets (i.e., cisplatin plus gemcitabine or carboplatin plus paclitaxel).

bIn Kim et al. (2011), treatment was a mix of cisplatin, fluorouracil, plus etoposide; carboplatin, paclitaxel, and etoposide; and carboplatin plus paclitaxel.

cIn Shintani et al. (2012), treatment consisted of cisplatin in triple combination with vindesine and mitomycin, or in double combination with vindesine or vinorelbine.

dIn Shiraishi et al. (2014), treatment consisted of a mix of cisplatin alone; cisplatin in combination with docetaxel, vindesine, or fluorouracil; or carboplatin combined with docetaxel.

eIn Martin et al. (2002), treatment consisted of cisplatin in triple combination with vinblastine plus mitomycin, carboplatin plus paclitaxel, or other.

Source: Sponsor’s submission.12

Figure 24: Redacted

Figure has been redacted, as requested by the sponsor.

Note: This figure has been redacted at the request of the sponsor.

Figure 25: Redacted

Figure has been redacted, as requested by the sponsor.

Note: This figure has been redacted at the request of the sponsor.

Critical Appraisal

The sponsor-submitted meta-analysis was informed by studies selected from an adequately conducted systematic review with clearly prespecified PICO criteria and conducted using PRISMA guidelines. The research question for the meta-analysis was adequately reported. The search strategy and the search were conducted using several databases and were adequately reported. The study-selection and data-extraction methods were appropriate. Articles were reviewed by 2 independent reviewers and an analyst extracted data. The study-selection and data-extraction methods were considered appropriate. The outcomes included in the meta-analysis were appropriate and align with those identified as important by patients and clinical experts in the CADTH review protocol. The treatments identified in the trials are commonly used in the Canadian setting. The sponsor did not present data on the risk-of-bias assessment for the included studies.

In the absence of detailed information on the baseline and study characteristics of patients enrolled in the studies included in the meta-analysis, the degree of heterogeneity among the included studies could not be assessed. Studies included had considerable variation in terms of study design (observational versus RCT) and sample size. Allocation concealment, methods for handling missing data, and eligibility criteria for inclusion in the studies were not reported for the RCTs included. Patients’ baseline characteristics were not adequately reported across studies, especially for the key baseline characteristics important for the current reimbursement population, such as PD-L1 expression level, ECOG PS, duration of therapy, dosing regimen, age, sex distribution, race, and geographic location. It was also unclear what the average follow-up time was for patients receiving treatment. In addition, pCR and MPR definitions differed across the included studies.

The sponsor used both frequentist and Bayesian models with random effects in the meta-analysis to quantify the association between pCR and/or MPR on EFS and/or OS. Although key baseline characteristics in the included studies were not provided, the sponsor assessed clinical and methodological heterogeneity among the studies included in the analyses was assessed using I2 and Cochran’s Q heterogeneity statistics. Results and effect sizes for each outcome were presented for each study, with effect size estimated with random-effect models, which was considered appropriate. Heterogeneity assessed in the studies included in the frequentist approach was 0% for most outcomes (except OS by pCR, where I2 was 20% but less than 40% which suggested that heterogeneity was not important). Heterogeneity was not reported for the Bayesian analysis and, owing to the lack of baseline data from the trials included, an assessment of the level of heterogeneity could not be made.

The meta-analysis suggests that achievement of pCR was associated with improved OS, based on the Bayesian and frequentist methods implemented in the analyses.

Long-Term Extension Studies

This section includes a study conducted in a real-world setting submitted by the sponsor to CADTH that was considered to address important gaps (e.g., the validity of surrogate and/or intermediate end points, shortness of the duration of the studies to assess long-term OS benefit) in the evidence included in the Systematic Review.

Real-World Study

One real-world study with data from EHRs, supplemented with chart reviews, was submitted by the sponsor. The purpose of this study was to generate real-world evidence characterizing the relationship between pathologic responses and survival, and to describe profiles of patients with surgically resectable NSCLC (stage IB [tumours ≥ 4 cm] to stage IIIA) treated in the US community oncology setting and neoadjuvant treatment patterns.

Methods

This study, entitled Early End Points in Patients With Resectable NSCLC in a Real-World Setting, is retrospective and observational and uses 2 sources of data from the real-world clinical setting in the US. First, the iKnowMed (iKM) EHR database from The US Oncology Network were used to assess the study objectives. The structured data fields in the iKM EHR database were the source of data for selected variables and metrics used in end point analyses. Second, a chart review for unstructured data in the medical record was performed.

Patients diagnosed with stage IB (tumours ≥ 4 cm) to stage IIIA (AJCC 7th edition) NSCLC and initiating neoadjuvant therapy from January 1, 2008, to January 31, 2019 (the study identification period), were identified. Patients were indexed to the first date of neoadjuvant treatment. The study observation period (January 1, 2008, to July 31, 2019) comprised a 6-month preindex period (i.e., baseline period) before the index date and a postindex period (i.e., follow-up period) spanning the index date to the end of the observation period for each patient (Figure 25).

The follow-up period varied for each patient; it ended at the last encounter and/or patient record, date of death, or end of the observation period (July 31, 2019), whichever occurred first. The last visit was defined as the final physical encounter, detected with vital sign records, for a patient in The US Oncology Network, based on the records available in the study’s structured dataset. If a neoadjuvant regimen consisted of more than 1 drug and drugs were given on different dates, the date of the first administration of any drug was used as the index date. Data used to evaluate medical history extended back to July 1, 2007. The medical history period ended the day before the index date (Figure 25).

The relationship between pathologic responses (pCR and MPR) and survival outcomes (OS and EFS) was assessed as the primary objective. Clinical and demographic characteristics were measured at baseline, before the index date, as a secondary objective. Exploratory outcomes were submitted by the sponsor but not included in this report. Safety was not investigated in this study.

Populations

Identification and verification of the study population occurred in 2 phases. For phase I, patients were assessed for eligibility with structured data in the iKM database, based on the inclusion and exclusion criteria defined here. In the phase II, key eligibility criteria were confirmed by leveraging unstructured information from patients’ charts. Briefly, eligible patients from phase I were further selected for chart review. Patients were disqualified based on information in the chart that differed from what was available in the structured iKM database (i.e., a second stage of verification). Reasons for disqualification were captured and reported. Disqualified patients were excluded from the updated phase I (landscape) assessment, and the phase II (chart review) objectives were assessed for the subpopulation ultimately eligible for chart review.

Figure 26: Study Design

The figure presents the study flow of the observational study. Patient identification ran from January 1, 2008, to January 31, 2019. The study observation period ran from on January 1, 2008, to July 31, 2019. Patients were indexed at the first date of neoadjuvant treatment. The follow-up period varied from patient to patient, as it ended at the earliest of last visit, death, or end-of-study observation period, which was July 31, 2019.

Jan = January; Jul = July.

Inclusion criteria consisted of the following:

Exclusion criteria consisted of the following:

In the overall population, the median age of the 425 patients included in the analysis was 66 years (range, 27 to 89 years), and the majority of patients were male (54.6%) and white (67.3%). The majority of patients were former (61.9%) or current (6.1%) smokers. Most of the patients were diagnosed with stage III NSCLC (66%), and more than half were reported to have an ECOG PS of 1 (60.5%). The most commonly reported comorbidities were hypertension (12%), ischemic disease (6.4%), and pulmonary disease and/or asthma (6.4%). The median number of additional visits following the index date was 25 (range, 1 to 171).

