CADTH Reimbursement Review

Amivantamab (Rybrevant)

Sponsor: Janssen Inc.

Therapeutic area: Non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Submitted for Review

EGFR = epidermal growth factor receptor; NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions; NSCLC = non–small cell lung cancer.

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada. In 2022, it was estimated that there would be 30,000 new cases of lung cancer diagnosed, and 20,700 deaths from lung cancer in Canada. It is estimated that 1 in 18 men, and 1 in 20 women, will die of lung cancer.¹ Lung cancer is classified as either non–small cell lung cancer (NSCLC) or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada.² Lung cancer symptoms may be nonspecific. The most common symptoms include unspecific cough, chest and shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, and fever.³

Approximately 15% of Canadians with NSCLC have an epidermal growth factor receptor (EGFR)–activating mutation in the region encoding the tyrosine kinase domain.^4-6 The most common activating EGFR mutations arise from exon 19 deletions or exon 21 L858R point substitutions, accounting for 85 to 90% of EGFR mutations.^5-11 Exon 20 insertion mutations are the third most common EGFR mutations, occurring in less than or equal to 12% of all EGFR mutations globally, though a Canadian-based retrospective observational cohort study suggested that this may only occur in approximately 4% of NSCLC EGFR mutations in Canada.¹² It has been estimated that patients with EGFR exon 20 insertion make up between 0.1% and 4.0% of all NSCLC cases globally and approximately 0.4% to 0.6% of overall NSCLC cases in Canada.^13,14

First-line standard of care (SOC) for patients with locally advanced or metastatic NSCLC harbouring EGFR exon 20 insertion mutations remains platinum-based chemotherapy (cisplatin or carboplatin),⁶ generally in combination with pemetrexed, followed by pemetrexed maintenance, though gemcitabine, vinorelbine, or paclitaxel are approved but rarely used. Following failure of first-line platinum-doublet chemotherapy, second-line treatment options are limited to single-agent non–platinum-based chemotherapeutic drugs, primarily docetaxel. For lack of a better option, EGFR tyrosine kinase inhibitors (TKIs), immunotherapy (IO), or platinum rechallenge may be used based on chart reviews and real-world evidence collected in Canada. The sponsor suggested that variability in treatment patterns exists in Canadian clinical practice, with patients receiving EGFR TKIs, platinum-based chemotherapy, or IOs in combination with platinum-based chemotherapy or chemotherapy in the front-line setting. Patients who progress on first-line therapy may receive an alternative drug class (often either EGFR TKI or IO) and, if progression continues, the terminal therapy may be supportive care or docetaxel, if not previously received, due to its toxicity.¹⁵ The sponsor suggested that, based on a retrospective population-based cohort study in patients with metastatic NSCLC with EGFR mutations (n = 6,666) receiving second-line therapy in Alberta, Canada, real-world median overall survival (OS) of patients with EGFR exon 20 insertion mutations was 8.1 months (95% confidence interval [CI], 6.0 to not reached) compared to patients with EGFR exon 19 deletions (median OS = 17.8; 95% CI, 13.7 to 20.1) or exon 21 L858R mutations (median OS = 14.9; 95% CI, 11.4 to 21.9).^12,15

Amivantamab is indicated by Health Canada for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.¹⁶ The Health Canada Notice of Compliance with conditions was granted on March 30, 2022, based on the October 2020 data cut-off (DCO), through Project Orbis. Conditions for authorization are pending the results of confirmatory and other ongoing trials including the phase III PAPILLON trial, which aims to evaluate the efficacy of amivantamab in combination with chemotherapy in the first-line treatment of locally advanced or metastatic EGFR exon 20 insertion NSCLC, and the final report for CHRYSALIS to verify the clinical benefit of amivantamab.¹⁵ The sponsor is requesting that amivantamab be reimbursed as per the indication from Health Canada. Amivantamab has not been previously reviewed by CADTH.

