Reimbursement Review

Durvalumab (Imfinzi)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Resectable non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Sources: Sponsor’s Summary of Clinical Evidence and Imfinzi product monograph.⁴⁵

Introduction

In 2024 alone, an estimated 32,100 Canadians were expected to be diagnosed with lung cancer and around 20,700 deaths were expected to be attributed to the disease — making lung cancer the most commonly diagnosed cancer and leading cause of cancer-related deaths in Canada.¹ Lung cancer predominantly affects older adults, with 98% of cases occurring in individuals aged 50 years and older.² Non–small cell lung cancer (NSCLC) accounts for approximately 88% of all lung cancer cases in Canada (excluding Quebec) and approximately 25% to 30% of patients with NSCLC present with resectable early-stage disease (stage II to stage III).^3,4 The standard of care for early-stage NSCLC has historically been surgical resection with curative intent followed by adjuvant chemotherapy. However, given that an estimated 30% to 55% of patients develop postoperative recurrence,⁵ there remains an unmet need for treatments that reduce recurrence and improve overall survival (OS). Further, patients with NSCLC experience a variety of symptoms, including dyspnea, malaise, depression, anxiety, worsening cough, hemoptysis, pain, weight loss, and hoarseness.^6,7 These symptoms, coupled with poor disease outlook, treatment modalities and side effects, and other comorbidities common in patients with NSCLC, significantly impact patients’ quality of life (QoL).^8-11 Patients with NSCLC also face significant productivity losses and stigma; notably, people who do not smoke experience negative perceptions associated with lung cancer.^12-14 The adjusted 5-year and 10-year net survival rates for all forms and stages of lung cancer are estimated to be 22% and 15%, respectively.¹⁵ Recently, immune checkpoint inhibitors (ICIs), such as neoadjuvant nivolumab with chemotherapy, have shown promising results such as improved survival and tumour response.^16,17 The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of perioperative durvalumab, 1,500 mg administered as an IV infusion once every 3 weeks in combination with neoadjuvant chemotherapy before surgery and once every 4 weeks as monotherapy after surgery for the treatment of resectable NSCLC in patients without any known EGFR mutations or ALK rearrangements.

Durvalumab has been previously reviewed by Canada’s Drug Agency (CDA-AMC) for the treatment of patients with locally advanced, unresectable NSCLC following curative-intent, platinum-based chemoradiation therapy, for up to a maximum of 12 months. The final recommendation, issued on May 3, 2019, was to reimburse with conditions.¹⁸ CDA-AMC has also reviewed durvalumab in extensive-stage small cell lung cancer, biliary tract cancer, unresectable hepatocellular carcinoma, endometrial cancer, limited-stage small cell lung cancer, and metastatic NSCLC, all of which received conditional positive reimbursement recommendations.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to the CDA-AMC call for input and from clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

A joint submission was received from the Canadian Cancer Survivor Network (CCSN), Lung Cancer Canada (LCC), and Lung Health Foundation (LHF) in response to the call by CDA-AMC for patient input on the current review of durvalumab.

Information for this submission was collected via an online survey conducted by CCSN from June 11 to July 17, 2024, with input from LCC and LHF. A total of 5 respondents completed the survey, all of whom were patients with lung cancer living in Canada; 4 patients were female and 1 was male. Three of the 5 survey respondents had prior experience with durvalumab.

Respondents included patients with various stages of lung cancer, primarily stage IV. Common symptoms affecting their QoL were fatigue, pain, and shortness of breath. Chemotherapy was the most common treatment received by survey respondents, followed by immunotherapy, targeted therapy, radiation, and surgery.

According to the survey respondents, key aspects of their disease to control included managing tumour growth, shortness of breath, pain, and chemotherapy-related side effects; a lack of mental health support and difficulties accessing counselling and managing travel costs to access treatment were identified as unmet needs.

Respondents experienced a range of side effects such as joint and/or muscle pain, fatigue, nausea, and diarrhea, with 3 of 5 respondents considering these side effects intolerable. In terms of treatment goals, maintaining QoL, finding a cure, and prolonging life were prioritized, followed by delaying symptoms and improving ease of use.

Durvalumab was reported as beneficial by the 3 respondents with prior experience using it. They rated durvalumab significantly better for symptom management and disease progression compared to other therapies, with side effects being similar. All 3 respondents recommended making durvalumab available to eligible patients.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts consulted for this review felt the overarching goal of NSCLC treatment is to cure the disease and in doing so, improve OS, reduce recurrence rates, improve QoL, and reduce the symptom burden. While recent treatment advancements have improved disease outlook, survival rates and disease burden remain suboptimal. According to the clinical experts, ICIs have achieved better results compared to chemotherapy alone;¹⁹ however, atezolizumab remains the only reimbursed ICI regimen in the adjuvant setting for NSCLC in Canada and more than half of patients are ineligible for it due to low PD-L1 expression status. In the neoadjuvant setting, neoadjuvant nivolumab in combination with chemotherapy is currently funded. At the time of submission for this review in 2024, no perioperative ICI regimens were approved for resectable NSCLC in Canada. Note that since April 2025, CDA-AMC has issued a positive reimbursement recommendation for perioperative pembrolizumab for resectable NSCLC. The clinical experts noted that patient selection (e.g., based on histology, PD-L1 expression, disease stage, patient preference) is key when determining which patients will best respond to treatment regimens including the use of neoadjuvant, adjuvant, and perioperative approaches; currently, there are no robust head-to-head data to compare these treatment regimens.

The clinical experts noted that perioperative durvalumab with neoadjuvant chemotherapy would add an alternative first-line treatment option for patients with resectable NSCLC. The experts felt that patients with resectable NSCLC who are fit for systemic chemotherapy and ICI without any EGFR mutations or ALK rearrangements would be best suited for perioperative durvalumab with neoadjuvant chemotherapy. Clinical experts highlighted the importance of patient preferences when selecting treatment and that those with questionable resectable disease or who are not fit for platinum-based chemotherapy may be less suited for this approach. Experts emphasized that a short time to treatment initiation is crucial to achieve the best treatment results and the proposed requirement for EGFR and ALK testing is 1 potential area associated with treatment delay.

Outcome metrics for resectable NSCLC used in clinical practice are typically aligned with those used in clinical trials. The clinical experts stated that in clinical trials, patient response to treatment is assessed at the time of surgery using pathological complete response (pCR) and major pathological response (MPR), using survival measures such as OS and disease-free survival (DFS) (i.e., recurrence-free) according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria, and by disease symptoms. In clinical practice, response at the time of surgery using pCR is the first step to assess benefit from therapy, followed by survival, QoL outcomes (such as patient-reported outcomes [PROs]), and adverse events (AEs). In clinical practice, as in trials, clinical assessments are performed before each cycle of therapy. However, assessments of disease response and recurrence usually occur every 3 months to 6 months during treatment, every 6 months in the first 2 years following the last treatment cycle, and then annually thereafter, which is generally less frequent than in clinical trials.

Clinical experts consulted for this review indicated that perioperative durvalumab with neoadjuvant chemotherapy should be discontinued in the event of disease progression (including the tumour no longer being resectable, metastasis, and/or tumour growth) or recurrence, significant side effects such as immune-related side effects that can be life-threatening or permanent, or upon a patient’s request.

Clinical experts consulted for this review indicated that treatment with perioperative durvalumab with neoadjuvant chemotherapy should be prescribed and managed in outpatient clinics or specialty clinics by a multidisciplinary thoracic team of thoracic surgeons, medical oncologists, and supportive staff such as nursing and allied health.

Clinician Group Input

Two clinician groups provided input for this review: LCC Drug Advisory Committee (18 clinicians contributed to the input) and Ontario Health (Cancer Care Ontario) (OH-CCO) (5 clinicians contributed to the input). Overall, the input was aligned with that of the clinical experts consulted by CDA-AMC.

Both clinician groups and the clinical experts consulted agreed that the treatment paradigm for patients with resectable NSCLC who do not have EGFR mutations or ALK rearrangements consists of 2 main phases: neoadjuvant and adjuvant. Neoadjuvant therapy, administered before surgery, includes chemotherapy and ICI. OH-CCO and LCC recommend neoadjuvant platinum-based chemotherapy combined with ICI (nivolumab) for 3 cycles. Additionally, LCC noted an alternative involving chemotherapy with ICI (durvalumab) for 4 cycles. Following surgery, adjuvant therapy involves chemotherapy and/or ICI, while radiation therapy is reserved for specific cases such as positive margins, as noted by the clinical experts consulted for this review.

The common treatment goals identified across clinician groups included achieving a cure, as measured by OS, and improving DFS. LCC and the clinical experts emphasized reducing recurrence rates and enhancing QoL.

The most significant treatment gap identified by the 2 clinician groups and the clinical experts is the lack of data comparing the efficacy and role of adjuvant ICI following neoadjuvant therapy, including which patients might benefit from it. This uncertainty makes it challenging to determine the optimal strategy for improving survival outcomes, especially given that not all patients respond to current treatments. Presently, ICI in the adjuvant setting is only available to those with high PD-L1 expression.

Both clinician groups and the clinical experts stated that perioperative durvalumab combined with neoadjuvant chemotherapy would offer an alternative treatment approach to neoadjuvant nivolumab in combination with chemotherapy for resectable NSCLC. The clinical experts emphasized its importance, especially for patients who do not achieve a complete pathological response to neoadjuvant therapy, highlighting the potential value of adjuvant ICI in such cases.

According to the clinician groups, the best-suited patients for perioperative durvalumab in combination with neoadjuvant chemotherapy are those with resectable NSCLC, no EGFR mutations or ALK rearrangements, and no contraindications to ICI. They emphasized the role of CT scans for monitoring, with imaging recommended before and after surgery and at regular intervals during and after treatment to check for disease recurrence. In clinical practice, treatment response is assessed through clinical symptoms, survival outcomes (OS and DFS), and pathological response at surgery (pCR and MPR), as highlighted by the clinical expert.

Both clinician groups indicated that factors for discontinuing treatment primarily include disease progression and significant side effects, with patient preferences also playing a key role. For treatment with perioperative durvalumab with neoadjuvant chemotherapy, patients should be treated in an outpatient setting under the supervision of a medical oncologist, or a pulmonologist experienced in the management of thoracic malignancies.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. Key factors identified that could potentially impact the implementation of the CDA-AMC recommendation for perioperative durvalumab with neoadjuvant chemotherapy were the use of alterative chemotherapies in the neoadjuvant phase, identifying which patients should be eligible for reimbursement, and the acceptability of switching treatments.

Clinical Evidence

Systematic Review

Description of Studies

One ongoing trial, a phase III, double-blind, placebo-controlled, randomized, multicentre, international study (including 5 sites in Canada) — the AEGEAN study — met the inclusion criteria for the systematic review conducted by the sponsor. The AEGEAN study was aimed at comparing the efficacy and activity of perioperative durvalumab with neoadjuvant chemotherapy to placebo with neoadjuvant chemotherapy. Following confirmation of eligibility, a total of 802 patients (including 8 patients in Canada) were randomized in a 1:1 ratio (intention-to-treat [ITT] population) using stratified randomization into the 2 treatment arms. Stratified randomization was conducted according to disease stage II versus stage III (AJCC [American Joint Committee on Cancer] Cancer Staging Manual, eighth edition, for tumour-nodes-metastasis [TNM] classification) and PD-L1 expression tumour cells of less than 1% versus tumour cells of 1% or more. Following a protocol amendment, 62 patients with known EGFR mutations or ALK rearrangements were excluded, leaving 740 patients in the modified intention-to-treat (mITT) population: 366 patients included in the perioperative durvalumab with neoadjuvant chemotherapy arm and 374 patients included in the placebo with neoadjuvant chemotherapy arm. The outcomes relevant to this review included the final pCR and MPR analyses performed at the November 10, 2022, data cut-off (DCO) date, and event-free survival (EFS), DFS, OS, PROs, and harms data collected at the May 10, 2024, DCO.

In the AEGEAN study, patients identified primarily as Asian (307 of 740 patients [41.5%]) or white (397 of 740 patients [53.6%]); all other races (including American Indian or Alaska Native, Black or African American, and other) accounted for 36 of 740 patients (4.9%). Patients were also primarily aged 50 years or older (703 of 740 patients [95.0%]) with a median age of 65.0 years (range, 39 years to 85 years); whereas 210 of 740 patients (28.4%) were female, most patients were male (530 of 740 patients [71.6%]). Most patients also either currently or formerly smoked (633 of 740 patients [85.5%]). Overall, at baseline, patients tended to have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 (506 of 740 patients [68.4%]), present with stage III disease (525 of 740 patients [70.9%]), and have a baseline PD-L1 expression status greater than or equal to 1% (493 of 740 patients [66.6%]). In total, | patients had unknown EGFR mutation status and ██ patients had unknown ALK translocation status; these patients were balanced across both treatment arms.

Efficacy Results

Efficacy outcomes presented as follows are from the most recent DCOs (November 10, 2022, for pCR, MPR, and neoadjuvant QoL outcomes and May 10, 2024, for all other outcomes).

Pathological Complete Response

pCR was tested at the pCR IA (the DCO date was January 14, 2022), where it was deemed statistically significant, and thus, statistical significance was not retested in the final analysis.

At the November 10, 2022, DCO, the final pCR analysis was completed. The percentage of patients achieving pCR was 17.21% (95% confidence interval [CI], 13.49% to 21.48%) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 4.28% (95% CI, 2.46% to 6.85%) in the placebo with neoadjuvant chemotherapy arm. The between-group difference in the percentage of patients achieving pCR was 12.96% (95% CI, 8.67% to 17.57%). Results of the sensitivity and subgroup analysis were consistent with the primary analysis.

Major Pathological Response

MPR statistical significance was tested at the pCR IA (the DCO date was January 14, 2022) where it was deemed statistically significant and thus, statistical significance was not retested at the final analysis.

At the November 10, 2022, DCO, the percentage of patients achieving MPR was 33.33% (95% CI, 28.52% to 38.42%) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 12.30% (95% CI, 9.15% to 16.06%) in the placebo with neoadjuvant chemotherapy arm. The between-group difference in the percentage of patients achieving MPR was 21.03% (95% CI, 15.14% to 26.93%).

Event-Free Survival

At the May 10, 2024, DCO, the median duration of EFS follow-up was █████ months (range, ███ to ████), at which point 124 EFS events (33.9%) had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm and 165 EFS events (44.1%) in the placebo with neoadjuvant chemotherapy arm. The Kaplan-Meier (KM) estimate for median EFS was not reached (NR) (95% CI, 42.3 months to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and was 30.0 months (95% CI, 20.6 months to NR) in the placebo with neoadjuvant chemotherapy arm, with a hazard ratio (HR) of 0.69 (95% CI, 0.55 to 0.88; P = █████). The between-group difference in the probability of EFS at 12 months and 36 months was 9.2% (95% CI, ███ ██ ████) and 12.2% (95% CI, ███ ██ ████), respectively. Results of the sensitivity and subgroup analysis were consistent with the primary analysis.

Disease-Free Survival

At the May 10, 2024, DCO, DFS was tested and did not meet the prespecified boundary for declaring statistical significance. The median of DFS follow-up was █████ months (range, ███ to ████), at which point 60 DFS events (24.8%) had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 81 DFS events (35.1%) in the placebo with neoadjuvant chemotherapy arm. The KM estimate for median DFS was NR (95% CI, NR to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and NR (95% CI, 41.5 months to NR) in the placebo with neoadjuvant chemotherapy arm, with a stratified HR of 0.66 (95% CI, 0.47 to 0.92). The between-group difference in the probability of DFS at 12 months and 36 months was 6.9% (95% CI, ████ ██████) and 9.8% (95% CI, ████ ██ ████), respectively.

Overall Survival

At the EFS interim analysis 2 (IA2) DCO, OS was not eligible for statistical testing (this is because DFS was not statistically significant and therefore, OS was not formally tested based on the multiple testing procedure [MTP]).

At the May 10, 2024, DCO, the median duration of OS follow-up was █████ months (range, ███ to ████), at which point 121 deaths (33.1%) had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm and 140 deaths (37.4%) in the placebo with neoadjuvant chemotherapy arm. The KM estimate for median OS was NR (95% CI, NR to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 53.2 months (95% CI, 44.3 months to NR) in the placebo with neoadjuvant chemotherapy arm, with a stratified HR of 0.89 (95% CI, 0.70 to 1.14). The between-group difference in the probability of survival at 12 months and 48 months was −1.0% (95% CI, ████ ██ ███) and 4.7% (95% CI, ████ ██ ████), respectively.

EORTC QLQ-C30 Global Health Status and QoL

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) questionnaire-based outcomes were secondary end points and not adjusted for multiplicity in the AEGEAN trial.

The change from baseline to week 12 in the EORTC QLQ-C30 global health status and QoL score was evaluated in the mITT population (n = 740) while the change from adjuvant baseline to week 44 was evaluated in the modified resected set (n = 473). The between-group difference for EORTC QLQ-C30 at week 12 of the neoadjuvant period was █████ (95% CI, █████ ██ █████. The between-group difference for EORTC QLQ-C30 at week 44 of the adjuvant period was █████ (95% CI, █████ ██ █████).