The median time from diagnosis to initiation of neoadjuvant therapy was 1.3 weeks (range, 0.1 to 11.3 weeks), and paclitaxel plus carboplatin (49.2%) was the most common neoadjuvant treatment used. A total of 225 (52.9%) patients underwent a surgical resection, and 72 (32%) of those patients received adjuvant treatment with cisplatin combined with etoposide (22%), the most commonly used adjuvant treatment. Of the 200 patients who did not undergo surgery, the most common reasons were physician recommendation (36.0%), progression (27.5%), other (14.5%), patient preference (7%), and death (7%). A total of 166 (39.1%) patients received subsequent systemic treatment for NSCLC, with carboplatin plus paclitaxel (27.1%) being the most common first-line therapy reported.

Interventions

Neoadjuvant treatment regimens were characterized as chemotherapy or chemoradiotherapy. In phase I, neoadjuvant therapy was defined as the line of therapy noted by the physician. For phase II, confirmation of neoadjuvant therapy administration by chart review was required.

To be eligible, explicit documentation of neoadjuvant therapy by the physician was required. If documentation was absent, then confirmation of chemotherapy before surgery was required. If no surgery took place, the plan or intent to get surgery was required to classify treatment as having neoadjuvant intent.

Outcomes

The following primary objectives were addressed during phase I (structured data only) and phase II (structured data and chart review):

The following secondary objectives were addressed during phase I of the study, using structured data:

Exploratory outcomes were submitted by the sponsor but are not reported in this section. Safety outcomes were not available.

The pCR and MPR for patients receiving neoadjuvant treatment and undergoing surgery were determined with a chart review of postsurgery physician notes and a pathology report of the primary lung tumour and lymph node surgical specimens following neoadjuvant treatment. pCR was defined as no viable tumour cells following surgery (pathologic stage pT0 pN0 or ypT0 ypN0). This definition indicates that involved lymph nodes are N0 after surgery. MPR was defined as residual tumour tissue in the resected lung of 10% or less.

The EFS was calculated, using KM methods, as the interval from the index date to the earliest recorded date of disease progression, precluding surgery, progression or recurrence after surgery, or death from any cause. Patients who did not undergo surgery for reasons other than progression were considered to have an event at progression or death. Relapse and/or recurrence and progression were assessed with chart review, and referred to progression recorded in physician notes only, not defined by traditional RECIST imaging (as this is affected by the frequency of imaging and may not be assessed in the same manner across groups in daily clinical practice). Patients without evidence of relapse, recurrence, progression, or death were censored on the study end date or the last visit date available in the database, whichever occurred first. OS was defined as the interval between the index date and the date of death documented in the Limited Access Death Master File or the iKM EHR database. Patients who did not die were censored on the study end date or the last visit date available in the database, whichever occurred first.

Statistical Analysis

All patients who met the inclusion criteria and none of the exclusion criteria during the specified study period were included in the final analyses. The analyses were conducted using all ascertained patient-level data, regardless of the sample size. A feasibility analysis identified 935 patients with NSCLC (stage IB [tumours ≥ 4 cm] to stage IIIA) receiving neoadjuvant therapy from January 1, 2008, to January 31, 2019. The final study population for analysis was defined after identification and review of the patient population meeting the eligibility criteria in the iKM database.

Descriptive statistics were used for continuous variables (means, SD, median, ranges), categorized continuous variables (e.g., treatment duration in weeks rather than days), and categorical variables (frequencies, counts and percentages). For percentages, the denominator was the total number of people in the study (patient count) at any point in time, and the numerator was a specific characteristic of these patients. Patients with no information available were classified as not documented.

For time-to-event end points, median times with 95% CIs were calculated. Briefly, KM methods were used to estimate time-to-event end points (e.g., OS, EFS) and generate event curves. For example, KM survival curves were generated for OS for patients who did and did not achieve pCR. With an unadjusted Cox analysis that used HRs with 95% CIs, the association between pCR and OS was obtained for the overall population. A Cox proportional hazards model was then conducted to determine the association between pCR and OS, after variables were controlled for (e.g., age, sex, disease stage, histology, site). Variables with a P value no higher than 0.20 in Cox univariate analyses were included in the multivariable analyses. The same analyses were conducted to explore the effect of pCR on EFS. The association between MPR and OS and/or EFS was explored, contingent on sample size, with a Cox proportional hazards model. Adjusted HRs and 95% CIs were estimated with a Cox proportional hazards analysis.

The follow-up period varied for each patient; it ended at the last encounter, death, or the end of the study period, whichever occurred first. However, no minimum or maximum follow-up was required for the analyses of study outcomes. A time-to-event analysis was conducted to account for differences in follow-up periods.

Patient Disposition

A total of 858 eligible NSCLC patients were identified in the structured dataset (phase I). After further inclusion and exclusion criteria were applied during the chart review (phase II), 425 patients were eligible for analysis of the overall population (Table 38).

Most patients — i.e., 28,465 (96.1%) during phase I and 291 (37.8%) owing to a lack of confirmation of neoadjuvant treatment — were excluded (Table 38).

Table 38: Patient Disposition

Inclusion and exclusion criterion

Patients excluded (N)

Patients remaining (N)

Patients with a documented diagnosis of stage IB to stage IIIB NSCLC (AJCC 7th or 8th edition) in The US Oncology Network

29,610

Provider-documented neoadjuvant therapy within The US Oncology Network during the study identification period

28,465

1,145

Age ≥ 18 years at index date (provider-documented neoadjuvant therapy)

0

1,145

At least 2 visits after initiation of provider-documented neoadjuvant therapy

1

1,144

A diagnosis of stage IB to stage IIIA NSCLC (stage IB to stage IIIA before January 2018, based on AJCC 7th edition; stage II to stage IIIB on or after January 2018, based on AJCC 8th edition)

135

1,009

Initiation of neoadjuvant therapy for stage IB to stage IIIA NSCLC (stage IB to stage IIIA before January 2018, based on the TNM 7th edition; stage II to stage IIIB on or after January 2018, based on the TNM 8th edition) during the study identification period

121

888

A current or prior primary diagnosis of cancer other than advanced NSCLC that required systemic or other treatment during a patient’s baseline or follow-up period

25

863

Known EGFR mutation or ALK rearrangement before the study identification period or on the index date

5

858

Target chart review population

Treatment at sites in which charts were accessible for research purposes

89

769

Other eligibility criteria (review) during chart review

Initiation of neoadjuvant therapy for stage IB to stage IIIA NSCLC during the study identification period

291

478

Enrolment and participation in a nonmetastatic NSCLC interventional clinical trial during the study observation period

10

468

A current or prior primary diagnosis of cancer other than advanced NSCLC that required systemic or other treatment during a patient’s baseline or follow-up period

25

443

Stage IB NSCLC (before January 2018) with tumour size < 4 cm before the study identification period

11

432

A confirmed EGFR mutation or ALK rearrangement before the study identification period

7

425

Overall study population

0

425

AJCC = American Joint Committee on Cancer; ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; NSCLC = non–small cell lung cancer; TNM = tumour, node, metastasis.