The objective of the current report is to review the beneficial and harmful effects of amivantamab (1,050 mg for patients weighing less than 80 kg, and 1,400 mg for patients weighing greater than or equal to 80 kg) for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.

Stakeholder Perspectives

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

Patient Input

Two patient groups, Lung Cancer Canada (LCC) and the Lung Health Foundation, submitted patient group input for this review. LCC gathered data through phone interviews with 4 EGFR-positive NSCLC patients, 2 of whom have EGFR exon 20 insertion mutations. All 4 patients were diagnosed with stage IV NSCLC and are currently part of the clinical trial for amivantamab in Ontario. The Lung Health Foundation obtained input from patients with lung cancer via an online survey (2 respondents) and telephone interviews (3 respondents), none of whom had experience with the treatment under review.

Input from LCC highlighted that conventional TKIs have poor efficacy in a majority of EGFR exon 20 insertion subtypes and therefore treatment options for these patients are limited, indicating a significant unmet need in this population. LCC respondents recalled their initial distress at receiving a stage IV NSCLC diagnosis. They cited various psychosocial effects, including anxiety and depression; however, symptoms such as a persistent cough and back pain were often mild. Respondents to both patient groups reported that future lung cancer treatments should be effective in curing their disease rather than slowing progression (though delayed disease progression remains important), provide additional treatment options with improved management of disease symptoms, and have minimal or manageable side effects so that they can participate in regular activities while on treatment and allow them to maintain quality of life (QoL). Regarding their experience with the treatment under review, the most common adverse events (AEs) were skin related, including inflammation of the nail bed, rashes on the face and legs, acne, and dry and sensitive skin. Other side effects that were reported include severe dry mouth, slight vision deterioration, severe muscle pain the first few days after treatment, fatigue, chronic constipation, and yeast infections. Some patients stated that although the side effect burden was more than what they had experienced with other targeted therapies, they would not consider discontinuing treatment because the hope of survival outweighed the side effects experienced. Two patients who began amivantamab as a first-line treatment stated that when they were feeling well, they were able to participate in physical activities and work they previously enjoyed and that they hoped to be able to continue to maintain their independence, functionality, and health-related quality of life (HRQoL). Two patients who were able to take amivantamab as a third-line treatment expressed the relief of having an additional treatment option after exhausting other alternatives. According to the Lung Health Foundation input, respondents found the psychosocial effects of having a disease with a poor prognosis challenging, as was maintaining relationships with families and friends. Patients noted that side effects related to some previous treatments severely affected their ability to participate in daily activities and their HRQoL.

Clinician Input

Input From Clinical Experts Consulted by CADTH

In patients with NSCLC with EGFR exon 20 insertion mutations, the clinical experts emphasized that not all patients benefit from current therapies, stating that there is a need for molecularly targeted therapies in this patient population due to the limited activity of EGFR TKIs or IO therapy in patients with exon 20 insertion mutations.

Currently, the mainstay of treatment for patients with EGFR exon 20 insertion mutations is platinum-doublet chemotherapy, most commonly cisplatin or carboplatin plus pemetrexed, followed by maintenance pemetrexed in first-line therapy. Docetaxel or pemetrexed would be used in second-line therapy following failure of platinum-based chemotherapy. According to the clinical experts, unless patients have private insurance, EGFR TKIs are not funded as second-line therapy, and activity with IO or TKIs is limited. The clinical experts believe that amivantamab would be used as monotherapy in patients with exon 20 insertion mutations following failure of platinum-doublet chemotherapy, displacing the current second-line and third-line options, though it would be reasonable to use amivantamab in any subsequent line of therapy. The clinical experts expressed that there is an unmet need for effective new treatment options that would improve QoL, delay progression or prolong survival, and reduce disease-related symptoms through demonstrated response to treatment.