Harms Results

Safety outcomes presented as follows are from the May 10, 2024, DCO.

An overview of safety data is initially presented for the modified safety analysis set (consisting of all patients in the AEGEAN trial who received at least 1 dose of the study treatment and excluding those whose tumours had EGFR mutations or ALK gene rearrangements [N = 367 for the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 370 for the placebo with neoadjuvant chemotherapy arm]). Because granular safety data were not available for the modified safety analysis set, additional data are presented for the safety analysis set, which consists of all randomized patients who received at least 1 dose of study treatment, with treatment arm allocation in accordance with the treatment actually received. The safety analysis set consisted of 799 patients (N = 401 in the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 398 in the placebo with neoadjuvant chemotherapy arm).

Adverse Events

In the modified safety analysis set, a ███████ percentage of patients in both treatment arms experienced any AE over the course of treatment (█████ ████████ in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ ████████ in the placebo with neoadjuvant chemotherapy arm). The 3 most frequently reported AEs in both treatment arms of the safety analysis set were anemia (34.9% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 32.2% in the placebo with neoadjuvant chemotherapy arm), nausea (25.7% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 29.9% in the placebo with neoadjuvant chemotherapy arm), and constipation (25.9% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 29.9% in the placebo with neoadjuvant chemotherapy arm).

Serious AEs

████████ ████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set experienced a serious adverse event (SAE) (█████ ██████████ than in the placebo with neoadjuvant chemotherapy arm (█████ █████████). In the safety analysis set, the 4 most frequently reported SAEs in the perioperative durvalumab with neoadjuvant chemotherapy arm were pneumonia (5.7%), anemia (1.7%), COVID-19 (1.7%), and pneumonitis (1.7%) while in the placebo with neoadjuvant chemotherapy arm, it was pneumonia (4.5%), pneumothorax (2.3%), anemia (1.3%), and COVID-19 (1.3%).

Withdrawals Due to AEs

████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set prematurely stopped study treatment (i.e., durvalumab, placebo, or neoadjuvant chemotherapy) due to AEs than in the placebo with neoadjuvant chemotherapy arm (█████ ███████ versus █████ ███████, respectively). In the safety analysis set, the 3 most common AEs leading to treatment discontinuation were blood and lymphatic system disorders (██████ respiratory, thoracic, and mediastinal disorders ███████ and nervous system disorder ██████ in the perioperative durvalumab with neoadjuvant chemotherapy arm compared to respiratory, thoracic, and mediastinal disorders (████), investigations (████), and blood and lymphatic system disorders (████) and nervous system disorder █████) in the placebo with neoadjuvant chemotherapy arm.

Mortality

As of May 10, 2024, in the modified resected set ████ ████████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and ████ ████████ of patients in the placebo with neoadjuvant chemotherapy arm experienced an AE resulting in death. In the safety analysis set, the 2 most common AEs resulting in death in the perioperative durvalumab with neoadjuvant chemotherapy arm were infections and infestations (3.2%) and respiratory, thoracic, and mediastinal disorders (1.5%) compared to infections and infestations (1.8%) and cardiac disorders (0.8%) in the placebo with neoadjuvant chemotherapy arm.

Immune-Mediated AEs

Immune-mediated AEs (imAEs) occurred in █████ ████████) of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and in █████ ███████) of patients in the placebo with neoadjuvant chemotherapy arm.

Critical Appraisal

The AEGEAN study is a double-blind, placebo-controlled, phase III, randomized controlled trial (RCT). Randomization and allocation concealment methods were adequate. The postrandomization exclusion of those with known EGFR mutations or ALK rearrangements were judged not to be related to treatment group assignment and therefore, are not expected to introduce bias.

To mitigate the potential bias arising from the subjective interpretation of disease progression and tumour response, a blinded independent review committee (IRC) reviewed all available radiographic tumour assessments to determine tumour response based on Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) criteria. As such, the risk of bias resulting from unblinding due to unbalanced harms across treatment arms is lower for pCR, MPR, and survival outcomes; however, there are some concerns for health-related quality of life (HRQoL) outcomes. While pCR and MPR are based on final analyses, EFS, DFS, OS, and HRQoL results should be interpreted in light of the fact that these are based on interim analyses (IAs) that may overestimate treatment effects.²⁰ At the most recent AEGEAN study DCO, results of the coprimary end points, pCR and EFS, were adjusted using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries that accounted for the actual number of patients at the time of analyses at an overall alpha of 0.5% and 4.5%, respectively. DFS and OS were included in the AEGEAN study’s MTP; OS was not eligible for statistical testing because DFS was not statistically significant. While there was an adequate number of patients at risk in the AEGEAN trial for earlier DFS and OS time points, only about 11% of patients in both treatment arms remained at risk for OS at 48 months and 13% to 19% remained at risk for DFS at 36 months, resulting in substantial uncertainty in results at later time points.

Biases resulting from the self-reporting nature of HRQoL outcomes were deemed to be minimal given that participants were blinded to the intervention received. In the EORTC QLQ-C30 analyses, aimed at estimating the impact to patients’ HRQoL, █████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ of patients in the placebo with neoadjuvant chemotherapy arm were available to provide assessments at week 12 of the neoadjuvant period. In the modified resected set, by week 44 of the adjuvant period █████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ of patients in the placebo with neoadjuvant chemotherapy arm were available to provide EORTC QLQ-C30 assessments. No data imputations were involved in these analyses, so there is a risk of bias due to missing outcomes data. Further, because analyses of the HRQoL end points were not adjusted for multiple testing, there is an increased risk of type I error for statistically significant results.

Given that the analysis of EORTC QLQ-C30 in the adjuvant period, as well as the DFS analyses, were limited to the modified resected set (n = 473) and because this is a subgroup of the mITT population (n = 740), randomization is not maintained and results are not measuring the effect of assignment to the intervention.

The outcomes measured in the AEGEAN trial evaluated the key treatment goals identified by patients’ input collected for this review and were deemed to be relevant by clinical experts consulted for this review. The generalizability of outcomes in the AEGEAN trial to the context in Canada is limited by the fact that only 8 patients included in the ITT population were from Canada. However, this limitation was deemed minimal by the clinical experts consulted for this review, who noted that the baseline characteristics of patients enrolled in the AEGEAN trial were aligned with those seen in clinical practice in Canada. The clinical experts consulted for this review noted that currently, the 2 most commonly used regimens in clinical practice in Canada are neoadjuvant nivolumab with chemotherapy and adjuvant chemotherapy. According to the clinical experts consulted for this review, adjuvant atezolizumab after surgery and adjuvant chemotherapy for patients with PD-L1 of 50% or greater was the least relevant comparator because the treatment decision for perioperative durvalumab has to be made before surgery, whereas the approach for adjuvant atezolizumab would be considered after surgery and adjuvant chemotherapy. In addition to the standard of care chemotherapy regimens used in the AEGEAN trial, clinical experts indicated that in Canada, carboplatin and gemcitabine could also be used for squamous cell NSCLC and cisplatin and vinorelbine may also sometimes be used for both squamous and nonsquamous cell NSCLC. The lack of these regimens used for standard chemotherapy in the AEGEAN trial further limits the generalizability to the setting in Canada; however, clinical experts consulted for this review noted that they would feel comfortable combining perioperative durvalumab with these regimens.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of the evidence for outcomes considered most relevant to inform deliberations by the CDA-AMC expert committee, and a final certainty rating was determined as outlined by the GRADE Working Group.^21,22 Following the GRADE approach, evidence from RCTs started as high certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• OS (probabilities at 12 months and 48 months), EFS (probabilities at 12 months and 36 months), and pCR

• HRQoL (change in EORTC QLQ-C30 global health status and QoL score from adjuvant baseline to week 12 and neoadjuvant baseline to week 44)

• harms (imAEs and SAEs).

Table 2 presents the GRADE summary of findings for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy for adults with resectable NSCLC without any EGFR mutations or ALK rearrangements.

Table 2: Summary of Findings for Perioperative Durvalumab With Neoadjuvant Chemotherapy vs. Placebo With Neoadjuvant Chemotherapy

AE = adverse event; CI = confidence interval; EFS = event-free survival EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; IA1 = interim analysis 1; IA2 = interim analysis 2; KM = Kaplan-Meier; NA = not applicable; NSCLC = non–small cell lung cancer; NR = not reported; OS = overall survival; pCR = pathological complete response; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in EFS at 12 months based on a clinically important between-group difference threshold of 5% to 10% suggested by clinical experts; however, the lower bound of the 95% CI crosses this threshold. The between-group difference in the probability of EFS was requested from the sponsor to aid in the interpretation of the results for this end point.

^bCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in EFS at 36 months based on a clinically important between-group difference threshold of 5% to 10% suggested by clinical experts; however, the lower bound of the 95% CI crosses this threshold. The between-group difference in the probability of EFS was requested from the sponsor to aid in the interpretation of the results for this end point.

^cCertainty was not rated down for study limitations, indirectness, or imprecision. The clinical expert consulted for this review suggested that a 5% to 10% between-group difference could be considered clinically meaningful. OS was not eligible for statistical testing at EFS IA2. The results are considered as supportive evidence. The between-group difference in survival probability was requested from the sponsor to aid in the interpretation of the results for this end point.

^dCertainty was not rated down for indirectness. Rated down 1 level due to serious study limitations. Visual inspection of the KM curves suggests substantial censoring after 24 months in both groups and few patients at risk at 48 months, contributing to uncertainty in the OS results. Rated down 1 level for imprecision. The point estimate suggests little to no difference while the upper bound of the 95% CI indicates benefits based on a clinically important between-group difference threshold of 5% to 10% suggested by clinical experts. OS was not eligible for statistical testing at EFS IA2. The results are considered as supportive evidence. The between-group difference in survival probability was requested from the sponsor to aid in the interpretation of the results for this end point.

^eCertainty was not rated down for indirectness or imprecision. Rated down 2 levels due to missing data in both arms at week 12 (█████ missing in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ in the placebo with neoadjuvant chemotherapy arm). EORTC QLQ-C30 was not adjusted for multiplicity in the trial and should be considered as supportive evidence.

^fCertainty was not rated down for indirectness. Rated down 2 levels due to missing data in both arms at week 44 (█████ missing in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ in the placebo with neoadjuvant chemotherapy arm) and given the modified resected set was analyzed, there may not be prognostic balance between the treatment groups. Rated down a third level for imprecision. ███ █████ ████████ ████████ ███████████ ██████ ██ █████ █████ ███ █████ █████ ██ ███ ███ ██ ███████ ███ █████████ █████████ ██████████ █████████ ██ ██ ██████████ ██ ███ ██████████. EORTC QLQ-C30 was not adjusted for multiplicity in the trial and should be considered as supportive evidence.

^gCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in pCR based on a clinically important between-group difference threshold of 10% suggested by clinical experts; however, the lower bound of the 95% CI crosses this threshold.

^hCertainty was not rated down for study limitations, indirectness, or imprecision. The clinical expert consulted for this review suggested that a 10% between-group difference could be considered clinically meaningful. The between-group difference was requested from the sponsor to aid in the interpretation of the results.

ⁱCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests little to no difference while the upper bound of the 95% CI indicates a clinically important increase in serious AEs based on a clinically important between-group difference threshold of 10% suggested by clinical experts. The between-group difference was requested from the sponsor to aid in the interpretation of the results.

Sources: AEGEAN study EFS IA1 Clinical Study Report²⁴ and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Comparisons

Description of Studies

Due to the lack of direct evidence comparing perioperative durvalumab (durvalumab in combination with chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery) with relevant comparator regimens, including neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant chemotherapy, and surgery only in the treatment of patients with resectable (tumours ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, the sponsor conducted indirect treatment comparisons (ITCs), including 2 matching-adjusted indirect comparisons (MAICs) and a network meta-analysis (NMA).

Efficacy Results

The MAIC analyses were insufficient to inform whether perioperative durvalumab or the comparator therapies were favoured for EFS. The 95% CIs (or credible intervals [CrIs] for the random-effects NMA) were wide and included the potential that either of the treatments being compared could be favoured. No other efficacy outcomes were assessed in the ITCs.

Harms Results

No ITCs were done for harms outcomes.

Critical Appraisal

Overall, the ITCs (2 MAICs and 1 NMA) were conducted according to accepted methodological guidance. The potential key limitations of the MAIC analyses included the fact that not all important effect modifiers (EMs) could be adjusted in the analysis. Furthermore, the MAIC methods reduced the effective sample size in both comparisons (████ reduction in the base-case analysis for the comparison versus neoadjuvant nivolumab while a smaller reduction [15% to 17%] occurred in the pembrolizumab comparison). Such reductions in effective sample size may indicate limited overlap in baseline characteristics between the trial populations and increase uncertainty in the weighted estimates. Imprecision (wide 95% CIs) in the effect estimates precluded conclusions as to whether perioperative durvalumab or the comparator therapies were favoured for EFS.

The potential key limitation of the NMA was the heterogeneity (in EMs) across the included studies in terms of the study designs and patient characteristics; notably, some included studies were conducted starting before 1990 and the standard of care has changed since that time. Given differences across studies in staging and tumour assessment criteria, the use of second-generation chemotherapy agents, and other unmeasured characteristics potentially impacting outcomes (e.g., smoking status was infrequently reported), the plausibility of the transitivity assumption is uncertain. In addition, several studies met the inclusion criteria for the ITC but were excluded due to the absence of EFS KM curves and HRs. The impact of the exclusion of these studies on the NMA results was unknown; however, there is a risk of bias due to missing evidence in the synthesis. Finally, all evidence networks were sparse, with no closed loops formed by multiple studies. The CrIs for all effect estimates (per the random-effects model) were wide, precluding conclusions as to whether perioperative durvalumab or the comparator therapies were favoured for EFS.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the systematic review evidence were submitted by the sponsor.

Conclusions

The AEGEAN study — a phase III, double-blind, placebo-controlled, international RCT — compared the efficacy and safety of perioperative durvalumab with neoadjuvant chemotherapy with placebo and neoadjuvant chemotherapy in adult patients with resectable NSCLC and no known EGFR mutations or ALK rearrangements. The AEGEAN trial demonstrated that there were added clinical benefits of perioperative durvalumab in pCR and EFS. Compared to placebo with neoadjuvant chemotherapy, perioperative durvalumab with neoadjuvant chemotherapy likely results in a clinically important increase in the number of patients achieving pCR (moderate certainty evidence) and a clinically important increase in EFS rates at 12 months and 36 months (moderate certainty evidence). Results for DFS, a key secondary outcome, were supportive of the primary EFS analyses. Per EFS IA2, perioperative durvalumab with neoadjuvant chemotherapy may result in little to no difference in the probability of being alive at 48 months; however, survival data remained immature (IA2 DCO indicated 35% of patients had died). Results for EFS from the ITCs comparing perioperative durvalumab with neoadjuvant chemotherapy versus neoadjuvant nivolumab plus chemotherapy, perioperative pembrolizumab plus neoadjuvant chemotherapy followed by adjuvant pembrolizumab, adjuvant chemotherapy, and surgery only were inconclusive, owing to methodological limitations and imprecision. Based on the AEGEAN trial, perioperative durvalumab with neoadjuvant chemotherapy, compared to neoadjuvant chemotherapy, likely results in little to no difference in QoL during the neoadjuvant period (moderate certainty evidence) and may result in clinically meaningful deterioration in HRQoL in the adjuvant period; however, these results had a high degree of missing data and adjuvant results were limited to only those achieving complete resection. According to clinical experts consulted for this review, the safety profile of perioperative durvalumab with neoadjuvant chemotherapy was consistent with their expectations and deemed acceptable. Harms were not investigated in the ITCs, so whether perioperative durvalumab with neoadjuvant chemotherapy results in an increase or decrease in harms compared with other therapies used in Canada is unknown.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of perioperative durvalumab, 1,500 mg administered as an IV infusion once every 3 weeks in combination with neoadjuvant chemotherapy before surgery and once every 4 weeks as monotherapy after surgery for the treatment of resectable NSCLC in patients without any known EGFR mutations or ALK rearrangements.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

Lung cancer is the most frequently diagnosed cancer in Canada and the leading cause of cancer-related deaths. In 2024 alone, approximately 32,100 Canadians were expected to be diagnosed with lung cancer, and 20,700 annual deaths were expected to be attributable to lung cancer.¹ Lung cancer predominantly affects older adults, with 98% of cases occurring in individuals aged 50 years and older.² The adjusted 5-year and 10-year net survival rates for all forms and stages of lung cancer are estimated to be 22% and 15%, respectively.¹⁵ In Canada, Indigenous Peoples face significant lung cancer disparities. First Nations adults have a 35% lower 5-year survival rate despite similar incidence rates; Métis adults are more likely to be diagnosed and have a 30% lower 5-year survival rate, and Inuit living in Inuit Nunangat (the Arctic homeland of Inuit in Canada) are more than twice as likely to be diagnosed.²⁵

Lung cancer is classified as either NSCLC or small cell lung cancer, with NSCLC accounting for approximately 88% of all lung cancer cases in Canada, excluding Quebec. NSCLC can be further categorized into adenocarcinoma, which is the most common type of lung cancer accounting for 48% of cases, followed by squamous cell carcinoma (20% of cases), and NSCLC not otherwise specified (20% of cases).²⁶ To date, several molecular alterations have been identified in NSCLC, with the 2 prominent ones being EGFR mutations and ALK rearrangements. EGFR mutations are particularly common in adenocarcinomas, resulting in abnormal signalling pathways that drive tumour growth.²⁷ Similarly, ALK rearrangements occur through gene fusions, leading to abnormal cell proliferation.²⁸ Driver alterations affect a small proportion of patients with NSCLC.²⁹ EGFR mutations are identified in about 10% to 30% of patients with nonsquamous NSCLC, while ALK and ROS1 rearrangements occur in about 2% to 5% and in about 1% to 4%, respectively, of nonsquamous NSCLC tumours. BRAF mutations are observed in 2% of patients with NSCLC.²⁹

NSCLC diagnosis begins with a comprehensive medical history, smoking assessment, and standard tests, including evaluations of lung, renal, and liver function, along with blood and biochemistry tests.⁷ Imaging techniques such as X-rays, CT scans, PET scans of the chest and abdomen, and MRI of the central nervous system are then used before tissue biopsy is performed to confirm the diagnosis.^30,31 To determine the prognosis and best course of treatment, NSCLC is staged using the AJCC staging criteria, which involves TNM classification based on the size and spread of the primary tumour (“T”), lymph node involvement (“N”), and distant metastasis (“M”).⁷

Approximately 25% to 30% of patients with NSCLC present with resectable early-stage disease (stage II to stage III),^3,4 and are usually treated with surgery and chemotherapy.³² However, an estimated 30% to 55% of patients continue to develop postoperative recurrence and ultimately die due to NSCLC.⁵

Patients with NSCLC experience a variety of symptoms, including dyspnea, malaise, depression, anxiety, worsening cough, hemoptysis, pain, weight loss, and hoarseness.^6,7 These symptoms, coupled with disease outlook, treatment modalities and side effects, and other comorbidities common among patients with NSCLC, significantly impact patients’ QoL.^8-11 Patients with NSCLC also face significant productivity losses and stigma; notably, those who do not smoke experience negative perceptions associated with lung cancer.^12-14

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

The treatment goal for patients with early-stage NSCLC is to achieve a complete cure, improve OS and DFS, reduce disease recurrence rates, reduce symptoms, and improve QoL.