Source: Clinical Study Report (Early End Points in Patients With Resectable NSCLC in a Real-World Setting).

Exposure to Study Treatments

The median follow-up was 81.7 weeks (range, 1.9 to 589.4 weeks) for patients in the overall population. More than 42% of the patients had at least 24 months of follow-up (Table 2). The median duration of neoadjuvant chemotherapy and chemoradiotherapy was 9.1 weeks (range, 0.1 to 28.3 weeks) and 6.3 weeks (range, 1 to 32.9 weeks), respectively, in the overall population (Table 39).

Table 39: Duration of Follow-Up and Treatment

Duration

Overall population (N = 425)

Follow-up duration, weeks

Mean (SD)

125.9 (117.3)

Median (range)

81.7 (1.9 to 589.4)

Follow-up duration, n (%)

< 6 months

75 (17.6)

6 to < 12 months

70 (16.5)

12 to < 18 months

61 (14.4)

18 to < 24 months

38 (8.9)

24 to < 30 months

32 (7.5)

30 to < 36 months

16 (3.8)

36+ months

133 (31.3)

Duration of neoadjuvant therapy, weeks

Mean (SD)

8.2 (4.8)

Median (range)

6.4 (0.1 to 32.9)

Duration of neoadjuvant therapy by subgroups

Neoadjuvant therapy

Chemotherapy (n = 147)

Chemoradiotherapy (n = 278)

Mean (SD), weeks

8.6 (4.8)

7.9 (4.8)

Median (range), weeks

9.1 (0.1 to 28.3)

6.3 (1 to 32.9)

SD = standard deviation.

Source: Clinical Study Report (Early End Points in Patients With Resectable NSCLC in a Real-World Setting).

Efficacy

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Critical Appraisal
Internal Validity

The study was conducted over a span of 10 years, had documented diagnostic, clinical, and treatment characteristics, and had outcomes data that are not easily captured in clinical trials. Also, the most widely used definition of pCR (0% viable tumour in the primary tumour and nodes, or ypT0N0) and National Comprehensive Cancer Network guidelines for treatment protocols were used to minimize heterogeneity across different clinical centres in The US Oncology Network.

However, residual heterogeneity across sites and investigators is expected to affect outcomes to various degrees in either direction. EHR data are for clinical practice purposes, not solely for research purposes. Therefore, there are limitations to the interpretation of data (e.g., incomplete data across the entire population for some variables of interest, heterogeneous analyses between pathologists and study sites). Also, no information regarding concomitant medication was provided. Even though it was generally a large population, when patients with pCR (11.3%) or MPR (18.8%) were considered in analyses of their relationship to EFS and/or OS, the size of the population starts to become limiting, especially for subgroup and/or sensitivity analyses (which were not included in this report). Without further details provided, it is unknown if the proportional hazards assumption was satisfied with Cox modelling. Last, the relationship between EFS and OS (exploratory outcome, results not included in this report) was investigated but only as an exploratory end point; therefore, the relationship between EFS and OS remains uncertain.

External Validity

This study captured the real-world experiences of patients with resectable NSCLC in the US community oncology setting, which may not be reflective of the clinical setting in Canada. However, there is a selection bias because only clinics in The US Oncology Network that use the full EHR capabilities of the iKM database are included. Practices that participate in the Network may be different from those that do not participate in areas such as the patient population seen or the prescribing practices of physicians. Also, the EHR data do not capture information about services or procedures provided outside of the practice if they are not documented in the EHR. Another source of selection bias is the fact that patients were selected after index dates.

During the 10-year study identification period, therapeutic options, such as immunotherapy and targeted therapy, for advanced NSCLC have evolved significantly, leading to improved survival rates. Therefore, further research is warranted using data comparing different treatment approaches, such as immunotherapy and targeted therapy, in the real-world setting. Because data from phase III studies of patients at earlier stages of NSCLC are still emerging in the neoadjuvant and adjuvant settings, the results from this study remain to be confirmed with clinical trial data.

Discussion

Summary of Available Evidence

This CADTH report summarizes evidence for nivolumab from 1 pivotal study (CheckMate 816), 1 ITC, 1 meta-analysis, and 1 noninterventional study submitted by the sponsor.

CheckMate 816 is an ongoing, open-label, randomized controlled, phase III trial assessing the efficacy and safety of nivolumab in combination with platinum-based chemotherapy administered every 3 weeks for 3 cycles, and platinum-chemotherapy as neoadjuvant treatment for patients with resectable (stage IB [≥ 4 cm], stage II, and resectable stage IIIA) NSCLC. pCR assessed by BIPR and EFS assessed by BICR were coprimary end points. Key secondary and exploratory end points included OS, TTDM, MPR, safety and tolerability, and HRQoL. By the October 20, 2021, data cut-off date (EFS IA1), 93.8% and 84.7% of treated patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively, had completed the course of neoadjuvant therapy. Most patients randomized in the nivolumab plus chemotherapy and chemotherapy arms, respectively, were male (71.5% and 70.9%), and about half of the patients enrolled in the study were white (49.7% and 44.7%) and about half were Asian (48.0% and 52.0%). In total, 48.6% and 53.1% of patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively, had NSCLC with squamous tumour histology, and 63.1% and 64.2%, respectively, had stage IIIA disease.

One sponsor-submitted ITC was summarized and critically appraised for this review. The ITC evaluated the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy relative to other relevant treatments, including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy, and surgery alone, in patients diagnosed with potentially resectable, nonmetastatic NSCLC. The primary efficacy end points investigated in the ITC were EFS and OS, the latter of which was based on an immature data cut-off date in the sponsor-conducted CheckMate 816 trial. Secondary outcomes included TTLRR, TTDM, and pCR. For each outcome, base-case and sensitivity analyses were carried out whenever data were available.

One sponsor-submitted meta-analysis describing clinical evidence of the potential for pCR or MPR as a surrogate end point for long-term outcomes (EFS, OS) in resectable NSCLC was also summarized. The systematic review used to inform the meta-analysis identified 32 studies that presented evidence of an association between OS and/or EFS and pCR and/or MPR, measured as an HR or with reported KM curves for OS and/or EFS by pCR and/or MPR status. Only results quantifying the association between pCR on OS are presented in this report.

One sponsor-submitted retrospective, observational study conducted with data from EHRs and supplemented with chart reviews was also summarized. The study characterized the relationship between pathologic response and survival, and described profiles of patients with surgically resectable NSCLC (stage IB [tumours ≥ 4 cm] to stage IIIA) treated in the US community oncology setting and neoadjuvant treatment patterns.

Interpretation of Results

Efficacy

EFS was met at the planned IA1 (October 20, 2021, data cut-off date). Median EFS was higher in patients receiving nivolumab plus chemotherapy than in those receiving chemotherapy, and the KM curves separated early and remained separated. The estimated HR suggested benefit in patients receiving nivolumab plus chemotherapy compared to chemotherapy alone. The findings were considered statistically and clinically significant. EFS was identified as an important outcome by the clinical experts, clinician groups, and patients. It is important to note that although EFS is a validated surrogate outcome for OS in some oncology trials, there is limited evidence that validates the correlation between EFS and OS in the neoadjuvant setting for patients with resectable NSCLC. Still, the clinical experts consulted considered the EFS findings clinically meaningful, and noted that, in the CheckMate 816 trial, EFS captured the surgical mortality of patients after neoadjuvant treatments.