Per the indication for amivantamab, patients are required to have confirmed EGFR exon 20 insertion mutations, though the clinical experts highlighted that there is no data to identify certain subgroups that do not benefit from therapy with amivantamab. The experts noted that treatment with amivantamab should be discontinued due to disease progression or unacceptable toxicity that cannot be managed. The experts noted that the trial allowed treatment beyond progression, where patients who originally had meaningful improvement before progression may still experience some benefit. The clinical experts noted that patients with NSCLC are typically under the care of expert medical and thoracic oncologists, and that, given the method of administration and potential for adverse reactions, patients should receive treatment in cancer-specific institutions under the supervision of an appropriately trained cancer specialist or unit with expertise in treating lung cancers and experience in managing infusion reactions, which are common and may be severe. Due to the difficulty in obtaining robust survival estimates in this rare population, tumour response or disease stabilization resulting in improvements in disease-related symptoms are the most meaningful outcomes. The clinical experts noted that, in clinical practice, response would be assessed every 9 to 12 weeks.

Clinician Group Input

Clinician group input was received from 2 groups: LCC – Medical Advisory Committee (LCC-MAC), with 21 clinicians contributing to the submission; and from the Ontario Health – Cancer Care Ontario (OH-CCO) Lung Cancer Drug Advisory Committee, with input from 5 clinicians. Based on global estimates, the LCC-MAC input noted that approximately 200 to 1,000 patients are diagnosed with EGFR exon 20 insertion NSCLC in Canada each year and experience resistance to the first-generation and second-generation EGFR TKIs. The clinician group also highlighted the rarity of the indication, stating that less than 2% of all EGFR exon 20 insertion NSCLC patients would be candidates for second-line amivantamab therapy, given the high number of patients considered to be too sick to receive first-line or second-line therapy for locally advanced or metastatic NSCLC. The clinician groups highlighted the poor prognosis for patients with locally advanced or metastatic NSCLC EGFR exon insertion due to the lack of effective targeted therapies, and emphasized a significant unmet need for novel targeted therapies that prolong progression-free survival (PFS) and improve HRQoL. Clinician groups stated that the ideal treatment for these patients should directly inhibit the driver mutation; be well tolerated, with a predictable and low toxicity profile; have a durable response; and correlate with an improvement in QoL. Both clinician groups stated that patients most likely to respond to amivantamab are those with an EGFR exon 20 insertion mutation. The clinician groups also stated that next-generation sequencing (NGS) is routinely conducted in all patients with advanced NSCLC with a non-squamous and squamous histology, and without a smoking history. In terms of place in therapy, the OH-CCO input notes that amivantamab would be used after all standard therapies acceptable to the patient have failed, usually following platinum-doublet chemotherapy with or without immunotherapy and maintenance pemetrexed, or after docetaxel therapy. The LCC-MAC also notes that such targeted therapies against driver mutations should ideally be offered in a first-line setting for maximal efficacy and that clinical trials are ongoing in this setting. Both submissions stated that a clinically meaningful end point is a radiological response to treatment. The submissions indicated that the drug should be administered at a cancer centre, infusion clinic, or hospital (outpatient) setting by a specialist or personnel experienced in administering chemotherapy drugs.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for continuation or renewal of therapy, considerations for discontinuation of therapy, considerations for prescribing of therapy, generalizability, funding algorithm issues, care provision issues, and system and economic issues. Refer to Table 3 for more details.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One study was included in the review. Study EDI1001 (CHRYSALIS) is an ongoing, phase I/Ib, single-arm, open-label, multicentre study of amivantamab as monotherapy in advanced NSCLC that includes both a dose-escalation phase (part 1) to determine the recommended phase II dose (RP2D) of amivantamab, and a dose-expansion phase (part 2) in which patients were treated with the RP2D of 1,050 mg amivantamab (1,400 mg for patients weighing greater than or equal to 80 kg). Treatment in part 2 was delivered once weekly for the first 4 weeks and then once every 2 weeks starting at week 5 until disease progression or unacceptable toxicity. A total of 489 patients across part 1 and part 2 received treatment with amivantamab monotherapy. Within part 2, individual cohorts were defined by mutation and previous treatment. Of interest to this review was cohort D, which enrolled a total of 153 patients with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. The primary outcome of the CHRYSALIS trial was overall response rate (ORR) per investigator and blinded independent central review (BICR) assessment in the primary efficacy population (patients who had undergone greater than or equal to 3 postbaseline disease assessments; N = 81), with secondary outcomes consisting of clinical benefit rate (CBR) and best overall response, PFS, OS, duration of response (DOR), and time to treatment failure (TTF).¹⁷