Before establishing a treatment plan, tumours should receive molecular testing to identify the presence of any oncogenic drivers and identify their PD-L1 status.³³ In patients without EGFR mutations or ALK rearrangements with stage II to stage IIIB NSCLC, the standard of care is surgery with curative intent.^32,34,35 Given that surgery alone is suboptimal at eliminating and/or eradicating micrometastases, guidelines recommend additional systemic therapy with platinum-based chemotherapy alone or in combination with ICIs, either before or after surgery.^32,36 While postoperative radiotherapy (PORT) is not recommended in patients with completely resected early-stage NSCLC, PORT may be considered in the case of R1 (microscopic residual tumour) resection.³⁷ This treatment pathway excludes patients who have EGFR or ALK alterations because these patients have limited response to immunotherapy and are treated with targeted treatment options.³⁸

Neoadjuvant Therapies

In Canada, the standard of care in the neoadjuvant setting has historically been surgery followed by systemic therapy or neoadjuvant chemoradiation followed by surgery; however, guidelines now support the use of neoadjuvant ICI treatment options. Neoadjuvant treatment with nivolumab (a PD-1 inhibitor) in combination with platinum-based chemotherapy followed by surgery and optional adjuvant platinum-based chemotherapy is recommended and widely funded by provincial drug plans for patients with stage IB and stage IIIA (AJCC Cancer Staging Manual, seventh edition, TNM classification) resectable (tumours ≥ 4 cm or node positive) NSCLC. Neoadjuvant nivolumab in combination with platinum-based chemotherapy received a positive conditional CDA-AMC final recommendation in 2023. In April 2025, CDA-AMC issued a conditional positive final recommendation for pembrolizumab for the treatment of adult patients with resectable stage II, stage IIIA, or stage IIIB (T3-4N2) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment and then continued as monotherapy in the adjuvant setting.

Adjuvant Therapies

Curative-intent surgery followed by adjuvant chemotherapy is the established standard of care in Canada for patients with resectable NSCLC. Adjuvant chemotherapy regimens include up to 4 cycles of platinum-based chemotherapy, where regimen selection is based on a patient’s histology (squamous versus nonsquamous).³⁹

For patients who did not receive treatment with an ICI drug in the neoadjuvant setting, ICI treatment with either atezolizumab or pembrolizumab (PD-L1 inhibitors) can be considered following surgical resection and completion of adjuvant chemotherapy.^40,41 In the setting in Canada, up to 16 cycles of atezolizumab following complete surgical resection and adjuvant chemotherapy is funded by drug plans participating in the CDA-AMC reimbursement review process for tumours with PD-L1 of 50% or greater. In February 2025, CDA-AMC issued a conditional positive final recommendation for pembrolizumab for the adjuvant treatment of adult patients with stage IB (tumour stage IIA [T2a] ≥ 4 cm), stage II, or stage IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy and whose tumours have a PD-L1 tumour proportion score of less than 50%. However, because this current file for perioperative durvalumab was initiated before the final recommendation for adjuvant pembrolizumab was issued, adjuvant pembrolizumab was not considered a relevant comparator for this review. It is important to note that there are no data to support a switch from the use of a neoadjuvant ICI treatment to an alternative adjuvant ICI treatment; as such, the back-to-back use of ICI therapies is not currently funded by drug plans participating in the CDA-AMC reimbursement review process or by cancer agencies.⁴²

Drug Under Review

Key characteristics of durvalumab are summarized in Table 3 with other treatments available for resectable NSCLC without any known EGFR mutations or ALK rearrangements.

Durvalumab 1,500 mg, single-use IV infusion, as neoadjuvant treatment in combination with platinum-containing chemotherapy, followed by durvalumab as monotherapy after surgery, for the treatment of patients with resectable stage II, stage IIIA, or stage IIIB (T3-4N2) NSCLC and no known EGFR mutations or ALK rearrangements received Health Canada authorization on February 20, 2026. While the sponsor’s reimbursement request is the same as the Health Canada indication, the wording between the 2 differs slightly (i.e., the Health Canada indication specifies the use of platinum-containing chemotherapy and includes specific NSCLC stages while the reimbursement request does not include these 2 items).

Durvalumab has been previously reviewed by CDA-AMC for the treatment of patients with locally advanced, unresectable NSCLC following curative-intent, platinum-based chemoradiation therapy, for up to a maximum of 12 months. The final recommendation, issued on May 3, 2019, was to reimburse with conditions.¹⁸ CDA-AMC has also reviewed durvalumab in extensive-stage small cell lung cancer, biliary tract cancer, unresectable hepatocellular carcinoma, endometrial cancer, limited-stage small cell lung cancer, and metastatic NSCLC, all of which received conditional reimbursement recommendations. The FDA and European Medicines Agency have approved durvalumab for the present indication under review.^43,44

Durvalumab is a fully human, high-affinity, immunoglobulin G1 kappa monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and cluster of differentiation 80 (B7.1) while leaving PD-1 and/or PD-L2 interaction intact. Durvalumab does not induce antibody-dependent cell-mediated cytotoxicity. The selective blockade of PD-L1 and/or PD-1 and PD-L1 and/or cluster of differentiation 80 interactions releases the inhibition of immune responses and enhances antitumour immune responses.⁴⁵

Table 3: Key Characteristics of Durvalumab, Nivolumab, and Atezolizumab, and Platinum-Based Chemotherapies

AJCC = American Joint Committee on Cancer; AUC 5 = area under the serum drug concentration-time curve 5; AUC 6 = area under the serum drug concentration-time curve 6; CD80 = cluster of differentiation 80; HSCT = hematopoietic stem-cell transplant; IgG1 = immunoglobulin G1; IgG4 = immunoglobulin G4; NSCLC = non–small cell lung cancer; OH-CCO = Ontario Health (Cancer Care Ontario); SJS = Stevens-Johnson syndrome, TC = tumour cell; TEN = toxic epidermal necrolysis; UICC = Union for International Cancer Control.

^aHealth Canada–approved indication.

Sources: Kris (2017),⁴⁶ Cancer Care Alberta,³⁹ and product monographs for durvalumab (Imfinzi),⁴⁵ pembrolizumab (Keytruda),⁴⁷ nivolumab (Opdivo),⁴⁸ atezolizumab (Tecentriq),⁴⁹ paclitaxel,⁵⁰ pemetrexed,⁵¹ vinorelbine,⁵² gemcitabine,⁵³ cisplatin,⁵⁴ and carboplatin.⁵⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

A joint submission was received from CCSN, LCC, and LHF in response to the call by CDA-AMC for patient input on the current review of durvalumab.

Information for this submission was collected via an online survey conducted by CCSN from June 11 to July 17, 2024, with input from LCC and LHF. The survey was disseminated across various platforms and organizations to collect responses.

A total of 5 respondents, all of whom were patients with lung cancer living in Canada, completed the survey; 4 respondents were female and 1 was male.

Respondents reported various stages of lung cancer, including stage IVA (n = 2), stage IVB (n = 1), and other stage IV classifications (n = 2). Common symptoms affecting their QoL included fatigue (n = 5), pain (n = 3), and shortness of breath (n = 2). Current treatments varied, with chemotherapy being the most common (n = 4), followed by immunotherapy (n = 3), targeted therapy (n = 2), radiation (n = 2), and surgical therapy (n = 1).

When asked about the most important aspects of their disease to control, respondents prioritized managing tumour growth, shortness of breath, and pain and side effects associated with chemotherapy. Survey respondents also identified the following unmet needs: a lack of mental health support, difficulties accessing counselling, and managing travel costs to access treatment. Respondents emphasized the importance of tumour control, managing symptoms, enhancing research and support for lung cancer, and the availability of alternative treatments in their cancer journey.

Respondents reported experiencing a range of adverse effects from their treatments, with joint and muscle pain being the most common, followed by fatigue and diarrhea, and, less frequently, neuropathy, weight loss, anemia, nausea, vomiting, and constipation. Three of the 5 patients considered these side effects intolerable, while 2 managed them with daily acetaminophen.

When asked to rate the importance of issues a new drug should address on a scale of 1 to 7 (with 1 being most important and 7 being least important), respondents prioritized maintaining QoL, providing a cure, and prolonging life, followed by delaying symptoms and improving ease of use. Reducing side effects and the importance of access to new treatment options were also valued, albeit to a lesser degree.

Respondents were asked to rate the level of side effects they would tolerate to extend survival by 2 months, 6 months, or 12 months, with side effects including nausea, fatigue, vomiting, and diarrhea. They reported varying tolerances, from mild effects for short-term extensions to severe effects for longer extensions. When asked about considerations for balancing the advantages and disadvantages of treatment, respondents mentioned factors such as the desire to extend life, maintaining comfort, keeping tumours stable, QoL, time with family, and the potential for new treatments.

Three of the 5 survey respondents had prior experience with durvalumab; these patients reported fatigue as the main adverse effect of durvalumab, with 1 experiencing hives. Respondents described the drug as beneficial, noting it helped keep tumours stable while allowing them to feel normal. Durvalumab was rated much better for symptom management and disease progression compared to other therapies, with little or no difference in side effects and ease of use. All 3 respondents noted that they would recommend durvalumab be available to all patients who qualify for it.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding 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, 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 for this review felt the overarching goal of NSCLC treatment is to cure the disease and in doing so, improve OS, reduce recurrence rates, improve QoL, and reduce the symptom burden. While recent treatment advancements have improved disease outlook, survival rates and disease burden remain suboptimal. According to the clinical experts, ICIs have achieved better results compared to chemotherapy alone; however, atezolizumab following adjuvant chemotherapy remains the only approved ICI regimen in the adjuvant resectable NSCLC setting in Canada and more than half of patients are ineligible for it due to low PD-L1 expression status. In the neoadjuvant setting, neoadjuvant nivolumab in combination with chemotherapy is currently funded. At the time of submission for this review in 2024, no perioperative ICI regimens had been approved for resectable NSCLC in Canada. Note that since April 2025, CDA-AMC has issued a positive reimbursement recommendation for perioperative pembrolizumab for resectable NSCLC. The clinical experts noted that patient selection (e.g., based on histology, PD-L1 expression, disease stage, patient preference) is key when determining which patients will best respond to treatment regimens including the use of neoadjuvant, adjuvant, and perioperative approaches; currently, there are no robust head-to-head data to compare these treatment regimens.

Place in Therapy

The experts felt that perioperative durvalumab with neoadjuvant chemotherapy would add an alternative first-line treatment option for patients with resectable NSCLC. Compared to current treatment options, the clinical experts noted that perioperative durvalumab with neoadjuvant chemotherapy would address the underlying disease process in addition to potentially improving symptoms. The clinical experts anticipated that this additional treatment option would be especially important for those patients identified as potentially not achieving a complete response at the time of surgery; however, currently, there is no evidence to support this.

Patient Population

The clinical experts noted that patients with resectable NSCLC who are fit for systemic chemotherapy and immunotherapy without any EGFR mutations or ALK rearrangements would be best suited for perioperative durvalumab with neoadjuvant chemotherapy. Patients’ preferences should be taken into consideration and patients with questionable resectable disease or who are not fit for platinum-based chemotherapy may be less suited for this approach. A short time to treatment initiation is essential to achieve the best treatment results, and the requirement for EGFR and ALK testing may contribute to perioperative durvalumab with neoadjuvant chemotherapy treatment delay. The experts stated that while recent perioperative durvalumab with neoadjuvant chemotherapy studies have not suggested any specific subgroup differences, exploratory evidence suggests that patients with stage III disease may benefit more from a perioperative immunotherapy approach. Further, it is possible that a subset of patients with specific markers may respond better to perioperative durvalumab with neoadjuvant chemotherapy; however, validated markers are not currently available.

Assessing the Response to Treatment

Outcome metrics for resectable NSCLC used in clinical practice are typically aligned with those used in clinical trials. The clinical experts noted that in clinical trials, patient response to treatment is assessed at the time of surgery using pCR, using survival measures such as OS and DFS according to the RECIST criteria, and by disease symptoms. In clinical practice, response at the time of surgery using pCR is the first step to assess benefit from therapy followed by survival, QoL outcomes (such as PROs), and AEs. In clinical practice, as in trials, clinical assessments are performed before each cycle of therapy. However, assessments of disease response and recurrence usually occur every 3 months to 6 months during treatment, every 6 months in the first 2 years following the last treatment cycle, and then annually thereafter, which is generally less frequent than in clinical trials.

Discontinuing Treatment

Clinical experts consulted for this review indicated that perioperative durvalumab with neoadjuvant chemotherapy should be discontinued in the event of disease progression (including the tumour no longer being resectable, metastasis, and/or tumour growth) or recurrence, significant side effects such as immune-related side effects that can be life-threatening or permanent, or upon a patient’s request.

Prescribing Considerations

Clinical experts indicated that treatment with perioperative durvalumab with neoadjuvant chemotherapy should be prescribed and managed in outpatient clinics or specialty clinics by a multidisciplinary thoracic team of thoracic surgeons, medical oncologists, and supportive staff such as nursing and allied health.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Two clinician groups provided input for this review: LCC Drug Advisory Committee (18 clinicians contributed to the input) and OH-CCO (5 clinicians contributed to the input). Overall, the input was aligned with that of the clinical experts consulted by CDA-AMC.

Both clinician groups and the clinical experts consulted agreed that the treatment paradigm for patients with resectable NSCLC who do not have EGFR mutations or ALK rearrangements consists of 2 main phases: neoadjuvant and adjuvant. Neoadjuvant therapy, administered before surgery, includes chemotherapy and ICI. OH-CCO and LCC recommend neoadjuvant platinum-based chemotherapy combined with ICI (nivolumab) for 3 cycles. Additionally, LCC noted an alternative involving chemotherapy with ICI (durvalumab) for 4 cycles. Following surgery, adjuvant therapy involves chemotherapy and/or ICI, while radiation therapy is reserved for specific cases such as positive margins, as noted by the clinical experts consulted for this review.

The common treatment goals identified across clinician groups included achieving a cure, as measured by OS, and improving DFS. LCC and the clinical experts emphasized reducing recurrence rates and enhancing QoL.

The most significant treatment gap identified by the 2 clinician groups and the clinical experts is the lack of data comparing the efficacy and role of adjuvant ICI following neoadjuvant therapy, including which patients might benefit from it. This uncertainty makes it challenging to determine the optimal strategy for improving survival outcomes, especially given that not all patients respond to current treatments. Presently, ICI in the adjuvant setting is only available to those with high PD-L1 expression.

Both clinician groups and the clinical experts stated that perioperative durvalumab combined with neoadjuvant chemotherapy would offer an alternative treatment approach to neoadjuvant nivolumab in combination with chemotherapy for resectable NSCLC. The clinical experts emphasized its importance, especially for patients who do not achieve a complete pathological response to neoadjuvant therapy, highlighting the potential value of adjuvant ICI in such cases.