OS, as estimated by HR, was statistically nonsignificant, based on the prespecified interim analysis stopping rule (P = 0.008 against a prespecified level of significance at the interim analysis of 0.0033). Although the results showed a promising treatment-effect benefit for OS, a final analysis is needed to strengthen confidence the findings of the trial, particularly for the exact estimate of difference in median survival, which was not estimable at the October 21, 2021, data cut-off date. A follow-up OS analysis is planned ||||| ||| || |||||| |||| |||||||| || |||| ||||| ||||. Despite the findings observed, the clinical experts considered the estimates to be convincing and clinically meaningful, suggesting better outcomes (e.g., better OS, more patients cured, fewer cases of recurrence) over time for patients treated with nivolumab plus chemotherapy in the neoadjuvant setting.

pCR was met at the September 16, 2020, data cut-off date. The pCR rate, per BIPR, was higher in the nivolumab plus chemotherapy arm than in the chemotherapy arm and was considered statistically and clinically meaningful by the clinical experts consulted. Sensitivity analyses were also consistent with the primary analysis. Although pCR is a validated surrogate outcome for OS in some oncology trials, it has not been established as a surrogate end point by Health Canada for patients with resectable NSCLC in the neoadjuvant setting. The clinical experts reported that available evidence in the neoadjuvant NSCLC setting suggests a correlation of pCR and MPR with OS after the use of chemotherapy.57,58 However, there is limited evidence to support a correlation of pCR and MPR with OS for targeted therapy or immunotherapy.11 The IONSECO study, which assessed durvalumab treatment for NSCLC in the neoadjuvant setting, showed that pCR was an independent prognostic factor for disease-free survival and OS.59 The ORs for MPR and pCR were higher in the nivolumab plus chemotherapy arm than in the chemotherapy arm.

The sponsor conducted a meta-analysis to address the potential for pCR or MPR to be a surrogate outcome for OS and EFS, pooling patient-level data from 32 studies that presented KM plots and HRs for OS by pCR in the resectable NSCLC setting. OS findings by pCR status in the frequentist and Bayesian analyses suggested a benefit across the included studies. The I2 statistic for the frequentist approach was 20%, suggesting less heterogeneity between the studies included in the analysis. However, several limitations were identified in the meta-analysis, such as variation in study design (observational versus RCT) and sample size. In addition, allocation concealment, methods for handling missing data, and eligibility criteria for inclusion in the studies were not reported for the included RCTs, and key baseline characteristics were not adequately reported across studies, such as PD-L1 expression level, ECOG PS, duration of therapy, and dosing regimen, which are important for the reimbursement population.

The EFS benefit of nivolumab plus chemotherapy over chemotherapy alone was observed across subgroups of interest in the CADTH protocol. More benefit was reported in the subgroup of patients with a PD-L1 expression level of at least 50% (HR = 0.24; 95% CI, 0.10 to 0.61) than in the subgroups with a PD-L1 expression level from 1% to 49% (HR = 0.58; 95% CI, 0.30 to 1.12), PD-L1 expression level of at least 1% (HR = 0.41; 95% CI, 0.24 to 0.70), and PD-L1 expression level of more than 1% (HR = 0.85, 95% CI, 0.54 to 1.32). Similarly, a larger benefit was observed in the subgroup with stage IIIA disease (HR = 0.54; 95% CI, 0.37 to 0.80) than in the subgroup with stage IB to II disease (HR = 0.87; 95% CI, 0.48 to 1.53), although there were fewer events reported for patients with stage IB to II disease (21 events in 65 patients) than for those with stage IIIA disease (43 events in 113 patients). Of note, randomization was stratified by disease stage and PD-L1 expression level in the CheckMate 816 trial. More benefit was observed in subgroups with non-squamous histology (HR = 0.50; 95% CI, 0.32 to 0.79) and more benefit was also observed in subgroups with an ECOG PS of 0 (HR = 0.61; 95% CI, 0.41 to 0.91) than with an ECOG PS of 1 (HR = 0.71: 95% CI, 0.41 to 1.21). The subgroup analyses also suggested that patients with stage IIIA disease derived more benefit from nivolumab plus chemotherapy than the other groups assessed in the CheckMate 816 trial (stage IB to II and other). Still, findings from the subgroup analyses should be interpretated with caution, given that the study was not statistically powered to assess subgroups individually or by type I error because multiplicity was not properly accounted for. Regardless of the magnitude of response observed, a benefit was observed in all subgroups and in the overall study population. In addition, some patients received adjuvant chemotherapy after surgery in the CheckMate 816 trial, which could have had an impact on OS and EFS.

The median TTDM was not reached in either study arm at the October 20, 2021, cut-off; however, the estimated HR suggested that patients receiving nivolumab plus chemotherapy benefited more than those receiving chemotherapy alone. The mean length of hospital stays following surgery for patients in the CheckMate 816 trial did not differ significantly in the 2 treatment arms. The clinical experts considered the findings to be in line with surgery hospital-stay data for NSCLC in current real-world practice.

HRQoL was identified as an important outcome by the clinical experts and patient groups consulted. The mean difference from baseline to week 4, week 7, postadjuvant visit 1, and post adjuvant visit 2 in EQ-5D-3L utility scores did not exceed MID values in either treatment group (0.06 in the US and 0.08 in the UK). The mean difference from baseline to week 4, week 7, postadjuvant visit 1, and postadjuvant visit 2 in the 2 groups in EQ VAS scores did not exceed the MID for VAS scores (range, 7 to 12). Caution should be taken when interpreting the findings, as the type I error rate was not accounted for during the analyses. The clinical experts noted that there was not detriment to HRQoL for patients receiving the nivolumab plus chemotherapy; the mean change from baseline to different assessment points for the VAS and the utility portion of the EQ-5D-3L did not exceed the MIDs. Nivolumab plus chemotherapy was considered tolerable to patients, which is usually desired for new treatments in current practice, according to the clinical experts and patients.

Surgery with curative intent followed by adjuvant chemotherapy was highlighted as the current standard of care in Canada by the clinical experts. Neoadjuvant chemotherapy is infrequently used for patients with resectable NSCLC in Canada because some patients can become ineligible for surgery because of disease progression or toxicity after chemotherapy. Therefore, in the absence of head-to-head trials or direct comparison studies that assess the benefit of nivolumab plus chemotherapy compared with upfront surgery followed by adjuvant chemotherapy, there is uncertainty in the magnitude of benefit derived from nivolumab plus chemotherapy in this patient population. The clinical experts noted that the magnitude of benefit in the estimated EFS HR for patients receiving nivolumab plus chemotherapy before surgery was clinically meaningful compared to current outcomes observed in patients who receive upfront surgery followed by adjuvant chemotherapy in current practice. The generalizability of the findings to patients with an ECOG PS higher than 2 is also limited, given that only patients with an ECOG PS of 0 or 1 were enrolled in the trial. The clinical experts noted that patients must have a good performance status to be eligible for the treatment, owing to the toxicity-associated risks and the potential for disease progression after treatment that can render patients ineligible for surgery. It is also uncertain whether the addition of nivolumab to chemotherapy drugs (and dosing and cycles of administration) not examined in the CheckMate 816 trial or in the Canadian product monograph will result in benefits similar to those seen with the chemotherapy drugs and doses used in that trial.