In the safety analysis set (patients who received ≥ 1 dose of amivantamab; N = 153), most patients were diagnosed with stage IV adenocarcinoma (78.9%). The median age of patients enrolled in cohort D was 61.0 years, and the majority of patients were Asian (62.1%), female (61.4%), and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (72.5%); 36 (23.5%) patients had brain metastases at baseline. The median number of prior lines of therapy was 2, and all patients received prior platinum-based chemotherapy (mostly carboplatin; 65.4%).¹⁷ Baseline characteristics for the primary efficacy population and the additional efficacy population were consistent with the safety analysis set.

Efficacy Results

At the time of the March 30, 2021, DCO, the median follow-up was 14.5 months. In the primary efficacy population (N = 81), a total of 31 (38.3%; 95% CI, 27.7% to 49.7%) patients achieved an ORR per investigator assessment, and 35 (43.2%; 95% CI, 32.2% to 54.7%) patients achieved ORR per BICR. Best response to treatment per investigator assessment consisted of only partial responses (PRs) (31; 38.3%), while 12 (14.8%) patients had a best response of progressive disease (PD). The results of subgroup analyses by age group, sex, race, smoking history, and prior IO therapy were consistent with the primary analyses. Among the 31 responders, the median duration of treatment was 14.03 months, and the median DOR was 12.45 months (95% CI, 6.54 to 16.13).¹⁷

As of the March 30, 2021, DCO, the median PFS was 8.25 months (95% CI, 5.49 to 12.32), and a total of 57 (70.4%) PFS events had occurred. The progression-free rate for amivantamab per investigator assessment was 75% (95% CI, 64% to 83%) at 3 months, 58% (95% CI, 47% to 68%) at 6 months, and 40% (95% CI, 29% to 50%) at 12 months. The progression-free rate for amivantamab per investigator assessment was 75% (95% CI, 0.64 to 0.83) at 3 months, 58% (95% CI, 0.47 to 0.68) at 6 months, and 40% (95% CI, 0.29 to 0.50) at 12 months. The median OS was estimated at 22.77 months (95% CI, 17.48 to not estimable). The estimated survival rates were 90% (95% CI, 81% to 95%) at 6 months, 74% (95% CI, 63% to 83%) at 12 months, and 41% (95% CI, 21% to 59%) at 24 months.¹⁷

Harms Results

All patients in cohort D of the CHRYSALIS trial experienced 1 or more treatment-emergent adverse events (TEAEs). The most frequent TEAEs were infusion-related reactions (IRRs), paronychia, rash, dermatitis acneiform, hypoalbuminemia, and stomatitis. Grade 3 or higher TEAEs were reported in 64 (41.8%) patients, with the most frequent consisting of pulmonary embolism, hypokalemia, diarrhea, dyspnea, hypoalbuminemia, paronychia, pneumonia, IRRs, and neutropenia. A total of 44 (28.8%) patients experienced serious adverse events (SAEs); the most frequently reported SAEs were pneumonia, dyspnea, pulmonary embolism, back pain, muscular weakness, and pneumonitis.¹⁷

IRRs were the most frequent reason for infusion modifications, reported in 90 (58.8%) patients. Dose reductions were reported in 22 (14.4%) patients, mostly due to dermatitis acneiform and paronychia, while dose interruptions were reported in 55 (35.9%) patients, mainly due to IRRs (15.0%). In total, 18 (11.8%) patients withdrew from treatment with amivantamab due to TEAEs, most frequently pneumonia, IRRs, pleural effusion, and pneumonitis.¹⁷