According to the clinician groups, the best-suited patients for perioperative durvalumab in combination with neoadjuvant chemotherapy are those with resectable NSCLC, no EGFR mutations or ALK rearrangements, and no contraindications to ICI. They emphasized the role of CT scans for monitoring, with imaging recommended before and after surgery and at regular intervals during and after treatment to check for recurrence. In clinical practice, treatment response is assessed through clinical symptoms, survival outcomes (OS and DFS), and pathological response at surgery (pCR and MPR), as highlighted by the clinical expert.

Both clinician groups indicated that factors for discontinuing treatment primarily include disease progression and significant side effects, with patient preferences also playing a key role. For treatment with perioperative durvalumab with neoadjuvant chemotherapy, patients should be treated in an outpatient setting under the supervision of a medical oncologist, or pulmonologist experienced in the management of thoracic malignancies.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

AJCC = American Joint Committee on Cancer; CDA-AMC = Canada’s Drug Agency; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IASLC = International Association for the Study of Lung Cancer; NEJM = New England Journal of Medicine; NSCLC = non–small cell lung cancer; PAG = Provincial Advisory Group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of perioperative durvalumab, 1,500 mg administered as an IV infusion every 3 weeks in combination with neoadjuvant chemotherapy before surgery and every 4 weeks as monotherapy after surgery for the treatment of resectable NSCLC in patients without any known EGFR mutations or ALK rearrangements. The focus will be placed on comparing durvalumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of durvalumab is presented in 2 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 1 pivotal study identified in the systematic review

• 3 ITCs.

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

AE = adverse event; AESI = adverse event of special interest; AJCC = American Joint Committee on Cancer; AUC 5 = area under the serum drug concentration-time curve 5; AUC 6 = area under the serum drug concentration-time curve 6; CTCAE = Common Terminology Criteria for Adverse Events; DFS = disease-free survival; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EFS = event-free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; EQ VAS = EQ visual analogue scale; HRQoL = health-related quality of life; IASLC = International Association for the Study of Lung Cancer; ITT = intention to treat; mITT = modified intention to treat; MPR = major pathological response; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathological complete response; PD = progressive disease; PGI-S = Patient Global Impression of Severity; PRO = patient-reported outcome; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours 1.1; TC = tumour cell.

^aIASLC is the group responsible for conducting research to inform future versions of the AJCC. Version 8 of the IASLC Staging Manual in Thoracic Oncology⁵⁷ was endorsed and published by the AJCC as the AJCC Cancer Staging Manual, eighth edition.⁵⁸ The 2 are considered interchangeable.

Sources: AEGEAN trial clinical study protocol and AEGEAN trial statistical analysis plan.^59,60 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The AEGEAN trial is an ongoing, randomized, double-blind, placebo-controlled, multicentre, phase III study aimed at evaluating the efficacy, activity, and safety of perioperative durvalumab with neoadjuvant chemotherapy in patients with resectable NSCLC. Patients were recruited from 183 international sites, including 5 sites in Canada. Patients were randomized 1:1 to receive either durvalumab and platinum-based chemotherapy before surgery, followed by durvalumab postsurgery (arm 1) or placebo and platinum-based chemotherapy before surgery, followed by placebo postsurgery (arm 2) (Figure 1). Randomization was stratified by disease stage (stage II versus stage III) and PD-L1 expression status (< 1% versus ≥ 1%).

The primary objectives were to compare pCR and EFS in patients treated with perioperative durvalumab with neoadjuvant chemotherapy versus neoadjuvant chemotherapy with placebo. The DCO dates for the results presented include the following:

• the first IA (interim analysis 1 [IA1]) of pCR (DCO date of January 14, 2022)

• the final analysis of pCR (DCO date of November 10, 2022)

• the first IA of EFS (EFS IA1 DCO date of November 10, 2022)

• the second IA of EFS (EFS IA2 DCO date of May 10, 2024).

At Screening

Baseline screening assessments were performed in the 28 days before randomization. During this period, informed signed consent was obtained, tumour samples were collected and sent for centralized PD-L1, EGFR, and ALK testing, patient eligibility was determined, and demographic and characteristic data were collected.

Neoadjuvant Phase

Treatment was to begin on day 1 of the study. Surgery was to occur within and including 40 days of the last neoadjuvant treatment administration or it was considered a delay.

Adjuvant Phase

PORT was allowed for patients in which it was indicated according to local guidance. The initiation of adjuvant treatment was scheduled as soon as clinically feasible and within 10 weeks after surgery or within 3 weeks after the completion of PORT.

Discontinuation and Lost to Follow-Up

Patients discontinued the study treatment if they withdrew consent, if they had an AE that contraindicated further dosing (according to the study investigator), if they had an AE that met the criteria for discontinuation, if they were or intended to become pregnant, if they were noncompliant with the study, if they underwent the initiation of alternative anticancer therapy, if they had a local or distant recurrence, if they had clinical progression, or if they were unable to undergo or complete surgery for reasons other than progressive disease.

Patients were considered lost to follow-up only if no contact had been established by the time the study was completed, such that there was insufficient information to determine the patient’s status at that time.

Figure 1: Schematic of AEGEAN Study Design

ctDNA = circulating tumour DNA; DFS = disease-free survival; EFS = event-free survival; HRQoL = health-related quality of life; IHC = immunohistochemistry; mITT = modified intention to treat; mPR = major pathological response; mRNA = messenger ribonucleic acid; NSCLC = non–small cell lung cancer; OS = overall survival; pCR = pathological complete response; Q3w = every 3 weeks; Q4w = every 4 weeks; R = randomize; TC = tumour cell.

Note: PD-L1 TC ≥ 1% = the expression of PD-L1 on tumour membrane, at any intensity, in ≥ 1% of tumour cells.

Source: AEGEAN study protocol.⁶⁰

Populations

Inclusion and Exclusion Criteria

Detailed inclusion and exclusion criteria are provided in Table 5. Briefly, the trial enrolled patients with newly diagnosed, previously untreated, resectable NSCLC (stage IIA to stage IIIB [N2 node stage] disease, either squamous or nonsquamous). At enrolment, patients had to be aged 18 years or older and be candidates for planned surgical treatment with lobectomy, sleeve resection, or bilobectomy. Enrolment was restricted to those with a WHO and/or ECOG PS score of 0 or 1, adequate organ and marrow function, and no prior exposure to immune-mediated therapies. To confirm patient eligibility, a central laboratory was used to analyze EGFR (unless known KRAS mutation), ALK (unless known KRAS mutation or squamous cell carcinoma), and PD-L1 status. With enrolment ongoing, the protocol was amended to exclude patients with tumours classified as T4 for any reason other than size (> 7 cm), whose planned surgery at enrolment was pneumonectomy, or who had documented test results that confirmed the presence of an EGFR mutation (confirmed by central testing) or ALK rearrangements (confirmed by local or central testing). Additional key exclusion criteria were previous exposure to anti–PD-L1, anti–PD-1, or anticytotoxic T-lymphocyte antigen 4 antibodies, uncontrolled intercurrent illness, previously documented autoimmune or inflammatory disorders, the existence of more than 1 primary tumour, and sublobar resections as planned surgery at the time of enrolment.

Interventions

The main study intervention was 1,500 mg fixed-dose durvalumab or placebo (i.e., sterile saline or dextrose solution) administered as a 1-hour infusion (up to a maximum of 8 hours in the case of interruptions) every 3 weeks up to a maximum of 4 cycles before surgery and every 4 weeks for 12 cycles following surgery. If a patient’s weight fell to 30 kg or less, a weight-based dosing equivalent to 20 mg/kg of durvalumab was given at the same interval until the patient’s weight improved to greater than 30 kg. In both treatment arms, chemotherapy was given in combination with the main study intervention during the neoadjuvant treatment phase. When chemotherapy was given on the same day as the main study intervention, the main study intervention was administered before administering chemotherapy. The choice of platinum-doublet chemotherapy regimen included 4 options and was selected based on the patient’s histology and at the discretion of the investigator:

• squamous tumour histology — carboplatin plus paclitaxel: carboplatin area under the serum drug concentration-time curve 6 and paclitaxel 200 mg/m² via IV infusion on day 1 of each 3-week cycle, for 4 cycles

• squamous tumour histology — cisplatin plus gemcitabine: cisplatin 75 mg/m² via IV infusion on day 1 of each 3-week cycle, for 4 cycles, and gemcitabine 1,250 mg/m² via IV infusion on day 1 and day 8 of each 3-week cycle, for 4 cycles

• nonsquamous tumour histology — pemetrexed plus cisplatin: pemetrexed 500 mg/m² and cisplatin 75 mg/m² via IV infusion on day 1 of each 3-week cycle, for 4 cycles

• nonsquamous tumour histology — pemetrexed plus carboplatin: pemetrexed 500 mg/m² and carboplatin area under the serum drug concentration-time curve 5 via IV infusion on day 1 of each 3-week cycle, for 4 cycles.

Dose delays were permitted for durvalumab with chemotherapy and placebo with chemotherapy; however, dose reductions were only permitted for chemotherapy regimens.

The standardized course of PORT included but was not limited to doses ranging from 50 Gy to 60 Gy, 1.8 Gy to 2 Gy per fraction, 5 fractions a week; for patients with positive margins of disease (R1), PORT included but was not limited to doses ranging from 60 Gy to 66 Gy, 1.8 Gy to 2 Gy per fraction, 5 fractions a week.

Approved concomitant medications or treatments included those deemed necessary to provide adequate prophylactic or supportive care (e.g., acetaminophen, diphenhydramine), those considered best supportive care (including antibiotics or nutritional support), and inactive viruses (such as the influenza vaccine), or those deemed necessary by the investigator for the patient’s safety and well-being. Rescue medications (steroids and other immunosuppressants) were made available to manage imAEs that could potentially be experienced by patients on durvalumab. Permitted immunosuppressants were infliximab (e.g., for colitis) and mycophenolate (e.g., for hepatitis).

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical expert(s) consulted by CDA-AMC and the perspectives of patients, clinician groups, and drug programs. Using the same considerations, the CDA-AMC review team selected end points that were considered to be most relevant to inform deliberations by the CDA-AMC expert committee and finalized this list of end points in consultation with members of the expert committee. In summary, EFS, OS, pCR, and HRQoL (measured with the EORTC QLQ-C30 tool) were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations were also assessed using GRADE. Results of MPR and DFS are presented in the Clinical Review Report to aid in clinical decision-making but were not appraised using GRADE. pCR was deemed to be the most relevant response outcome because it is commonly used in clinical practice; MPR was noted by the clinical experts consulted for this review to be more commonly used in clinical trials than in clinical practice (while MPR results have been summarized in this Clinical Review Report, they have not been assessed in the GRADE assessment). While EFS reflected the whole study period for all randomized patients (i.e., events occurring in the neoadjuvant, adjuvant, and follow-up periods of the study), DFS was a less comprehensive assessment reflecting the period after complete surgical resection for patients in which this was achieved; EFS was included in the GRADE assessment while DFS was summarized in this Clinical Review Report but not assessed using the GRADE tool. Similarly, results from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), a 13-item module about lung cancer, are presented to aid in clinical decision-making; however, they were not appraised using GRADE because the EORTC QLQ-C30 was deemed to be more relevant by clinical experts consulted for this review.

Table 6: Outcomes Summarized From the AEGEAN Trial

AE = adverse event; CDA-AMC = Canada’s Drug Agency; DCO = data cut-off; DFS = disease-free survival; EFS = event-free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; FA = final analysis; GRADE = Grading of Recommendations Assessment, Development and Evaluation; IA1 = interim analysis 1; IA2 = interim analysis 2; MPR = major pathological response; OS = overall survival; pCR = pathological complete response; QoL = quality of life; SoF = summary of findings.

^aStatistical testing for these end points was adjusted for multiple comparisons (hierarchical testing).

Sources: AEGEAN study EFS IA1 Clinical Study Report.²⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Tumour evaluation using RECIST 1.1 was conducted at screening (within 28 days before randomization), after completion of the neoadjuvant period (before surgery), then postsurgery every 12 weeks (± 1 week) until week 48, then every 24 weeks (± 2 weeks) until week 192 (approximately 4 years), and then every 48 weeks (± 2 weeks) thereafter, until local or distant recurrence (as determined by the investigator using RECIST 1.1), consent withdrawal, or death.

Patient-monitoring data, including the reporting of AEs, were collected at screening, at the same time as neoadjuvant and adjuvant durvalumab or placebo administration, after completion of the neoadjuvant period (before surgery), postsurgery (within 10 weeks of surgery), and at month 1, month 2, and month 3 following the last dose of durvalumab or placebo.

PROs followed the same schedule of assessments as patient monitoring, with 1 additional assessment taken 6 months following the last dose of durvalumab or placebo.

Pathological Complete Response

pCR was a coprimary outcome in the AEGEAN study and was defined as the absence of any residual viable tumour at the time of surgical resection in the primary lung lesion and all sampled lymph nodes. The analysis of pCR was based on a blinded assessment per central pathology review. The estimated between-group difference threshold at which clinical experts consulted for this review deemed the pCR difference to be clinically meaningful in resectable NSCLC was 10%.

Major Pathological Response

MPR, defined as 10% or less residual viable tumour tissue in the lung primary tumour at the time of resection, was a key secondary end point in the AEGEAN study. The analysis of MPR was based on assessment per central pathology review and recorded as yes, no, or not evaluable. Clinical experts consulted for this review advised that a between-group difference of 10% in MPR is considered clinically meaningful.

Event-Free Survival

EFS was the second coprimary outcome in the AEGEAN study. EFS was defined as the time from randomization to the first of any of the following: local or distant recurrence; death due to any cause (the event date is the date of death); or progressive disease that precludes surgery (the event date is the date of this determination) or progressive disease discovered and reported by the investigator upon attempting surgery that prevents completion of surgery (the event date is the date of the first attempt at surgery). The EFS analysis was based on a blinded independent central review (BICR) per RECIST 1.1. Clinical experts consulted for this review advised that a between-group difference of 5% to 10% is considered clinically meaningful.

Disease-Free Survival

DFS was a key secondary outcome and was defined as the time from the date of surgery until the first of either of the following: the date of disease recurrence (local or distant), or the date of death due to any cause. The analysis of DFS was based on BICR per RECIST 1.1. Clinical experts consulted for this review advised that a DFS between-group difference of 5% to 10% is considered clinically meaningful.

Overall Survival

The final key secondary outcome in the AEGEAN trial was OS. OS was defined as the time from randomization until death due to any cause, regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy. Clinical experts consulted for this review advised that an OS between-group difference of 5% to 10% is considered clinically meaningful.

HRQoL End Points

To compare disease-related symptoms and HRQoL, data from the EORTC QLQ-C30 and EORTC QLQ-LC13 measures were collected as other secondary outcomes in the AEGEAN trial.^61,62 Descriptions of each measure are as follows (further details are in Table 7).

• The EORTC QLQ-C30 is a multidimensional, cancer-specific, self-administered measure of HRQoL consisting of 30 questions across 5 multi-item functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom scales (fatigue, pain, and nausea and vomiting); a 2-item global QoL scale; 5 single items assessing additional symptoms commonly reported by patients with cancer (dyspnea, loss of appetite, insomnia, constipation, and diarrhea), and 1 item on the financial impact of the disease. Each item is evaluated using 4-point and 7-point Likert scales; raw scores for each scale are computed as the average of the items that contribute to a particular scale, and each raw scale score is converted to a standardized score that ranges from 0 to 100 using a linear transformation, with a higher score reflecting better function on the function scales, higher symptoms on the symptom scales, and better HRQoL on the global QoL scale.⁶¹

• The EORTC QLQ-LC13 is a 13-item lung cancer–specific questionnaire. The module comprises both multi-item and single-item measures of lung cancer–associated symptoms (i.e., coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (i.e., hair loss, neuropathy, sore mouth, and dysphagia).⁶² A high score represents a high level of symptom burden.

Changes in scores compared with baseline were evaluated for the scales and items from EORTC QLQ-C30 and EORTC QLQ-LC13 in the neoadjuvant period and for scales and items from EORTC QLQ-C30 in the adjuvant period. Baseline in the neoadjuvant period was defined as the last predose assessment (i.e., neoadjuvant cycle 1, day 1, predose assessment; in the absence of the cycle 1, day 1, predose assessment, the latest assessment before treatment can be used — namely, screening). Baseline in the adjuvant period was defined as the latest measurement after surgery but before the first dose of adjuvant treatment.

A between-group minimal important difference (MID) in the EORTC QLQ-C30 global health status and QoL score has previously been estimated for patients with lung cancer as an increase or decrease of 4 points for improvement and deterioration, respectively.⁶³ No MID for the EORTC QLQ-LC13 in patients with NSCLC was identified.