To address the lack of direct evidence comparing nivolumab plus chemotherapy with upfront surgery followed by adjuvant chemotherapy, the sponsor submitted 1 ITC. The clinical experts noted that adjuvant atezolizumab was an appropriate comparator, and that comparing nivolumab plus chemotherapy with surgery alone or with surgery plus adjuvant systematic should be adjusted for the time-lag bias. Patients with stage IIIA or stage IIIA N2 resectable NSCLC showed more improvement in EFS following neoadjuvant nivolumab in combination with chemotherapy compared to relevant comparators (i.e., neoadjuvant chemotherapy and surgery alone for stage IIIA disease, and neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy for stage IIIA N2 disease). However, in patients with stage IB to II NSCLC, neoadjuvant nivolumab in combination with chemotherapy was not superior to neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone. The treatment effects observed between patients with stage IIIA or stage IIIA N2 disease and those with stage IB to II disease (e.g., between neoadjuvant nivolumab in combination with chemotherapy and neoadjuvant chemotherapy, EFS was statistically significant in patients with stage IIIA or stage IIIA nonsquamous disease but nonsignificant in patients with stage IB to II disease) suggested that the pooled ITC results in the stage-agnostic population (i.e., stage IB to stage IIIA) were significantly biased and that pooling was inappropriate, methodologically, although neoadjuvant nivolumab in combination with chemotherapy significantly improved EFS compared with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone for patients with stage-agnostic NSCLC. No conclusions could be drawn about safety outcomes in the absence of a quantitative synthesis. Several sources of uncertainty were identified in the ITC, such as the significant heterogeneity in the RCTs included, sparse networks, the potential for misclassification of tumour stage when different versions of the guidelines were used, and immature data for OS, which limits the interpretability of the findings.

The sponsor-submitted retrospective study demonstrated a longer median OS for patients with a pCR than for those without. Similarly, MPR was found to be associated with improved EFS and OS, with adjusted HRs showing similar patterns. Median OS was higher in patients with an MPR than in those without. Most of the patients included in the study had stage III NSCLC, and more than half reportedly had an ECOG PS of 1. The study, conducted over 10 years, adapted the most widely used definition of pCR (ypT0N0), and National Comprehensive Cancer Network guidelines for treatment protocols were used to minimize heterogeneity across clinical centres in The US Oncology Network. There were several limitations identified in the real-world study, including the potential for missing or incomplete data for some variables in EHRs and patient charts. Further, applying definitions of pCR or MPR to the overall population reduced the sample size needed to properly assess the relationship between these end points and EFS and OS. The study also had external validity issues, such as selection bias, differences between the US community oncology setting and the clinical setting in Canada, use of the full EHR capabilities of the iKM database by specific networks that could have excluded certain populations, and patient selection after the index dates. The key limitation identified was that the study did not include immunotherapy and/or targeted therapy in neoadjuvant treatment options.

Harms

Overall, the proportion of patients reporting at least 1 AE was comparable in the 2 arms. The most frequently reported AEs in the nivolumab plus chemotherapy arm were nausea, constipation, anemia, decreased appetite, fatigue, and neutropenia. There were slightly more SAEs in the nivolumab plus chemotherapy arm than in the chemotherapy alone arm. There were slightly more dose delays or dose reductions related to AEs in the chemotherapy arm than in the nivolumab plus chemotherapy arm (37.5% versus 30.1%), but AEs leading to discontinuation did not differ significantly between the 2 arms (11.4% versus 10.2%). There were more deaths reported in the chemotherapy arm than in the nivolumab plus chemotherapy arm by the data cut-off date (October 20, 2021). Immune-related AEs reported in the nivolumab plus chemotherapy arm were consistent with the safety profile of immunotherapies.

The clinical experts consulted during the review did not identify any major concerns or new safety signals in the 2 study arms, and generally agreed that the safety of nivolumab plus chemotherapy was acceptable and manageable. The safety profile aligns with clinical expectations following the use of nivolumab or chemotherapy. The AEs reported, according to the experts, have been properly documented in literature and are manageable in clinical practice.

Conclusions

Although statistically significant EFS and favourable OS outcomes were observed in the CheckMate 816 trial for nivolumab plus chemotherapy compared to chemotherapy alone for the neoadjuvant treatment of adults with resectable NSCLC (tumours ≥ 4 cm or node-positive disease), there remains uncertainty about the magnitude of the treatment effect, given that the results are based on interim analyses, the OS data were immature at the October 20, 2021 cut-off date, and the HR for death was not statistically significant. Although EFS is a validated surrogate for OS, final analyses may be warranted to increase confidence in the trial findings. Prespecified EFS subgroup analyses suggested that the majority of the benefits derived from nivolumab plus chemotherapy were in subgroups of patients with stage IIIA disease and a PD-L1 expression level above 50%. However, efficacy results in these subgroup analyses should be interpreted with caution, as the study was not statistically powered to assess individual subgroups. The clinical experts indicated that patients with the highest risk of recurrence (i.e., patients with stage IIIA disease) and a PD-L1 expression level above 50% would be more likely to derive benefit from the treatment, and clinicians might be more apt to treat them with this regimen. However, regardless of the magnitude of response observed, a benefit was observed in all subgroups and in the overall study population. No detriment to quality of life was observed for patients in the trial, and the mean differences from baseline to predefined time points did not exceed the MIDs for the VAS and utility score portions of the EQ-5D-3L questionnaire. Notable differences between the trial population and patients in the Canadian setting were related to the younger age of the enrolled population, the higher proportion of patients enrolled with stage IIIA disease than seen in clinical practice, and the lack of a comparator arm with the current standard of care. However, the clinical experts noted that these differences are unlikely to affect the generalizability of the efficacy results to the Canadian population. The clinical experts explained that this treatment will typically be administered to patients with surgically resectable NSCLC (tumours ≥ 4 cm and/or node-positive disease) who have good a ECOG PS (0 or 1). The safety profile of nivolumab was consistent with the known safety profile of immunotherapies, and no new safety signals were identified. The AEs reported were considered manageable in practice by the clinical exerts consulted.

It is worth noting that the comparator in the CheckMate 816 trial (neoadjuvant chemotherapy) is not the current standard of care in Canada for patients with resectable NSCLC (which is upfront surgery with curative intent followed by adjuvant chemotherapy), and no direct evidence was available to assess the efficacy of nivolumab plus chemotherapy relative to surgery followed by adjuvant chemotherapy. Findings from the sponsor-submitted NMA suggest improvement in EFS with nivolumab plus chemotherapy for patients with stage IIIA, resectable NSCLC, compared with surgery and adjuvant chemotherapy. However, there were sources of uncertainty identified, such as the significant heterogeneity in the included RCTs, sparse networks, and immature data for OS. In addition, there were no quantitative safety data presented, so no conclusions could be drawn. The sponsor-submitted meta-analysis and real-world evidence showed favourable OS outcomes for patients treated with neoadjuvant nivolumab based on pCR status compared to those without pCR status. However, both studies have study design limitations that preclude definitive conclusions.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases

Date of search: September 29, 2022

Alerts: Bi-weekly search updates until project completion

Search filters applied: Randomized controlled trials; controlled clinical trials.