Harms End Points

To compare the safety and tolerability profile of study treatments, data on AEs were collected from the date of informed consent until 90 days after the last dose of study treatment. AEs were coded based on the Medical Dictionary for Regulatory Activities (version 25.1) and graded for severity according to Common Terminology Criteria for Adverse Events (version 5.0). AE data were evaluated according to the following categories: all AEs (including those causality-related to study treatment), AEs of Common Terminology Criteria for Adverse Events grade 3 or higher, AEs leading to dose modification, AEs with an outcome of death, SAEs, and discontinuation due to AEs.

Adverse events of special interest (AESIs) and adverse events of potential interest (AEPIs) included those from the durvalumab clinical development program:

• AESIs were defined as AEs with a likely inflammatory or immune-mediated pathophysiological basis resulting from the mechanism of action of durvalumab and requiring more frequent monitoring and/or interventions such as corticosteroids, immunosuppressants, and/or endocrine therapy.

• AEPIs were defined as AEs that could have a potential inflammatory or immune-mediated pathophysiological basis resulting from the mechanism of action of durvalumab but were more likely to have occurred due to other pathophysiological mechanisms; thus, the likelihood of the event being inflammatory or immune-mediated in nature is not high and/or is most often explained by the other causes.

ImAEs were identified from both AESIs and AEPIs based on programmatic rules that consider interventions involving systemic steroid therapy, immunosuppressant use, and/or endocrine therapy.

AEs were further categorized based on the time point in which they occurred:

• overall period — includes AEs occurring while receiving treatment, a period which is defined as occurring between the first dose of study treatment until the earliest of the maximum of (last dose of study treatment or surgery) plus 90 days, the date of the DCO, or the date of the first dose of subsequent anticancer therapy (which does not include radiation therapy)

• neoadjuvant period — includes AEs between the date of the first dose and the day before surgery, or for patients without surgery, up to the earliest of either 90 days after the date of the last dose of neoadjuvant treatment, or the first dose of subsequent anticancer therapy

• postsurgery period — includes AEs between the date of surgery (including the day of surgery) and the earliest of either the date of surgery plus 90 days, or the first dose of subsequent anticancer therapy

• adjuvant period — includes AEs between the date of the first dose of study treatment postsurgery and the earliest of either 90 days following the date of the last dose of adjuvant treatment, or the first dose of subsequent anticancer therapy.

Table 7: Summary of Outcome Measures and Their Measurement Properties

BPI = Brief Pain Inventory; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; FACT-G = Functional Assessment of Cancer Therapy–General; HADS = Hospital Anxiety and Depression Scale; HRQoL = health-related quality of life; MID = minimal important difference; NSCLC = non–small cell lung cancer; QoL = quality of life; vs. = versus.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Considerations that informed the selection of efficacy outcomes to be summarized and assessed using GRADE include the following.

• Survival outcomes were identified by the patient and clinician group input and specified by the clinical experts consulted for this review to include OS. EFS was a key input for the pharmacoeconomic model and was deemed relevant by the clinical experts consulted for this review. The clinical experts noted that outcomes at the longest follow-up were critical to informing long-term benefits or harms of the treatment and those at earlier time points were necessary to assess any sustained benefit or harm. As such, the earliest time point (12 months for both OS and EFS) and latest time point (48 months for OS and 36 months for EFS) were selected for GRADE.

• HRQoL outcomes were identified by the patient and clinician groups as an important outcome and the clinical experts consulted for this review further specified the EORTC QLQ-C30 global health status and QoL to be the most informative scale.

• pCR was identified as important by the clinical experts consulted for this review and is routinely used in clinical practice.

• Safety and toxicity outcomes were identified as important outcomes by patient and clinical group input; imAEs and SAEs were identified as the most important safety outcomes by the clinical experts consulted for this review.

Statistical Analysis

The statistical analyses for all study end points included in this review are presented in Table 8.

Table 8: Statistical Analysis of Efficacy End Points in the AEGEAN Study

CI = confidence interval; CMH = Cochran Mantel-Haenszel; DFS = disease-free survival; EFS = event-free survival; EOTRC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EOTRC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; FA = final analysis; HR = hazard ratio; IA = interim analysis; IA1 = interim analysis 1; mITT = modified intention to treat; MMRM = mixed model of repeated measures; MPR = major pathological response; MTP = multiple testing procedure; NA = not applicable; OS = overall survival; pCR = pathological complete response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1; TC = tumour cell; vs. = versus.

Note: The AEGEAN trial is an ongoing study. Per the MTP, DFS and OS will be formally assessed at subsequent IA and/or FA.

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study statistical analysis plan.^24,59 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Sample Size and Power Calculation

The study planned to screen approximately 1,333 patients to randomize approximately 800 eligible patients in the ITT population and approximately 740 patients in the mITT population. The study was sized to characterize the EFS and pCR benefit of the perioperative durvalumab with neoadjuvant chemotherapy arm versus the placebo with neoadjuvant chemotherapy arm in patients with resectable stage IIA to stage IIIB NSCLC. Enrolment of patients occurred over approximately 4 years, with the first patient enrolled on December 6, 2018, and the last patient enrolled on March 18, 2022.

IAs were planned within the study for the primary end points of pCR (1 planned IA) and EFS (2 planned IAs). The alpha level allocated to pCR was controlled at the interim and final time points by the Lan-DeMets⁶⁷ spending function with the O'Brien-Fleming boundary, where the significance level applied at the interim depends upon the proportion of information available.

A total of 0.5% alpha was allocated to the pCR end point. The final analysis for pCR was planned to occur when all patients (i.e., approximately 800 patients in the ITT population and 740 patients in the mITT population) had the opportunity to undergo surgery and complete the pathology assessment (where applicable). The planned IA of pCR (based on the mITT population of 400 patients) had a 55% power to detect a between-group difference of 12 percentage points at a 2-sided significance level of 0.008%.

A total of 4.5% alpha was initially allocated to the EFS end point. The first planned IA of EFS (based on 740 patients in the mITT population with 224 events) had a 50% power to show an HR for disease progression, recurrence, or death of 0.69 with a 2-sided significance level of 0.665%. The second planned IA of EFS (based on 740 patients in the mITT population with 296 events) had an 84% power to show an HR for disease progression, recurrence, or death of 0.68 with a 2-sided significance level of 1.9243%. The final EFS analysis is planned to occur when approximately 371 EFS events have been reported (approximately 50% maturity in the mITT population).

Statistical Test or Model

Both pCR and MPR were analyzed using the Cochran-Mantel-Haenszel test stratified by disease stage (stage II versus stage III) and PD-L1 expression status (< 1% versus ≥ 1%) in the mITT population. The effect of treatment was estimated by the difference in proportions between treatment groups, together with their corresponding CI and P values. The CIs for the difference in proportions between groups were estimated using Miettinen-Nurminen’s confidence limits.

For survival outcomes EFS, DFS, and OS, the effects of treatment were estimated by HRs together with their corresponding 95% CIs estimated from the stratified Cox proportional hazards model adjusted for disease stage (stage II versus stage III) and PD-L1 expression status (< 1% versus ≥ 1%). EFS and OS analyses were performed in the mITT population and DFS in the modified resected set. The Cox models were fitted using PROC PHREG with the Efron method to control for ties and the CI was calculated using a profile likelihood approach.

Additionally, KM plots of EFS, DFS, and OS were presented by treatment arm. Summaries of the number and percentage of patients experiencing an event and the type of event were provided along with the median EFS, DFS, and OS and associated 95% CI for each treatment. EFS, DFS, and OS rates at a landmark (12 months, 24 months, 36 months, 48 months, and 60 months, as relevant) along with 95% CIs were estimated using the KM method for each treatment arm.

PRO instruments (EORTC QLQ-C30 and EORTC QLQ-LC13) were summarized descriptively using change from baseline presented separately for the neoadjuvant period (in the mITT population) and the adjuvant period (in the modified resected set population). In the absence of the cycle 1, day 1, predose assessment, the latest assessment before treatment was used (i.e., screening). For the adjuvant period (EORTC QLQ-C30 only), a second summary was produced on the modified resected set for adjuvant period visits where the baseline was defined as the latest measurement after surgery but before the first dose of adjuvant treatment. Change from baseline was also derived using a mixed model of repeated measures analysis for the following scales and items:

• EORTC QLQ-C30 symptoms — fatigue and appetite loss

• EORTC QLQ-C30 function — physical and role

• EORTC QLQ-C30 global health status and QoL

• EORTC QLQ-LC13 symptoms — dyspnea, chest pain, and cough.

When fewer than 20 patients were present at a time point in either arm, that time point was excluded from the mixed model of repeated measures analysis. The adjusted mean change from baseline estimates per treatment group and corresponding 95% CIs were presented along with an overall estimate of the treatment difference, 95% CI, and P value.

Multiple Testing Procedure

To strongly control the 2-sided type I error rate at 0.05, a hierarchical MTP that included a gatekeeping strategy was used across the primary end points (EFS and pCR in the mITT population) and alpha-controlled secondary end points (MPR and OS in the mITT population, and DFS in the modified resected population), with alpha allocation and recycling between end points at the interim and final analyses. The overall 2-sided 5% type I error was split between the 2 primary end points, with an alpha level of 0.5% allocated to the pCR analysis and an alpha level of 4.5% allocated to the EFS analysis. If statistical significance was demonstrated for both pCR and MPR, EFS would be tested with an alpha level of 5.0% due to alpha recycling (Figure 2).

Figure 2: Multiple Testing Procedure and Alpha Recycling in the AEGEAN Study

DFS = disease-free survival; EFS = event-free survival; mPR = major pathological response; OS = overall survival; pCR = pathological complete response.

Source: AEGEAN trial statistical analysis plan.⁵⁹

At the preplanned pCR IA (with a DCO date of January 14, 2022), the analysis of the interim mITT cohort (N = 402 patients) demonstrated that the prespecified boundary for declaring statistical significance of pCR was met (2-sided interim significance boundary = 0.0082%, based on a total 0.5% 2-sided alpha for pCR across interim and final analysis). Consequently, the test mass was recycled to test MPR (key secondary end point), which was also statistically significant at this DCO date. This resulted in a total alpha level of 5% allocated to the EFS analyses, due to alpha recycling.

Based on the analysis of the mITT population (N = 740 patients) at the preplanned EFS IA1 (with a DCO date of November 10, 2022), EFS was also declared statistically significant (2-sided interim significance boundary = 0.9899%, based on a total 5% 2-sided alpha for EFS across interim and final analyses). Data maturity for EFS was 31.9% (i.e., 236 patients had an EFS event among all 740 patients included in the mITT population) at EFS IA1. While the final analysis of pCR and MPR was also performed at this time (with a DCO date of November 10, 2022; N = 740), statistical significance was not retested due to these end points meeting the threshold for declaring significance at the pCR IA.

Per the MTP, DFS was tested at EFS IA1; however, it did not meet the prespecified boundary for declaring statistical significance (the interim significance boundary was based on a total 5% 2-sided alpha for DFS across interim and final analyses). Because DFS was not statistically significant at EFS IA1, OS was not formally tested based on the MTP. Due to the importance of OS, a descriptive summary of OS was provided at EFS IA1. The overall maturity of OS data at EFS IA1 was 22.1% (i.e., 163 mortality events occurred among all 740 patients included in the mITT population).

At the EFS IA2 DCO (May 10, 2024), DFS was tested again and did not meet the prespecified boundary for declaring statistical significance (defined as 30% maturity; adjusted significance boundary = 0.012303, based on an information fraction of 67.8% in the modified resected set). As such, OS was not formally tested at EFS IA2. Because EFS met the prespecified boundary for declaring statistical significance at EFS IA1, statistical significance was not retested at EFS IA2 nor will it be retested at the final analysis.

PROs were not included in the MTP.

Subgroup Analyses

Prespecified subgroup analyses were performed to assess the consistency of treatment effect across expected prognostic and/or predictive factors in the following subgroups:

• sex (female or male)

• age at randomization (aged < 65 years or ≥ 65 years)

• PD-L1 expression status at baseline (< 1% or ≥ 1%) as defined by integrated web response system

• PD-L1 expression status at baseline (< 1% or ≥ 1%) as defined by source data

• PD-L1 expression status at baseline (< 50% or ≥ 50%) as defined by source data

• PD-L1 expression status at baseline (< 1%, 1% to 49%, or ≥ 50%) as defined by source data

• PD-L1 expression status at baseline (< 25% or ≥ 25%) as defined by source data

• histology (squamous or nonsquamous)

• disease stage (stage II or stage III) as defined by integrated web response system

• disease stage (stage II or stage III) as defined by source data

• smoking (currently, previously, or never)

• race (Asian versus not Asian)

• region (Asia, Europe, North America, or South America)

• ECOG PS (0 versus 1)

• chemotherapy doublet at baseline (cisplatin versus carboplatin)

• lymph node station (N2 single station versus N2 multistation)

• PORT received (yes or no).

Sensitivity Analyses

For all efficacy outcomes, a sensitivity analysis was performed on the primary treatment comparison using PD-L1 expression status at baseline (< 1% versus ≥ 1%) and disease stage (stage II versus stage III) as defined by source data (instead of integrated web response system) as stratification factors. In the instance of missing source data, the integrated web response system value was imputed.

For pCR and MPR, a sensitivity analysis was performed that only included patients with an evaluable pathology sample.

The following sensitivity analyses were run for EFS (mITT population) and DFS (modified resected set):

• The primary analyses were rerun based on investigator assessment using RECIST 1.1.

• To assess the possible evaluation-time bias that may have been introduced if scans were not performed at the protocol-scheduled time points, the midpoint between the time of progression and the previous evaluable disease assessment (using the final date of the assessment) was analyzed using a stratified log-rank test. Note that midpoint values resulting in noninteger values were rounded down. For patients whose death was treated as an EFS event, the date of death was used to derive the EFS time used in the analysis. To support this analysis, the mean of patient-level average interassessment times was tabulated for each treatment. This approach used BICR tumour assessments.

• Attrition bias was assessed by repeating the EFS analysis, except that the actual EFS event times, rather than the censored times, of patients with an EFS event immediately following 2 or more nonevaluable disease assessments was included. In addition, and within the same sensitivity analysis, for patients who took subsequent therapy (note that for this analysis, radiotherapy is not considered a subsequent anticancer therapy) before their last evaluable RECIST assessment, progression that precludes surgery or results in incomplete surgery or death was censored at their last evaluable assessment before taking the subsequent therapy. This analysis was supported by a KM plot of the time to censoring using the EFS data, where the censoring indicator of the EFS analysis is reversed.

• Ascertainment bias was assessed by analyzing the site investigator data.

Because the OS end point does not include RECIST assessments, the following OS sensitivity analyses were performed on the mITT:

• An analysis was performed examining the censoring patterns to rule out attrition bias using a KM plot of time to censoring where the censoring indicator of OS is reversed.

• Patients who took subsequent therapy before their last known alive date were censored at the start date of subsequent therapy (note that for this analysis, radiotherapy is not considered a subsequent anticancer therapy).

Analysis Populations

The analysis populations are defined in Table 9.

Table 9: Analysis Populations of the AEGEAN Study

DFS = disease-free survival; EFS = event-free survival; HRQoL = health-related quality of life; IA1 = interim analysis 1; ITT = intention to treat; mITT = modified intention to treat; MPR = major pathological response; OS = overall survival; pCR = pathological complete response; RECIST = Response Evaluation Criteria in Solid Tumours.

^aThe primary and key secondary efficacy analyses for pCR, EFS, MPR, and OS were repeated on the ITT population, to allow comparison between the ITT population, mITT population, and EGFR mutation and ALK gene rearrangements subgroups.

^bThe resected set consists of all patients in the ITT population who had surgical resection following the neoadjuvant period, who did not have R2 (macroscopic residual tumour) margins, and whose first scan following surgery showed no evaluable disease, defined as no postsurgery R2 margins and no RECIST evidence of disease based on the investigator data (i.e., no target lesion, nontarget lesion, or new lesions, unless they were pathologically confirmed to be a new primary malignancy).

Sources: AEGEAN study EFS IA1 Clinical Study Report.²⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Patient disposition is summarized in Table 10. Of 1,480 patients enrolled in the AEGEAN study, 802 patients were included in the ITT analysis set. Due to EGFR mutation–positive or ALK gene rearrangement–positive tumours, 62 randomized patients (8%) were excluded from the mITT analysis set, leaving 366 patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and 374 patients in the placebo with neoadjuvant chemotherapy arm. Four cycles of neoadjuvant chemotherapy agents were completed by a similar percentage of patients in both treatment arms (84.7% of patients [310 of 366] in the perioperative durvalumab with neoadjuvant chemotherapy arm and 87.2% of patients [326 of 374] in the placebo with neoadjuvant chemotherapy arm). Slightly ████ patients randomized to perioperative durvalumab with neoadjuvant chemotherapy discontinued neoadjuvant durvalumab compared to placebo (█████ versus ██████ respectively). Across both arms, the primary reason for neoadjuvant durvalumab or placebo discontinuation was AEs. A similar percentage of patients in both arms underwent surgery (80.6% of patients in the durvalumab with neoadjuvant chemotherapy arm versus 80.7% of patients in the placebo with neoadjuvant chemotherapy arm) and completed surgery (77.6% of patients in the durvalumab with neoadjuvant chemotherapy arm versus 76.7% of patients in the placebo with neoadjuvant chemotherapy arm).

As of the most recent DCO, the EFS IA2 DCO on May 10, 2024, a similar percentage of patients in both arms of the mITT analysis set underwent PORT (7.1% of patients [26 of 366] in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 6.4% of patients [24 of 374] in the placebo with neoadjuvant chemotherapy arm). Slightly more patients in the perioperative durvalumab with neoadjuvant chemotherapy arm had completed adjuvant treatment (i.e., 12 cycles of durvalumab or placebo) by the EFS IA2 DCO (45.4% of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 40.4% of patients in the placebo with neoadjuvant chemotherapy arm). In the durvalumab with neoadjuvant chemotherapy arm, 20.8% of patients discontinued adjuvant treatment compared to 23.0% of patients in the placebo with neoadjuvant chemotherapy arm; the primary reason for discontinuation in both arms was radiological progression.

Table 10: AEGEAN Study Summary of Patient Disposition in mITT Population

DCO = data cut-off; EFS = event-free survival; IA1 = interim analysis 1; IA2 = interim analysis 2; ITT = intention to treat; mITT = modified intention to treat; NA = not available; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1; vs. = versus.

Note: The EFS IA1 DCO date was November 10, 2022; the EFS IA2 DCO date was May 10, 2024.

^aAll percentages were calculated from the number of patients randomized, with the exception of rows with reference to footnote “c.”

^bExcludes patients with surgery done outside of study.

^cPercentages were calculated from the number of patients who received treatment in the neoadjuvant period.

^dIncludes 4 patients who did not complete surgery (1 patient for durvalumab + chemotherapy vs. 3 patients for placebo + chemotherapy).

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ^24,23 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics of the mITT population are outlined in Table 11 and are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. In the AEGEAN study, patients were primarily Asian (41.5% of patients [307 of 740]) or white (53.6% of patients [397 of 740]) with just 1.4% of patients (10 of 740) identifying as American Indian or Alaska Native, 0.9% of patients (7 of 740) identifying as Black or African American, and 2.6% of patients (19 of 740) identifying with other races. Patients were primarily aged 50 years or older (95.0% of patients [703 of 740]) with a median age of 65.0 years (range, 39 years to 85 years), and either currently or formerly smoked (85.5% of patients [633 of 740]). In the perioperative durvalumab with neoadjuvant chemotherapy arm, 68.9% of patients (252 of 366) were male compared to 74.3% of patients (278 of 374 patients) in the placebo with neoadjuvant chemotherapy arm. Overall, at baseline, patients tended to have an ECOG PS score of 0 (68.4% of patients [506 of 740]), present with stage III disease (70.9% of patients [525 of 740]), and have a baseline PD-L1 expression status greater than or equal to 1% (66.6% of patients [493 of 740]). A slightly higher percentage of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm had nonsquamous histology (53.6% of patients [196 of 366]) compared to those in the placebo with neoadjuvant chemotherapy arm (47.9% of patients [179 of 374]). In total, || patients had unknown EGFR mutation status (|| in the perioperative durvalumab with neoadjuvant chemotherapy arm and || in the placebo with neoadjuvant chemotherapy arm) and ██ patients had unknown ALK translocation status (|| in the perioperative durvalumab with neoadjuvant chemotherapy arm and || in the placebo with neoadjuvant chemotherapy arm).

Baseline demographics in the mITT population were generally similar to those in the ITT population (Appendix 1, Table 39).

Exposure to Study Treatments

Exposure to Durvalumab or Placebo

In the modified safety analysis set (N = 737) at the EFS IA2 DCO (May 10, 2024), the median total duration of treatment exposure for the overall period was longer for the durvalumab arm (█████ weeks) than for the placebo arm (█████ weeks) (Table 12). During the neoadjuvant period, the median total duration of treatment exposure was similar in both arms (█████ weeks in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ weeks in the placebo with neoadjuvant chemotherapy arms). The median total duration of treatment exposure during the adjuvant period was the same in both arms (█████ weeks).

After accounting for any dose delays, there were no notable differences across arms in the actual duration of exposure in the neoadjuvant and adjuvant periods (█████ weeks and █████ weeks in both arms, respectively). The median actual duration of exposure to the perioperative durvalumab with neoadjuvant chemotherapy arm versus the placebo with neoadjuvant chemotherapy arm for the overall period was similar in each arm (█████ versus █████ weeks, respectively).

Table 11: AEGEAN Study Summary of Baseline Characteristics in mITT Population

AJCC = American Joint Committee on Cancer; DCO = data cut-off; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EFS = event-free survival; IA1 = interim analysis 1; IXRS = interactive web response system; mITT = modified intention to treat; NOS = not otherwise specified; SD = standard deviation; TC = tumour cell; TNM = tumour-nodes-metastasis.

Notes: Baseline is defined as the last observation before randomization if available or, otherwise, an observation after randomization but before the first dose of randomized treatment.

Percentages were calculated based on the number of patients in the analysis set of N.

The DCO date was November 10, 2022.

^aAge was calculated using date of randomization.

^bRacial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^cStages according to AJCC Cancer Staging Manual, eighth edition.

^dCentral laboratory EGFR and ALK data are considered to determine EGFR and ALK status if available; otherwise, local laboratory data may be used. Data from all assessments, including postbaseline data, are considered.

^ePer protocol, patients with KRAS gene mutation do not require EGFR or ALK testing; patients with squamous histology do not require ALK testing.

^fTNM classification is based on the AJCC Cancer Staging Manual, eighth edition.

Sources: AEGEAN study EFS IA1 Clinical Study Report.²⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 12: AEGEAN Study Summary of Patient Exposure to Durvalumab or Placebo in the Modified Safety Analysis Set

DCO = data cut-off; EFS = event-free survival; IA2 = interim analysis 2; NR = not reported; Q1 = quantile 1; Q3 = quantile 3; SD = standard deviation.

Notes: One patient randomized to placebo + chemotherapy received 1 cycle of adjuvant durvalumab. This patient is reported in the durvalumab + chemotherapy arm with 0 neoadjuvant exposure.

The DCO date was May 10, 2024.

^aTotal treatment duration = ([minimum {last dose date where dose > 0 + 20, date of death, or date of DCO} – first dose date] + 1) ÷ 7, where minimum is whichever occurred first.

^bActual treatment duration = total treatment duration minus the total duration of dose delays for each period.

^cTotal treatment duration = ([minimum {last dose date where dose > 0 + 27, date of death, or date of DCO} – first dose date postsurgery] + 1) ÷ 7, where minimum is whichever occurred first.

^dTotal treatment duration of both phases, as the addition of total neoadjuvant duration and total adjuvant duration.

^eActual treatment duration = total treatment duration minus the total duration of dose delays for both periods.

Sources: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Duration of Exposure to Chemotherapy

In the safety analysis set (n = 799) at the EFS IA1 DCO (November 10, 2022), the exposure to any chemotherapy and to individual chemotherapy agents was similar across both arms, with a median total duration of exposure to any chemotherapy of 12.14 weeks in each arm (Table 13). The exposure to chemotherapy, which was only given in the neoadjuvant portion of treatment, remained unchanged as of the EFS IA2 DCO (May 10, 2024).

The median total duration of exposure to individual chemotherapy treatments was similar across both treatment arms (ranging from 12.00 weeks to 12.14 weeks in each arm) (Table 28). Overall, 26 patients switched platinum-based chemotherapy (██ patients switched from cisplatin to carboplatin as permitted by the protocol and || patients had off-protocol switching from carboplatin to cisplatin). Switching occurred in ████████ ████ patients randomized to perioperative durvalumab with neoadjuvant chemotherapy (████ █████████ than those randomized to placebo with neoadjuvant chemotherapy (████ ██████). In addition, 6 patients had off-protocol switching of non–platinum chemotherapy (|| patients switched from paclitaxel to gemcitabine and || patient switched from pemetrexed to paclitaxel) with ██████████ occurring in the perioperative durvalumab with neoadjuvant chemotherapy arm █████ ████████ and █████████ occurring in the placebo with neoadjuvant chemotherapy arm (████ ██████).

Table 13: AEGEAN Study Summary of Exposure to Neoadjuvant Chemotherapy in the Safety Analysis Set Population

DCO = data cut-off; EFS = event-free survival; IA1 = interim analysis 1; IA2 = interim analysis 2; SD = standard deviation.

Note: The EFS IA1 DCO date was November 10, 2022; the EFS IA2 DCO date was May 10, 2024.

^aTotal treatment duration = (minimum [death, DCO, last non-0 dose of chemotherapy {cycle X, day 1} + 20] – first dose date of chemotherapy) + 1 ÷ 7, where minimum is whichever occurred first.

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ^24,23 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications

At the EFS IA2 DCO, ██████ ███ patients had received ██ █████ ███ concomitant medication during the study (███████ ████████ Table 14). The use of concomitant medications was generally well balanced across treatment arms ████ ███ █████████ ██ █████ ████ ███ ███████████ ██████ █████████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ █████████ in the placebo with neoadjuvant chemotherapy arm) ███ ███████ ███ ██████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ in the placebo with neoadjuvant chemotherapy arm) in which a ████████ ██████ ██████████ of those randomized to perioperative durvalumab with neoadjuvant chemotherapy use said treatments than those randomized to placebo with neoadjuvant chemotherapy.

The disallowed concomitant medications administered in the AEGEAN trial did not raise any concerns on the outcome measures of the study. Overall (EFS IA2, mITT population), 1 or more disallowed concomitant medication during study treatment was reported for ███████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and ███████ patients in the placebo with neoadjuvant chemotherapy arm (ITT population); most frequently, these were ██████ ██████████ ████████ ██ ████████ █████; data not shown).

Table 14: AEGEAN Study Summary of Concomitant Medication Used in the mITT Population

ATC = Anatomical Therapeutic Chemical; DCO = data cut-off; EFS = event-free survival; HMG-CoA = hydroxymethylglutaryl-CoA; IA1 = interim analysis 1; IA2 = interim analysis 2; mITT = modified intention to treat.

Notes: A patient could have 1 or more generic term reported under a given ATC classification text. Concomitant medication is defined as started, ended, or ongoing between the first dose date of study treatment and last dose of study treatment + 90 days, as per WHO Drug Dictionary, version September 2022.

The EFS IA1 DCO date was November 10, 2022; the EFS IA2 DCO date was May 10, 2024.

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ^24,23 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Subsequent Treatment

Overall, the percentage of patients in the mITT population who had received a subsequent anticancer therapy was 17.2% (127 of 740) at the EFS IA1 DCO (November 10, 2022) and █████ █████████ at the EFS IA2 DCO (May 10, 2024) (Table 15). While at the EFS IA1 the use of subsequent anticancer therapy was generally well balanced across the mITT arms — with the exception of the use of immunotherapy treatment, which was slightly higher in the placebo with neoadjuvant chemotherapy arm — ███████ ███████████ were observed at the EFS IA2 DCO. At the EFS IA2 DCO, a ██████ percentage of patients in the placebo with neoadjuvant chemotherapy arm used any form of subsequent anticancer therapy (█████ █████████ versus █████ ████████ in the perioperative durvalumab with neoadjuvant chemotherapy arm). The use of both systemic therapy and radiotherapy was ██████ in the placebo with neoadjuvant chemotherapy arm than in the perioperative durvalumab with neoadjuvant chemotherapy arm (█████ versus █████ and █████ versus ██████ respectively). Across treatment groups, subsequent anticancer therapy tended to be most commonly used for palliative care.

Table 15: AEGEAN Study Summary of Subsequent Anticancer Therapy in the mITT Population

DCO = data cut-off; EFS = event-free survival; IA1 = interim analysis 1; IA2 = interim analysis 2; mITT = modified intention to treat.

Notes: Therapies postdiscontinuation of study treatment. Regimen categories and the line of subsequent therapy have been identified from a medical review of preferred terms using treatment start dates.

Patients with therapies in more than 1 category were counted once in each of those categories. Percentages were calculated from the number of patients in the mITT population in that treatment arm.

The EFS IA1 DCO date was November 10, 2022; the EFS IA2 DCO date was May 10, 2024.

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ^24,23 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

The median duration of follow-up from randomization to the November 10, 2022, DCO was 9.61 months (range, 0.0 months to 46.1 months) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 8.94 months (range, 0.0 months to 32.4 months) in the placebo with neoadjuvant chemotherapy arm. At the May 10, 2024, DCO, the median duration of follow-up was 20.70 months (range, 0.0 months to 58.6 months) and 13.86 months (range, 0.0 months to 58.5 months), respectively.

Pathological Complete Response

As of the November 10, 2022, DCO, the percentage of patients achieving pCR by an IRC was 17.21% (95% CI, 13.49% to 21.48%) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 4.28% (95% CI, 2.46% to 6.85%) in the placebo with neoadjuvant chemotherapy arm, as detailed in Table 16. The difference in pCR for the comparison of perioperative durvalumab with neoadjuvant chemotherapy to placebo with neoadjuvant chemotherapy was 12.96% (95% CI, 8.67% to 17.57%). Results from the sensitivity and subgroup analyses were generally consistent with those of the main analysis. Forest plots of the prespecified subgroup analyses are presented in Figure 9 in Appendix 2.

A similar magnitude of effect and 95% CI was observed at the pCR IA1 DCO. Per protocol, pCR statistical significance was tested at the first IA and because it was statistically significant (P = 0.000036), pCR was not retested for statistical significance at the final analysis.

Major Pathological Response

As of the November 10, 2022, DCO, the percentage of patients achieving MPR was 33.33% (95% CI, 28.52% to 38.42%) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 12.30% (95% CI, 9.15% to 16.06%) in the placebo with neoadjuvant chemotherapy arm (Table 16). The difference with MPR for the comparison of perioperative durvalumab with neoadjuvant chemotherapy to placebo with neoadjuvant chemotherapy was 21.03% (95% CI, 15.14% to 26.93%).

A similar magnitude of effect and 95% CI was observed at the pCR IA1 DCO. Per protocol, MPR statistical significance was tested and deemed statistically significant at the first IA (P = 0.000002); MPR was not retested for statistical significance at the final analysis.

Table 16: Summary of Key Tumour Response Efficacy Results From the AEGEAN Study

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DCO = data cut-off; FA = final analysis; IA1 = interim analysis 1; IXRS = interactive web response system; MPR = major pathological response; MTP = multiple testing procedure; NA = not applicable; pCR = pathological complete response; TC = tumour cell; vs. = versus.

^aAdjusted for multiplicity. Based on a Lan-DeMets alpha spending function with the O’Brien-Fleming boundary calculated using the actual number of patients at the interim vs. the final analysis, the boundary for declaring statistical significance is 0.0082% for a total 0.5% 2-sided alpha. Corresponding CIs are shown.

^bResponse is defined as having 0% residual viable tumour cells within all resected tissue, without R1 (microscopic residual tumour) or R2 (macroscopic residual tumour) margins, and without carcinoma in any examined lymph nodes at the time of resection as assessed by the central pathology laboratory.

^cCIs for response rate are calculated using the Clopper-Pearson exact method.

^dThe analysis was performed using a CMH test stratified by disease stage (stage II vs. stage III) and by PD-L1 expression status at baseline (TC < 1% vs. ≥ 1%), using the stratification factors from the IXRS. A difference > 0 favours perioperative durvalumab + neoadjuvant chemotherapy. CIs for difference in proportions are computed using the Miettinen and Nurminen’s stratified method.

^eBecause IA1 was statistically significant per the MTP, pCR and MPR were not retested for statistical significance at the FA.

^fResponse is defined as having 10% or less residual viable tumour tissue in the lung primary tumour at the time of resection as assessed by the central pathology laboratory.

Sources: AEGEAN study EFS IA1 Clinical Study Report.²⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Event-Free Survival

As of the EFS IA2 DCO on May 10, 2024, a total of 289 patients had experienced an EFS event (per RECIST 1.1) in the mITT population, with a lower percentage of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm experiencing an event than in the placebo with neoadjuvant chemotherapy arm (33.9% of patients [124 of 366] versus 44.1% of patients [165 of 374], respectively) (as detailed in Table 17). The median EFS was NR in the perioperative durvalumab with neoadjuvant chemotherapy arm (95% CI, 42.3 months to NR) and was 30.0 months (95% CI, 20.6 months to NR) in the placebo with neoadjuvant chemotherapy arm. The overall HR was 0.69 (95% CI, 0.55 to 0.88) (Figure 3). For patients in the perioperative durvalumab with neoadjuvant chemotherapy arm, the probability of remaining event-free from randomization to 12 months was 73.3% (95% CI, 68.1% to 77.7%), to 24 months was 65.0% (95% CI, 59.4% to 70.0%), and to 36 months was 60.1% (95% CI, 53.9% to 65.8%). For patients in the placebo with neoadjuvant chemotherapy arm, the corresponding probability of remaining event-free was 64.1% (95% CI, 58.7% to 69.0%) for randomization to 12 months, 54.4% (95% CI, 48.7% to 59.6%) to 24 months, and 47.9% (95% CI, 41.8% to 53.8%) to 36 months. Across time points, the difference in EFS probabilities for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy ranged from 9.2% (95% CI, ███ ██ ████) at 12 months to 12.2% (95% CI, ███ ██ ████) at 36 months. Results from the sensitivity and subgroup analyses were generally consistent with those of the main analysis. Forest plots of the subgroup analyses are presented in Figure 10 in Appendix 2.