Limits

Table 42: Syntax Guide

Syntax

Description

/

At the end of a phrase, searches the phrase as a patient heading

MeSH

Medical Patient Heading

.fs

Floating subheading

exp

Explode a patient heading

*

Before a word, indicates that the marked patient heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings

#

Truncation symbol for one character

?

Truncation symbol for one or no characters only

adj#

Requires terms to be adjacent to each other within # number of words (in any order)

.ti

Title

.ot

Original title

.ab

Abstract

.hw

Heading word; usually includes patient headings and controlled vocabulary

.kf

Keyword heading word

.dq

Candidate term word (Embase)

.pt

Publication type

.mp

Mapped term

.rn

Registry number

.nm

Name of substance word (MEDLINE)

.yr

Publication year

.jw

Journal title word (MEDLINE)

.jx

Journal title word (Embase)

freq = #

Requires terms to occur # number of times in the specified fields

medall

Ovid database code: MEDLINE All, 1946 to present, updated daily

oemezd

Ovid database code; Embase, 1974 to present, updated daily

cctr

Ovid database code; Cochrane Central Register of Controlled Trials

Multidatabase Strategy

  1. Nivolumab/

  2. (opdivo* or nivolumab* or nivo or bms 936558 or bms936558 or cmab 819 or cmab819 or mdx 1106 or mdx1106 or ono 4538 or ono4538 or HSDB 8256 or HSDB8256 or GTPL 7335 or GTPL7335 or 31YO63LBSN).ti,ab,kf,ot,hw,rn,nm.

  3. 1 or 2

  4. Carcinoma, Non-Small-Cell Lung/

  5. exp LUNG/ and Carcinoma, Large Cell/

  6. (NSCLC* or LCLC*).ti,ab,kf.

  7. ((non small cell* or nonsmall cell* or large cell or undifferentiated) adj5 (lung* or bronch* or pulmonar*) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf.

  8. ((bronchial or pulmonary or lung) adj3 (adenocarcinoma* or adeno-carcinoma*)).ti,ab,kf.

  9. ((bronchioloalveolar or bronchiolo alveolar) adj3 (carcinoma* or cancer* or neoplas* or tumor* or tumour*)).ti,ab,kf.

  10. or/4-9

  11. 3 and 10

  12. 11 use medall

  13. *nivolumab/

  14. (opdivo* or nivolumab* or nivo or bms 936558 or bms936558 or cmab 819 or cmab819 or mdx 1106 or mdx1106 or ono 4538 or ono4538 or HSDB 8256 or HSDB8256 or GTPL 7335 or GTPL7335).ti,ab,kf,dq.

  15. 13 or 14

  16. non small cell lung cancer/ or large cell lung carcinoma/ or lung adenocarcinoma/

  17. (NSCLC* or LCLC*).ti,ab,kf,dq.

  18. ((non small cell* or nonsmall cell* or large cell or undifferentiated) adj5 (lung* or bronch* or pulmonary*) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf,dq.

  19. ((bronchial or pulmonary or lung) adj3 (adenocarcinoma* or adeno-carcinoma*)).ti,ab,kf,dq.

  20. ((bronchioloalveolar or bronchiolo alveolar) adj3 (carcinoma* or cancer* or neoplas* or tumor* or tumour*)).ti,ab,kf,dq.

  21. or/16-20

  22. 15 and 21

  23. 22 use oemezd

  24. 23 not (conference abstract or conference review).pt.

  25. 12 or 24

  26. (Randomized Controlled Trial or Controlled Clinical Trial or Pragmatic Clinical Trial or Equivalence Trial or Clinical Trial, Phase III).pt.

  27. Randomized Controlled Trial/

  28. exp Randomized Controlled Trials as Topic/

  29. “Randomized Controlled Trial (topic)”/

  30. Controlled Clinical Trial/

  31. exp Controlled Clinical Trials as Topic/

  32. “Controlled Clinical Trial (topic)”/

  33. Randomization/

  34. Random Allocation/

  35. Double-Blind Method/

  36. Double Blind Procedure/

  37. Double-Blind Studies/

  38. Single-Blind Method/

  39. Single Blind Procedure/

  40. Single-Blind Studies/

  41. Placebos/

  42. Placebo/

  43. Control Groups/

  44. Control Group/

  45. (random* or sham or placebo*).ti,ab,hw,kf.

  46. ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf.

  47. ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf.

  48. (control* adj3 (study or studies or trial* or group*)).ti,ab,kf.

  49. (Nonrandom* or non random* or non-random* or quasi-random* or quasirandom*).ti,ab,hw,kf.

  50. allocated.ti,ab,hw.

  51. ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw,kf.

  52. ((equivalence or superiority or non-inferiority or noninferiority) adj3 (study or studies or trial*)).ti,ab,hw,kf.

  53. (pragmatic study or pragmatic studies).ti,ab,hw,kf.

  54. ((pragmatic or practical) adj3 trial*).ti,ab,hw,kf.

  55. ((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)).ti,ab,hw,kf.

  56. (phase adj3 (III or “3”) adj3 (study or studies or trial*)).ti,hw,kf.

  57. or/26-56

  58. 25 and 57

  59. remove duplicates from 58

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search terms: Opdivo (nivolumab) AND non–small cell lung cancer (NSCLC)

WHO ICTRP

International Clinical Trials Registry Platform, produced by WHO. Targeted search used to capture registered clinical trials.

[Search terms: Opdivo (nivolumab) AND non–small cell lung cancer (NSCLC)

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms: Opdivo (nivolumab) AND non–small cell lung cancer (NSCLC)

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms: Opdivo (nivolumab) AND non–small cell lung cancer (NSCLC)

Grey Literature

Search dates: September 29, 2022 – October 3, 2022

Keywords: Opdivo (nivolumab) AND non–small cell lung cancer (NSCLC)

Limits: no limit

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 43: Excluded Studies

Reference

Reason for exclusion

Duan et al., 202160

Study design

Jiang et al., 202261

Study design

Cascone et al., 202162

Study design

Appendix 3: Protocol Deviations and Treatment Exposure

Note that this appendix has not been copy-edited.

Important Protocol Deviations

Table 44: Protocol Deviations in the Nivolumab Plus Chemotherapy and Chemotherapy Arms

Status (%)

Nivolumab plus chemotherapy (N = 179)

Chemotherapy (N = 179)

Patients with at least 1 deviation

2 (1.1)

4 (2.2)

At entrance

Patients with inadequate disease stage

1 (0.6)

2 (1.1)

Patients with baseline ECOG PS > 1

0

0

On-treatment deviations

Patients receiving concurrent cancer therapy

1 (0.6)

2 (1.1)

Patients treated differently than as randomized

0

0

Informed consent and/or ethics (IEC/IRB) deviations

Failure to obtain written informed consent on the correct approved version and maintain in the study record

6

3

Consistent failure to obtain ICF update from patient

3

5

Failure to report all SAEs in accordance with the time period required by GCP, the protocol and applicable regulations

8

9

Use of prohibited concomitant medications

2

3

Inclusion or exclusion deviations

Incorrect disease stage at baseline

1

3

Screening procedure not done or out of window

11

11

Patient enrolled with EGFR positive mutation

1

2

Incorrect dosing or study treatment assignment

1

5

Trial procedures

Consistent issues with tumour assessments out of window

3

6

Definitive pathology sample not collected per study requirements

1

3

Presurgery scan out of window

2

1

Protocol required biomarker labs routinely not drawn

1

3

Safety labs not done

8

5

ECG not performed within 28 days of randomization

0

1

Other

Misclassified stratification level [IRT vs. Clinical database]

1

1

Follow-up visit documentation missing

4

3

Drug accountability not completed per protocol (Receipt of study drug and unassigned kits not accounted for)

0

1

Chemo = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGFR = Epidermal growth factor receptor; GCP = Good Clinical Practice; ICF = informed consent form; IEC = independent ethics committee; IRB = institutional review board; Nivo = nivolumab; SAEs = serious adverse events; vs = versus.