A similar magnitude of effect and 95% CI was observed at the EFS IA1 DCO. Per protocol, EFS statistical significance was tested and deemed statistically significant at IA1 (P = 0.003902); EFS was not retested for statistical significance at EFS IA2.

Figure 3: KM Plot of EFS (Using BICR per RECIST 1.1) (mITT Population, EFS IA2)

BICR = blinded independent central review; CI = confidence interval; EFS = event-free survival; HR = hazard ratio; IA2 = interim analysis 2; mITT = modified intention to treat; NR = not reached; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1; SoC = standard of care.

Notes: EFS is defined as the time from randomization to the earliest progression of disease that precludes surgery or progression with surgery not completed, local or distant disease recurrence, or death due to any cause. Patients who have not experienced an EFS event at the time of analysis are censored at the time of the last disease assessment. If the event occurs after 2 or more consecutive missed visits, the patient is censored at the last disease assessment before the 2 missed visits. A new malignancy that is not NSCLC, as confirmed by pathology, is not considered an EFS event, as per RECIST 1.1.

The data cut-off date of the EFS IA2 was May 10, 2024.

Source: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³

Disease-Free Survival

At both the EFS IA1 and IA2 DCOs, DFS was tested but did not meet the prespecified boundary for declaring statistical significance (at EFS IA2, P = 0.013652 and with a P value of < 0.012303 was required to declare statistical significance at this IA) (Table 17). DFS remains eligible for formal statistical testing per the MTP and will be re-evaluated at the final analysis.

By May 10, 2024, 141 patients had experienced a DFS event (based on a BICR per RECIST 1.1) in the modified resected set, with more patients in the placebo with neoadjuvant chemotherapy arm experiencing an event than in the perioperative durvalumab with neoadjuvant chemotherapy arm (35.1% of patients [81 of 231] versus 24.8% of patients [60 of 242], respectively). While median DFS was NR in both arms, the overall HR was 0.66 (95% CI, 0.47 to 0.92) (Figure 4). For patients in the perioperative durvalumab with neoadjuvant chemotherapy arm, the probability of remaining disease-free from surgical resection to 12 months was 81.0% (95% CI, 75.2% to 85.5%), to 24 months was 75.1% (95% CI, 68.7% to 80.4%), and to 36 months was 71.2% (95% CI, 63.8% to 77.3%). For patients in the placebo with neoadjuvant chemotherapy arm, the corresponding probability of remaining disease-free to 12 months was 74.1% (95% CI, 67.8% to 79.3%), to 24 months was 62.4% (95% CI, 55.2% to 68.8%), and to 36 months was 61.4% (95% CI, 54.0% to 68.0%). Across time points, the difference in survival probabilities for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy ranged from 6.9% (95% CI, ████ ██ ████) at 12 months to 12.7% (95% CI, ███ ██ ████) at 24 months.

Figure 4: KM Plot of DFS (Using BICR per RECIST 1.1) (Modified Resected Set, EFS IA2)

BICR = blinded independent central review; CI = confidence interval; DFS = disease-free survival; EFS = event-free survival; HR = hazard ratio; IA2 = interim analysis 2; NR = not reported; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1; SoC = standard of care; vs. = versus.

Notes: The HR was calculated using a stratified Cox proportional hazards model. Stratification factors included disease stage (stage II vs. stage III) and PD-L1 (< 1% vs. ≥ 1%). An HR < 1 favours durvalumab + chemotherapy.

The data cut-off date was May 10, 2024.

Source: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³

Overall Survival

At both the EFS IA1 and EFS IA2 DCOs, OS was not eligible for statistical testing (this is because DFS was not statistically significant; therefore, OS was not formally tested based on the MTP).

At the time of EFS IA2 (May 10, 2024), 261 deaths had occurred in the mITT population, with a similar percentage occurring across treatment arms (33.1% of patients [121 of 366] in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 37.4% of patients [140 of 374] in the placebo with neoadjuvant chemotherapy arm); this was described in Table 17. The median OS was NR (95% CI, NR to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and was 53.2 months (95% CI, 44.3 months to NR) in the placebo with neoadjuvant chemotherapy arm; the HR was 0.89 (95% CI, 0.70 to 1.14) (Figure 5). For patients in the perioperative durvalumab with neoadjuvant chemotherapy arm, the probability of survival from randomization to 12 months was 84.3% (95% CI, 80.1% to 87.7%), to 24 months was 74.4% (95% CI, 69.5% to 78.6%), to 36 months was 67.1% (95% CI, 61.6% to 71.9%), and to 48 months was 57.6% (95% CI, 50.1% to 64.3%). For patients in the placebo with neoadjuvant chemotherapy arm, the corresponding probability of survival from randomization to 12 months was 85.3% (95% CI, 81.2% to 88.5%), to 24 months was 72.2% (95% CI, 67.3% to 76.5%), to 36 months was 63.9% (95% CI, 58.4% to 69.0%), and to 48 months was 52.9% (95% CI, 45.7% to 59.7%). Across time points, the difference in survival probabilities for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy ranged from −1.0% (95% CI, ████ ██ ████ at 12 months to 4.7% (95% CI, ████ ██ ████) at 48 months.

As of the EFS IA1 DCO, the median OS was NR in both arms; the HR was 1.02 (95% CI, 0.75 to 1.39).

Figure 5: KM Plot of OS (mITT Population, EFS IA2)

CI = confidence interval; EFS = event-free survival; HR = hazard ratio; IA2 = interim analysis 2; mITT = modified intention to treat; NR = not reported; OS = overall survival; SoC = standard of care.

Notes: A circle indicates a censored observation; 1 month = 30.4375 days.

OS is defined as the time from date of randomization until death due to any cause. Patients who had not experienced an OS event at the time of analysis were censored at the date last known alive.

HR is calculated using a stratified Cox proportional hazards model adjusted for disease stage and PD-L1 expression status at baseline. An HR < 1 favours durvalumab + chemotherapy, to be associated with longer OS than placebo + chemotherapy.

The data cut-off date was May 10, 2024.

Source: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³

Table 17: Summary of Key Survival Efficacy Results From the AEGEAN Study

BICR = blinded independent central review; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DCO = data cut-off; DFS = disease-free survival; EFS = event-free survival; HR = hazard ratio; IA1 = interim analysis 1; IA2 = interim analysis 2; IXRS = interactive web response system; mITT = modified intention to treat; MTP = multiple testing procedure; NA = not applicable; NC = not calculated; NR = not reported; NSCLC = non–small cell lung cancer; OS = overall survival; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1.

^aTwo missed visits rule applied.

^bCalculated using Kaplan-Meier technique.

^cCalculated using a stratified Cox proportional hazards model adjusted for disease stage and PD-L1 expression status at baseline. An HR < 1 favours perioperative durvalumab + neoadjuvant chemotherapy over placebo + neoadjuvant chemotherapy.

^dP value has been adjusted for multiple testing.

^eBased on a Lan-DeMets alpha spending function with an O'Brien-Fleming boundary with the observed number of events, the boundary for declaring statistical significance is 0.9899% for a 5% overall alpha, as per RECIST 1.1.

^fCalculated using a stratified log-rank test adjusting for disease stage and PD-L1 expression status at baseline.

^gAs IA1 was statistically significant per the MTP, this updated analysis is considered exploratory and a nominal P value has been included for information only rather than for formal hypothesis testing.

^hEstimated among the modified resected set.

ⁱDoes not include events occurring after 2 missed RECIST 1.1 assessments. A new malignancy that is not NSCLC, as confirmed by pathology, is not considered a DFS event.

^jA P value of < 0.012303 was required to declare statistical significance at IA2.

^kAt the DCO date of EFS IA1 and EFS IA2, OS was not eligible for statistical testing (because DFS was not statistically significant, OS was not formally tested based on the MTP).

Sources: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. ^24,23 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Health-Related Quality of Life

At the EFS IA1 DCO (November 10, 2022), HRQoL was evaluated in the mITT population for the neoadjuvant period using EORTC QLQ-C30 and EORTC QLQ-LC13; at the EFS IA2 DCO (May 10, 2024), HRQoL was reassessed in the modified resected set for the adjuvant period using just the EORTC QLQ-C30 measure.

At the EFS IA1 neoadjuvant baseline, the adherence rate for EORTC QLQ-C30 and EORTC QLQ-LC13 was █████ █████████ for the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ █████████ for the placebo with neoadjuvant chemotherapy arm; by week 12, these rates were █████ ████ evaluable forms/███ patients still under PRO follow-up at week 12) and █████ ████ evaluable forms/███ patients still under PRO follow-up at week 12). At neoadjuvant week 12, there were █████ of patients (███ out of ███ patients at baseline) available to provide assessments in the perioperative durvalumab with neoadjuvant chemotherapy group and █████ of patients (███ out of ███ patients at baseline) available to provide assessments in the placebo with neoadjuvant chemotherapy group.

At the EFS IA2 adjuvant baseline, the adherence rate was █████ █████████ and █████ █████████, respectively, and at week 44, they were █████ ████ evaluable forms/███ patients still under PRO follow-up at week 44) and █████ ████ evaluable forms/███ patients still under PRO follow-up at week 44). At adjuvant week 44, there were █████ of patients (███ out of ███ patients at adjuvant baseline) available to provide assessments in the perioperative durvalumab with neoadjuvant chemotherapy group and █████ of patients (███ out of ███ patients at adjuvant baseline) available to provide assessments in the placebo with neoadjuvant chemotherapy group.

Baseline EORTC QLQ-C30 and EORTC QLQ-LC13 were similar across both treatment arms (Appendix 3, Table 50 and Table 52). At adjuvant baseline, all scores other than ████ ███████████ (mean [standard deviation] perioperative durvalumab with neoadjuvant chemotherapy arm = ████ ███████ versus ████ ███████ in the placebo with neoadjuvant chemotherapy arm) and ██████ ███████████ (mean [standard deviation] perioperative durvalumab with neoadjuvant chemotherapy arm = ████ ███████ versus ████ ███████ in the placebo with neoadjuvant chemotherapy arm) were similar (Appendix 3, Table 51).

Given that the between-group differences in EORTC QLQ-C30 global health status and QoL, physical functioning, role functioning, fatigue, and appetite loss, and in EORTC QLQ-LC13 dyspnea, coughing, and pain in chest were estimated in the AEGEAN trial and deemed to be important by the clinical experts consulted for this review, these outcomes are reported in this section.

During the neoadjuvant period, the point estimate for the between-group difference for the change in EORTC QLQ-C30 global health status and QoL score from baseline to week 12 ███ ███ meet the MID threshold of 4 points (estimated mean difference [95% CI] = █████ ██████ ██ ██████ Table 18).⁶³ However, a between-group difference in the change in EORTC QLQ-C30 global health status and QoL score from adjuvant baseline to week 44 of █████ ████ ████████ ██ ██████ was observed during the adjuvant period (Table 19)

During the neoadjuvant period, the largest between-group difference for the change in scores from baseline to week 12 was observed in the ███████ domain of the EORTC QLQ-C30 (estimated mean difference [95% CI] = ████ █████ ██ ██████ and the smallest was for ████ ██ █████ measured by EORTC QLQ-LC13 (estimated mean difference [95% CI] = █████ ██████ ██ ██████ Table 18). During the adjuvant period, only the EORTC QLQ-C30 was measured and the largest between-group difference for the change in scores from adjuvant baseline to week 44 was ████ ███████████ (estimated mean difference [95% CI] = █████ ███████ ██ ███████ and the smallest was for ████████ ████ (estimated mean difference [95% CI] = ████ ██████ ██ ████; Table 19).

Table 18: Change From Neoadjuvant Baseline to Week 12 in EORTC QLQ-C30 Version 3 and EORTC QLQ-LC13 Scores by MMRM Analysis (mITT Population)

CI = confidence interval; EFS = event-free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; IA1 = interim analysis 1; mITT = modified intention to treat; MMRM = mixed model of repeated measures.

Notes: The analysis was performed using an MMRM analysis of change from baseline for all postbaseline adjuvant visits, with treatment, visit, and treatment by visit interaction included as explanatory variables and the baseline score as a covariate. Neoadjuvant baseline was the last predose assessment or screening if this is missing. Time points are only included if at least 20 patients are present in each treatment group.

A higher score on the global measure of health status and quality of life and functioning scales indicates better health status and function; thus, a positive change score reflects improvement. Higher scores on symptom scales and items represent greater symptom severity; thus, a negative change score reflects improvement.

The data cut-off date was November 10, 2022.

^aNot adjusted for multiple testing.

Sources: AEGEAN study EFS IA1 Clinical Study Report.²⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 19: Change From Adjuvant Baseline to Week 44 in EORTC QLQ-C30 Version 3 Scores by MMRM Analysis (Modified Resected Set)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; MMRM = mixed model of repeated measures.

Notes: The analysis was performed using an MMRM analysis of change from baseline for all postbaseline adjuvant visits, with treatment, visit, and treatment by visit interaction included as explanatory variables and the baseline score as a covariate. Adjuvant baseline is the latest measurement after surgery but before the first dose of adjuvant treatment. Time points are only included if at least 20 patients were present in each treatment group.

A higher score on the global measure of health status and quality of life and functioning scales indicates better health status and function; thus, a positive change score reflects improvement. Higher scores on symptom scales and items represent greater symptom severity; thus, a negative change score reflects improvement.

The data cut-off date was May 10, 2024.

^aNot adjusted for multiple testing.

Sources: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Safety Evaluation Plan

Data presented in this section are from the EFS IA2 DCO (May 10, 2024). An overview of safety data is initially presented for the modified safety analysis set (consisting of all patients in the AEGEAN trial who received at least 1 dose of the study treatment and excluding those whose tumours had EGFR mutations or ALK gene rearrangements; N = 367 for the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 370 for the placebo with neoadjuvant chemotherapy arm). As granular safety data were not available for the modified safety analysis set, additional data are presented for the safety analysis set, which consists of all randomized patients who received at least 1 dose of study treatment, with treatment arm allocation in accordance with the treatment actually received. The safety analysis set consisted of 799 patients (N = 401 in the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 398 in the placebo with neoadjuvant chemotherapy arm).

Table 20 presents data for the modified safety analysis set and Table 21 presents safety data from the overarching safety analysis set; both tables present data from the EFS IA2 DCO. Table 22 presents summaries of AEs for the safety analysis set from the EFS IA2 DCO by study period (i.e., neoadjuvant period, postsurgery period, adjuvant period, and overall study period).

Adverse Events

At the EFS IA2 DCO of May 10, 2024, a ███████ percentage of patients in both treatment arms of the modified safety analysis set experienced 1 or more AE over the course of treatment (█████ ████████ in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ ████████ in the placebo with neoadjuvant chemotherapy arm).

Similar results were observed in the safety analysis set (96.5% of patients [387 of 401] in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 95.2% of patients [379 of 398] in the placebo with neoadjuvant chemotherapy arm). The 3 most frequently reported AEs in both treatment arms of the safety analysis set were anemia (34.9% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 32.2% in the placebo with neoadjuvant chemotherapy arm), nausea (25.7% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 29.9% in the placebo with neoadjuvant chemotherapy arm), and constipation (25.9% in the perioperative durvalumab with neoadjuvant chemotherapy arm and 29.9% in the placebo with neoadjuvant chemotherapy arm).

Grade 3 or grade 4 AEs occurred in a ███████ percentage of patients in both arms of the modified safety analysis set arms (██████████████ in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ ████████ in the placebo with neoadjuvant chemotherapy arm). Similarly, in the overall safety analysis set, 43.6% of patients (175 of 401) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 43.2% of patients (172 of 398) in the placebo with neoadjuvant chemotherapy arm experienced a grade 3 or grade 4 AE.

Serious AEs

There were ████████ ████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set who experienced 1 or more SAE (█████ █████████) than in the placebo with neoadjuvant chemotherapy arm (█████ █████████).

Similar results were observed over the same time period in the overall safety analysis set (39.2% of patients [157 of 401] in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 31.7% of patients [126 of 398] in the placebo with neoadjuvant chemotherapy arm experienced 1 or more SAE). In the safety analysis set, the 4 most frequently reported SAEs in the perioperative durvalumab with neoadjuvant chemotherapy arm were pneumonia (5.7%), anemia (1.7%), COVID-19 (1.7%), and pneumonitis (1.7%) while in the placebo with neoadjuvant chemotherapy arm, they were pneumonia (4.5%), pneumothorax (2.3%), anemia (1.3%), and COVID-19 (1.3%).

Withdrawals Due to AEs

████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set prematurely stopped study treatment (i.e., durvalumab, placebo, or chemotherapy) due to AEs than in the placebo with neoadjuvant chemotherapy arm (█████ ████████ versus █████ ███████, respectively).