Source: Clinical Study Report.15

Exposure to Study Treatments

Table 45: Cumulative Dose and Relative Dose Intensity in the Neoadjuvant Period — All Treated Patients

Nivolumab plus chemotherapy (n = 176)

Characteristics

Nivolumab (n = 176)

Carboplatin (n = 51)

Cisplatin (n = 136)

Number of doses received, n (%)

1

4 (2.3)

4 (7.8)

10 (7.4)

2

8 (4.5)

11 (21.6)

11 (8.1)

3

164 (93.2)

36 (70.6)

115 (84.6)

Cumulative dose (unit)a

Mean (SD)

1,047.3 (129.2)

12.9 (3.5)

203.3 (42.6)

Median (Min-Max)

1,080.0 (360 to 1,080)

14.2 (4.7 to 18.4)

223.4 (74.5 to 231.5)

Relative dose intensity n (%)

≥ 110%

0

3 (5.9)

0

90% to < 110%

154 (87.5)

28 (54.9)

99 (72.8)

70% to < 90%

19 (10.8)

18 (35.3)

33 (24.3)

50% to < 70%

3 (1.7)

1 (2.0)

4 (2.9)

< 50%

0

0

0

Not reported

0

1 (2.0)

0

Characteristics

Gemcitabine (n = 65)

Paclitaxel (n = 28)

Pemetrexed (n = 83)

Number of doses received n (%)

1

0

2 (7.1)

0

2

1 (1.5)

2 (7.1)

6 (7.2)

3

2 (3.1)

24 (85.7)

77 (92.8)

4

4 (6.2)

0

0

5

11 (16.9)

0

0

> 5

47 (72.3)

0

0

Cumulative dose (unit)a

Mean (SD)

5,731.1 (1,096.3)

460.428 (122.89)

1,459.145 (132.54)

Median (Min-Max)

5,986.8 (2,457.7 to 7,636.3)

518.9 (11.65 to 558.9)

1,500.0(964.5 to 1,591.7)

Relative dose intensity n (%)

≥ 110%

0

0

0

90% to < 110%

30 (46.2)

17 (60.7)

71 (85.5)

70% to < 90%

28 (43.1)

9 (32.1)

12 (14.5)

50% to < 70%

5 (7.7)

1 (3.6)

0

< 50%

2 (3.1)

1 (3.6)

0

Not reported

0

0

0

Max = maximum; Min = minimum; SD = standard deviation

aDose in units: Nivolumab in mg (Arm C); Vinorelbine, Cisplatin, Docetaxel, Gemcitabine, Pemetrexed, and Paclitaxel, in mg/ m2, Carboplatin in AUC.

Source: Clinical Study Report.15

Table 46: Cumulative Dose and Relative Dose Intensity in the Neoadjuvant Period — All Treated Patients

Detail

Chemotherapy (N = 179)

Characteristic

Carboplatin (n = 42)

Cisplatin (N = 143)

Docetaxel (N = 29)

Number of doses received

   1

8 (19.0)

13 (9.1)

1 (3.4)

   2

6 (14.3)

16 (11.2)

2 (6.9)

   3

28 (66.7)

114 (79.7)

26 (89.7)

   4

0

0

0

   5

0

0

0

   > 5

0

0

0

Cumulative dose (unit)a

Mean (SD)

11.929 (4.176)

203.857 (102.392)

196.896 (39.215)

Median (min - max)

12.965 (2.90 to 18.00)

221.883 (73.37 to 1287.65)

218.187 (60.00 to 227.12)

Relative dose intensity (%)

≥ 110%

0

1 (0.7)

0

90% to < 110%

25 (59.5)

99 (69.2)

19 (65.5)

70% to < 90%

15 (35.7)

40 (28.0)

10 (34.5)

50% to < 70%

2 (4.8)

3 (2.1)

0

< 50%

0

0

0

Not reported

0

0

0

Characteristic

Gemcitabine (N = 49)

Paclitaxel (N = 22)

Pemetrexed (N = 63)

Vinorelbine (N = 13)

Number of doses received

   1

0

2 (9.1)

5 (7.9) 0

0

   2

1 (2.0)

2 (9.1)

5 (7.9)

1 (7.7)

   3

0

18 (81.8)

53 (84.1)

1 (7.7)

   4

2 (4.1)

0

0

2 (15.4)

   5

9 (18.4)

0

0

4 (30.8)

   > 5

37 (75.5)

0

0

5 (38.5)

Cumulative dose (unit)a

Mean (SD)

5,912.493 (1,124.455)

486.388 (123.506)

1,362.166 (291.134)

119.811 (33.403)

Median (min - max)

6,000.131

(2019.61 to 7614.90)

516.835

(172.97 to 607.12)

1,489.446

(491.12 to 1518.69)

125.145

(49.85 to 153.36)

Relative dose intensity (%)

≥ 110%

0

0

0

0

90% to < 110%

31 (63.3)

18 (81.8)

50 (79.4)

3 (23.1)

70% to < 90%

11 (22.4)

4 (18.2)

13 (20.6)

7 (53.8)

50% to < 70%

7 (14.3)

0

0

3 (23.1)

< 50%

0

0

0

0

Not reported

0

0

0

0

aDose units: Vinorelbine, Cisplatin, Docetaxel, Gemcitabine, Pemetrexed, and Paclitaxel, in mg/m2, Carboplatin in AUC.

Data cut-off: October 20, 2021

Source: Clinical Study Report.

Appendix 4: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Subgroup Analyses: EFS

Table 47: EFS per BICR, Subgroup Analyses — All Randomized Patients

Subgroup

Nivolumab plus chemotherapy

Chemotherapy

Nivolumab + chemotherapy vs. chemotherapy

Unstratified Hazard Ratio (95% CI)

Number of events

(n of patients)

Number of events

(n of patients)

PD-L1 Status

PD-L1 < 1%

37 (78)

41 (77)

0.85 (0.54 to 1.32)

PD-L1 ≥ 1%

21 (89)

41 (89)

0.41 (0.24 to 0.70)

PD-L1 1% to 49%

15 (51)

21 (47)

0.58 (0.30 to 1.12)

PD-L1 ≥ 50%

6 (38)

20 (42)

0.24 (0.10 to 0.61)

Indeterminate/not evaluable

6 (12)

5 (13)

0.92 (0.26 to 3.17)

Disease Stage at study entry

Stage IB to II

21 (65)

24 (62)

0.87 (0.48 to 1.56)

Stage IIIA

43 (113)

62 (115)

0.54 (0.37 to 0.80)

Other

0 (1)

1 (2)

-

ECOG PS

0

42 (124)

53 (117)

0.61 (0.41 to 0.91)

1

22 (55)

34 (62)

0.71 (0.41 to 1.21)

Histology at Study Entry

Squamous Cell Carcinoma

33 (87)

43 (95)

0.77 (0.49 to 1.22)

Nonsquamous

31 (92)

44 (84)

0.50 (0.32 to 0.79)

CI = confidence interval; CRF = case report form; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EFS = event-free survival; HR = hazard ratio; IRT = Interactive Response Technology; mEFS = median event-free survival; NA = not available; PD-L1 = programmed death ligand 1; TMB = tumour mutation burden; vs = versus.