Similar results were observed in the safety analysis set (19.5% of patients [78 of 401] in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 9.8% of patients [39 of 398] in the placebo with neoadjuvant chemotherapy arm discontinued treatment due to AEs), with the most common AEs leading to treatment discontinuation being blood and lymphatic system disorders and respiratory, thoracic, and mediastinal disorders in the perioperative durvalumab with neoadjuvant chemotherapy arm compared to respiratory, thoracic, and mediastinal disorders and investigations in the placebo with neoadjuvant chemotherapy arm.

Mortality

As of May 10, 2024, in the modified resected set ████ ████████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and ████ ███████) of patients in the placebo with neoadjuvant chemotherapy arm experienced an AE resulting in death.

Results were similar in the safety analysis set, with 5.7% of patients (23 of 401) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 3.8% of patients (15 of 398) in the placebo with neoadjuvant chemotherapy arm who experienced an AE resulting in death. In this analysis set, the most common AE in both arms resulting in death was infections and infestations.

Notable Harms

By May 10, 2024, in the modified safety analysis set, ████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm had experienced an AESI or AEPI ██████ ████████) than in the placebo with neoadjuvant chemotherapy arm (█████ █████████). imAEs occurred in █████ ████████) of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and in █████ ███████) of patients in the placebo with neoadjuvant chemotherapy arm.

Similar results were observed in the safety analysis set over the same time period (66.8% of patients [268 of 401] in the perioperative durvalumab with neoadjuvant chemotherapy arm and 52.5% of patients [209 of 398] in the placebo with neoadjuvant chemotherapy arm experienced an AESI or AEPI), with ███████████████ events being the most common type in both arms. ImAEs occurred in 25.4% of patients [102 of 401] in the perioperative durvalumab with neoadjuvant chemotherapy arm and 10.3% of patients [41 of 398] in the placebo with neoadjuvant chemotherapy arm.

Table 20: Overview of AEs by Category (Modified Safety Analysis Set — Overall Study Period at EFS IA2)

AE = adverse event; AEPI = adverse event of potential interest; AESI = adverse event of special interest; EFS = event-free survival; IA2 = interim analysis 2; PT = preferred term; SAE = serious adverse event.

Note: The data cut-off date was May 10, 2024.

^aPatients with multiple events in the same category are counted only once in that category. Patients with events in more than 1 category are counted once in each of those categories.

^bStudy treatment refers to durvalumab and/or placebo or any chemotherapy and does not include surgery.

^cTaken from the SURG module.

^dDue to either an AE or unresolved toxicity.

^eAn AESI or AEPI is of scientific and medical interest to the study treatment. An AESI or AEPI may be serious or nonserious. Incudes AEs between the date of the first dose and the earliest of the following: the maximum date of (last dose or surgery) + 90 days, or the date of the first dose of subsequent anticancer therapy. Includes AEs with an onset date during this period and AEs with an onset date before dosing that worsen during this period.

Sources: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 21: Summary of Key Harms Data in the AEGEAN Study (Safety Analysis Set — Overall Study Period at EFS IA2)

AE = adverse event; AEPI = adverse event of potential interest; AESI = adverse event of special interest; EFS = event-free survival; IA2 = interim analysis 2; imAE = immune-mediated adverse event; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event.

Notes: Includes AEs between the date of the first dose and the earliest of the following: the maximum date of (last dose or surgery) + 90 days or the date of the first dose of subsequent anticancer therapy. Includes AEs with an onset date during this period and AEs with an onset date before dosing that worsen during this period.

Reported by preferred term per MedDRA version 25.1.

The data cut-off date was May 10, 2024.

^aPatients with multiple events are counted once per preferred term.

^bAction taken: Drug permanently discontinued. Study treatment includes durvalumab, placebo, and chemotherapy.

Sources: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 22: Overview of AEs by Category and by Study Treatment Period (Safety Analysis Set at EFS IA2)

AE = adverse event; AEPI = adverse event of potential interest; AESI = adverse event of special interest; EFS = event-free survival; IA2 = interim analysis 2; NA = not applicable; PT = preferred term; SAE = serious adverse event.

Note: The data cut-off date was May 10, 2024.

^aPatients with multiple events in the same category are counted only once in that category. Patients with events in more than 1 category are counted once in each of those categories.

^bStudy treatment refers to durvalumab, placebo, and any chemotherapy and does not include surgery.

^cTaken from the SURG form. Note that 1 additional patient in the placebo + neoadjuvant chemotherapy arm had an AE leading to surgery not done (5 patients in total), without an AE number (identifying the PT) specified on the SURG form.

^dTaken from the SURG form (including AE and unresolved toxicity). Note that 1 additional patient in the durvalumab + chemotherapy arm had an AE (unresolved toxicity) leading to a delay in surgery, without an AE number (identifying the PT) specified on the SURG form (16 patients in total) and 1 additional patient in the placebo + neoadjuvant chemotherapy arm had an AE leading to a delay in surgery, without an AE number (identifying the PT) specified on the SURG form (17 patients in total).

Sources: AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures.²³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

The AEGEAN study is a double-blind, placebo-controlled, phase III RCT. The study used computer-generated blocked randomization with stratification based on PD-L1 status and disease stage. Allocation concealment methods were adequate. With the exception of a higher percentage of males and a slightly higher percentage of squamous histology in the perioperative durvalumab with neoadjuvant chemotherapy arm — which was deemed to be likely attributable to chance — the study generally reports balanced baseline characteristics suggesting that randomization was successful. Further, the postrandomization exclusion of those with known EGFR mutations or ALK rearrangements were judged not to be related to treatment group assignment, and therefore were not expected to introduce bias. The patients, investigators, and study centre staff were all blinded to the durvalumab or placebo allocation while the study centre pharmacists were unblinded. In the case of a medical emergency, investigators could request to be unblinded.

Patient disposition was similar across both mITT arms, with a similar percentage of patients in each arm completing neoadjuvant treatment, receiving and completing surgery, receiving PORT, and completing adjuvant treatment. As of the most recent DCO on May 10, 2024, no patients had been lost to follow-up (defined as no contact established by the time of the DCO such that there was insufficient information to determine the patient’s status at that time). However, 20 patients had withdrawn consent (i.e., withdrawn from further study treatment and declined to allow any further follow-up information to be obtained: 12 of 366 patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and 8 of 374 patients in the placebo with neoadjuvant chemotherapy arm). The disallowed concomitant medications administered in the AEGEAN study did not raise any concerns on the outcome measures of the study.

pCR, MPR, EFS, DFS, and OS end points were addressed using the multiplicity hierarchical testing procedure, which controlled for type I error. The criteria used for disease progression and tumour response are based on radiographic images and clinical assessment, with the potential for subjective interpretation. To mitigate this potential bias, a blinded IRC reviewed all available radiographic tumour assessments to determine tumour response based on RECIST 1.1 criteria. As such, the risk of bias resulting from unblinding due to unbalanced harms across treatment arms is lower for pCR, MPR, and survival outcomes; however, there are some concerns for HRQoL outcomes.

While pCR and MPR are based on final analyses, EFS, DFS, OS, and HRQoL results should be interpreted in light of the fact that these are based on IAs, which may overestimate treatment effects.²⁰ The HRs and CIs for survival outcomes were estimated from the stratified Cox proportional hazards model adjusted for stratification factors, which relies on the assumption of proportional hazards in both treatment arms. Statistically, there was insufficient evidence to suggest that the nonproportional hazards assumption had been violated from the Grambsch-Therneau proportional hazards test (at EFS IA2, P value for EFS = █████, P value for OS = █████, P value for DFS = █████). However, for EFS and OS results, there was some evidence from visual inspection of log-log plots and a Schoenfeld residuals plot that the proportional hazards assumption may have been violated. Visual inspection of the KM plots by the CDA-AMC review team revealed that for EFS and DFS, the curves for the intervention and comparator treatment did not separate until approximately 4 months. In the KM plot for OS, the curves crossed multiple times and did not begin to separate until approximately 34 months. As such, it is possible that the estimated HRs for these end points may be misleading, given that HRs may not remain constant over time. Nevertheless, all relevant information contributed to the evaluation of these end points, and the overall certainty of evidence was not affected because it was informed by absolute between-group differences in event-free probabilities at clinically relevant time points. While subgroup analyses were planned a priori and generally showed consistent results with those of the main analysis, they may not have been powered to identify differences.

While there was an adequate number of patients at risk in the AEGEAN trial for earlier DFS and OS time points, only about 11% of patients in both treatment arms remained at risk for OS at 48 months and 13% to 19% remained at risk for DFS at 36 months, resulting in substantial uncertainty in results at later time points. At the time of the EFS IA2 DCO, the median OS had not yet been reached in the perioperative durvalumab with neoadjuvant chemotherapy group. Across the treatment groups, 35% of patients had died. Visual inspection of the KM curves suggests substantial censoring after 24 months in both groups, contributing to uncertainty in the OS results, particularly at longer follow-up times. OS was not eligible for statistical testing at this IA because DFS was not statistically significant.

At the most recent DCO on May 10, 2024, DFS and OS data remained statistically nonsignificant, with the median time to a DFS event NR in either treatment group and the median time to a survival event only reached in the placebo with neoadjuvant chemotherapy group. Further, results for DFS and adjuvant HRQoL were estimated among the modified resected set (n = 473) and, because this is a subgroup of the mITT population (n = 740), randomization was not maintained, so there is an increased risk of prognostic imbalances across the treatment arms in this analysis population.

While previous systematic literature reviews (SLRs) and meta-analyses have found positive correlations between EFS and DFS with OS,^68,69 results are limited to treatment with neoadjuvant and adjuvant chemotherapy, which cannot be generalized to perioperative durvalumab. As such, the validity of EFS or DFS as a surrogate for OS in the current context is unknown.

While a ███████ percentage of patients in both treatment arms of the modified safety analysis set experienced any AE over the course of treatment, ████ patients in the perioperative durvalumab with neoadjuvant chemotherapy arm stopped treatment early due to AEs and had an imAE. Clinical experts consulted for this review indicated the ██████ percentage of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm experiencing an imAE was expected and deemed the safety profile to be acceptable.

A higher percentage of patients in the placebo with neoadjuvant chemotherapy arm received subsequent anticancer therapy than in the perioperative durvalumab with neoadjuvant chemotherapy arm. This differential could potentially introduce a confounding effect on OS because the survival results might be partially attributable to treatments administered after disease progression rather than the study treatment itself. However, the risk of bias due to deviations from the intended interventions in the AEGEAN trial was deemed to be low and clinical experts confirmed that the subsequent anticancer treatments used in the AEGEAN trial were in line with those used in clinical practice in Canada. Further, given that subsequent treatments are expected to be used in real-world clinical practice, this limitation is not expected to impact the generalizability of the results.

Biases resulting from the self-reporting nature of HRQoL outcomes were deemed to be minimal given that patients were blinded to the intervention received. In the EORTC QLQ-C30 analyses, █████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ of patients in the placebo with neoadjuvant chemotherapy arm were available to provide assessments at week 12 of the neoadjuvant period. In the modified resected set, by week 44 of the adjuvant period █████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ of patients in the placebo with neoadjuvant chemotherapy arm were available to provide EORTC QLQ-C30 assessments. No data imputations were involved in these analyses, so there is a risk of bias due to missing outcomes data. Further, given that analyses of the HRQoL end points were not adjusted for multiple testing, there is an increased risk of type I error for statistically significant results.

External Validity

With the exception of excluding those with an ECOG PS score of 2, the clinical experts consulted for this review felt the inclusion and exclusion criteria used in the AEGEAN study were generally aligned with what would be expected in NSCLC clinical trials. While the AEGEAN trial only enrolled 8 Canadians in the ITT population (4 in each arm), which may lower the generalizability of the results to the setting in Canada, clinical experts consulted for this review deemed the baseline characteristics to align with those seen in clinical practice in Canada. Nonetheless, there were a few generalizability concerns. For example, the study primarily included Asian and white patients (704 of 740 patients [95.1%] in the mITT population), potentially limiting the generalizability of findings to Canadians of different racial groups. There were relatively few patients who were younger than 50 years (37 of 740 patients [5.0%] in the mITT population) and who were aged 75 years or older (80 of 740 patients [10.8%] in the mITT population). The clinical experts consulted on this review indicated that the age distribution was in line with clinical practice in Canada, where NSCLC is relatively rare in people aged younger than 50 years. Finally, there were relatively few patients who had stage IIA NSCLC (42 of 740 patients [5.7%] in the mITT population); however, the clinical experts consulted for this review noted that the low percentage of patients with stage IIA disease is expected because these patients are typically treated with surgery followed by adjuvant treatment. The distribution of the remaining patients across NSCLC stage IIB (23.1% of patients [172 of 740]), stage IIIA (45.7% of patients [338 of 740]), and stage IIIB (25.1% of patients [186 of 740]) was in line with what clinical experts would expect to see in the clinical setting in Canada.

The outcomes measured in the AEGEAN trial evaluated the key treatment goals identified by patient input collected for this review and were deemed to be relevant by clinical experts consulted for this review. Further, clinical experts consulted for this review deemed the efficacy and harms outcomes of the AEGEAN trial’s comparator arm, placebo with neoadjuvant chemotherapy, to be in line with their expectations. When the AEGEAN study initially started recruiting patients, neoadjuvant chemotherapy followed by surgery was common practice for the treatment of resectable NSCLC; however, clinical experts consulted for this review noted that this treatment strategy is now rarely used in clinical practice and surgery followed by adjuvant chemotherapy may be a more relevant comparator. The clinical experts consulted for this review noted that currently, the 2 most commonly used regimens in clinical practice in Canada are neoadjuvant nivolumab with chemotherapy and adjuvant chemotherapy. According to the clinical experts consulted for this review, adjuvant atezolizumab monotherapy after surgery and adjuvant chemotherapy for patients with PD-L1 of 50% or greater was the least relevant comparator because the treatment decision for perioperative durvalumab has to be made before surgery, whereas the approach for adjuvant atezolizumab would be considered after surgery and adjuvant chemotherapy. In addition to the standard of care chemotherapy regimens used in the AEGEAN study, clinical experts indicated that in Canada, carboplatin and gemcitabine could also be used for squamous cell NSCLC and cisplatin and vinorelbine may also sometimes be used for both squamous and nonsquamous cell NSCLC. The lack of these regimens used for standard chemotherapy in the AEGEAN study further limits the generalizability to the setting in Canada; however, clinical experts consulted for this review noted that they would feel comfortable combining perioperative durvalumab with these regimens.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^21,22

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy for adults with resectable NSCLC without any EGFR mutations or ALK rearrangements. The selected outcomes for GRADE assessment include OS, EORTC QLQ-C30 global health score and QoL, EFS, pCR, imAEs, and SAEs.

Long-Term Extension Studies

No long-term extension studies were submitted.

Indirect Evidence

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

In the absence of head-to-head trial data of durvalumab in combination with chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery (also termed as perioperative durvalumab with neoadjuvant chemotherapy throughout this section) compared with relevant comparators for the treatment of patients with resectable (tumours ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, the sponsor conducted 3 ITCs: 2 MAICs that assessed the comparative efficacy (i.e., EFS) of perioperative durvalumab with neoadjuvant chemotherapy versus neoadjuvant nivolumab with chemotherapy and versus perioperative pembrolizumab with chemotherapy, and an NMA that assessed the efficacy (i.e., EFS) of perioperative durvalumab with neoadjuvant chemotherapy versus adjuvant chemotherapy (i.e., surgery + adjuvant chemotherapy), and surgery only. The objective of this section is to summarize and critically appraise the sponsor-submitted ITCs.

Description of Indirect Comparisons

The objective of the ITCs (1 NMA and 2 MAICs) was to compare the treatment effect on EFS of perioperative durvalumab with neoadjuvant chemotherapy with relevant comparators in resectable NSCLC, including nivolumab in combination with platinum-based doublet chemotherapy in the neoadjuvant setting (the CheckMate 816 study,^16,70-74 also termed as neoadjuvant nivolumab with chemotherapy throughout this section), pembrolizumab in combination with platinum-based chemotherapy in the perioperative setting, adjuvant chemotherapy, and surgery only.

Study Selection Methods

An SLR was conducted in July 2022 to identify clinical evidence (efficacy and safety) from RCTs that enrolled adults with stage I to stage III NSCLC who were candidates for surgical resection and had received any or no treatment before surgery. The SLR was supplemented with a targeted literature review in September 2022 to identify RCTs of immunotherapies (atezolizumab, durvalumab, nivolumab, and pembrolizumab) in the adjuvant setting for patients with completely resected NSCLC. Updates to both the SLR and targeted literature review were conducted in October 2023. Published data for the AEGEAN study were identified as part of the SLR update.^56,75-77 No other new studies relevant to the EFS networks were identified in the October 2023 search. Following the October 2023 search, the clinical trial landscape and literature were monitored for new data relevant to comparators considered in the ITC until the time of submission to CDA-AMC in August 2024. Results from the AEGEAN study EFS IA2 became available and more recent EFS data were presented at clinical congresses from the CheckMate 816 trial.¹⁷ The SLR was not updated, but the new data cuts were assessed in an ITC addendum.⁷⁸ Study selection criteria and methods are summarized in Table 23.

Table 23: Study Selection Criteria and Methods for Indirect Comparisons