Data cut-off: October 20, 2021

Source: Clinical Study Report.15

Subgroup Analyses: pCR

Table 48: pCR by BIPR, Subgroup Analysis — All Randomized Patients

Subgroup

Nivolumab plus chemotherapy

Chemotherapy

Number of responses

(n of patients)

pCR (%) (95% CI)

Number of responses

(n of patients)

pCR (95% CI)

PD-L1 Status

PD-L1 < 1%

13 (78)

16.7 (9.2 to 26.8)

2 (77)

2.6 (0.3 to 9.1)

PD-L1 ≥ 1%

29 (89)

32.6 (23 to 43.3)

2 (89)

2.2 (0.3 to 7.9)

PD-L1 1% to 49%

12 (51)

23.5 (12.8 to 37.5)

0 (47)

0 (0 to 7.5)

PD-L1 ≥ 50%

17 (38)

44.7 (28.6 to 61.7)

2 (42)

4.8 (0.6 to 16.2)

Indeterminate/not evaluable

1 (12)

8.3 (0.2 to 38.5)

0 (13)

0 (0 to 24.7)

Disease Stage at study entry

Stage IB to II

17 (65)

26.2 (16.0 to 38.5)

3 (63)

4.8 (1.0 to 13.3)

Stage IIIA

26 (113)

23.0 (15.6 to 31.9)

1 (115)

0.9 (< 0.1 to 4.7)

Other

0 (1)

0 (0 to 97.5)

0 (1)

0 (0 to 97.5)

ECOG PS

0

33 (124)

26.6 (19.1 to 35.3)

2 (117)

1.7 (0.2 to 6.0)

1

10 (55)

18.2 (9.1 to 30.9)

2 (62)

3.2 (0.4 to 11.2)

Histology at study entry

Squamous Cell Carcinoma

22 (87)

25.3 (16.6 to 35.7)

4 (95)

4.2 (1.2 to 10.4)

Nonsquamous

21 (92)

22.8 (14.7 to 32.8)

0 (84)

0 (0 to 4.3)

CI = confidence interval; CRF = case report form; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HR = hazard ratio; IRT = Interactive Response Technology; mEFS = median event-free survival; NA = not available; PCR = pathologic complete response; PD-L1 = programmed death ligand 1; TMB = tumour mutation burden; vs = versus.

Data cut-off: September 16, 2020

Source: Clinical Study Report.15

Table 49: Completion Rates of EQ-5D-3L Questionnaire

Nominal point

EQ-5D-3L Descriptive System

EQ-5D-3L VAS

Nivolumab plus chemotherapy

N = 179

Chemotherapy

N = 179

Nivolumab plus chemotherapy

N = 179

Chemotherapy

N = 179

Baseline, n (%)

169 (94.4)

171 (95.5)

169 (94.4)

170 (95.0)

On treatment

Week 3

NA

NA

NA

NA

Week 4

168/174 (96.6)

158/166 (95.2)

168/174 (96.6)

159/166 (95.8)

Week 5

NA

NA

NA

NA

Week 7

151/167 (90.4)

145/154 (94.2)

152/167 (91.0)

145/154 (94.2)

Postneoadjuvant visit 1

156/176 (88.6)

146/174 (83.9)

156/176 (88.6)

146/174 (83.9)

Postneoadjuvant visit 2

134/165 (81.2)

132/168 (78.6)

134/165 (81.2)

133/168 (79.2)

Data cut-off: October 20, 2021

Source: Sponsor submission12

Figure 31: EFS per BICR, Primary Definition in Predefined Subgroups — All Randomized Patients

Alt-text:

Figure 32: pCR Rates per BIPR in Predefined Subgroups — All Randomized Patients

Alt-text:

Appendix 5: Description and Appraisal of Outcome Measures

Note that this appendix has not been copy-edited.

Aim

To describe the following outcome measure and review its measurement properties (validity, reliability, responsiveness to change, and MID):

Finding

EQ-5D 3-Levels Questionnaire

EQ-5D-3L is a generic preference-based HRQoL instrument that has been applied to a wide range of health conditions and treatments.36,37 One part of the EQ-5D-3L is a descriptive system that classifies respondents (aged ≥ 12 years) into 1 of 243 distinct health states. The descriptive system consists of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 possible levels, 1, 2, and 3, representing ‘no problems,’ ‘some problems,’ and ‘extreme problems,’ respectively. Respondents are asked to choose 1 level that reflects their own health state for each of the 5 dimensions. A scoring function can be used to assign a value, i.e., EQ- 5D-3L index score, to each self-reported health state based on a set of population-based preference weights.36,37 The other part of EQ-5D-3L is a vertical, calibrated visual analogue scale (EQ VAS) that has end points labelled 0 and 100, with respective anchors of ‘worst imaginable health state’ and ‘best imaginable health state.’ Respondents are asked to rate their own health by drawing a line from an anchor box to the point on the EQ VAS which best represents their own health on that day. Hence, the EQ-5D-3L produces 3 types of data for each respondent:

The EQ-5D-3L index score is generated by applying a multiattribute utility function to the descriptive system. Different utility functions are available that reflect the preferences of specific populations (e.g., US or UK). The lowest possible overall score (corresponding to severe problems on all 5 attributes) varies depending on the utility function that is applied to the descriptive system (e.g., −0.59 for the UK algorithm and −0.109 for the US algorithm). Scores less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1 are assigned to the health states ‘dead’ and ‘perfect health,’ respectively.

One limitation of the EQ-5D-3L was a significant ceiling effect and left skew of the data, therefore, EQ-5D-3L may be more useful in a population with worse overall health status.

Measurement properties

Evidence of validity, reliability, and responsiveness to change of EQ-5D-3L in patients with NSCLC has not been found through systematic literature search.

Minimally Important Difference

Pickard et al.41 estimated minimally important differences (MIDs) in 534 patients with cancer (50 of whom were patients with lung cancer) using both anchor-based (ECOG PS ratings and FACT-G total score-based quartiles) and distribution-based (SD and SEM) methods for EQ-5D-3L index-based utility (UK and US) and VAS scores. In patients with lung cancer, an estimated MID for EQ-5D-3L index score is 0.06 (US) or 0.08 (UK) using anchor-based method. An MID for VAS score estimated using ECOG grade is 7 and using FACT-G quintile subgroups is 12. MIDs estimated by distribution-method are reported as additional evidence to triangulate or confirm the anchor-based approaches (Table 50).

Table 50: MID Estimates for EQ-5D-3L in Patients With Lung Cancer