Overall, 11 (7.2%) patients treated with amivantamab experienced a TEAE leading to death, with respiratory, thoracic, and mediastinal disorders the most common TEAE leading to death in 6 (3.9%) patients. As of the March 30, 2021, DCO, 45 (29.4%) patients in the CHRYSALIS trial died, primarily due to PD (31; 20.3%).¹⁷

The most frequent notable harm associated with amivantamab included IRRs (97; 63.4%), most of which were nonserious (grade 1 or 2) and occurring mainly on day 1 of cycle 1 (66.3%), and rash events (130; 85.0%), which were also mostly grade 1 or 2, and occurred mostly during the first treatment cycle. Other notable harms included interstitial lung disease (ILD) (6; 3.9%), paronychia (81; 52.9%), and ophthalmologic disorders (19; 12.4%).¹⁷

Table 2: Summary of Key Results From Pivotal and Protocol Selected Studies (Investigator Assessed; March 30, 2021, DCO)

AE = adverse event; BICR = blinded independent central review; CI = confidence interval; CR = complete response; DCO = data cut-off; DOR = duration of response; IRR = infusion-related reaction; NA = not applicable; NE = not estimable; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; SD = stable disease; WDAE = withdrawal due to adverse event.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021).¹⁷

Critical Appraisal

CHRYSALIS was a first-in-human phase I/Ib clinical study with the primary purposes of determining the RP2D (part 1) and subsequently assessing the safety of the selected dose in part 1 and estimating the clinical activity of amivantamab (part 2). A phase I/b or phase II trial may not accurately predict the harm or effectiveness of treatments. The clinical experts consulted by CADTH noted that, despite the high unmet need, conducting a randomized controlled trial (RCT) in this setting with a targeted therapy, such as amivantamab, compared to the available therapies currently used in Canadian clinical practice, would likely not be feasible. No inferential statistical testing was performed for the efficacy outcomes in cohort D; thus, no P values were reported. Point estimates with 95% CIs were reported to estimate the magnitude of treatment effect. The threshold for a positive study outcome for cohort D was observing a 95% CI for ORR with a lower limited larger than 12%. Interpretation of time‐to‐event end points such as OS or PFS is limited in single‐arm studies; because all patients in cohort D received the same treatment, the extent to which the observed survival is due to the natural history of the tumour or the intervention remains unclear. The results for patient-reported outcomes (PROs) were inconclusive given the small sample size (N = 36); the noncomparative, open-label design of the trial; the substantial decline in patients available to provide assessments over time; and the descriptive nature of the analysis.

The clinical experts conducted by CADTH indicated that although the inclusion and exclusion criteria were appropriate, they hypothesized that the exclusion criteria may have been restrictive, selecting for ideal patients who were less severely ill. The clinical experts also noted that the baseline characteristics of the included population were generally reflective of Canadian clinical practice; however, there was a high proportion of patients who were Asian (62.1%) enrolled, though this was not considered likely to affect the generalizability of the results per the clinical experts.

The noncomparative design of the CHRYSALIS trial precludes the ability to assess the relative therapeutic benefit or safety of amivantamab against currently available therapies in Canadian clinical practice. As noted previously, the clinical experts consulted by CADTH agreed that direct randomized comparisons between amivantamab and currently used therapies are unlikely to take place for advanced or metastatic NSCLC with exon 20 insertion that has progressed after platinum-based chemotherapy. In the absence of a direct comparison of amivantamab with relevant treatment options, the sponsor submitted an adjusted treatment comparison using external control arms derived from real-world data sources. The results of the adjusted treatment comparison favoured amivantamab for ORR, PFS, and OS compared to treatment of physician’s choice. The CADTH review team identified several limitations (e.g., concerns regarding heterogeneity across the study designs and populations and the inability to adjust for important potential confounders and prognostic variables across each cohort) and concluded that no firm conclusions could be drawn about how amivantamab compared to other relevant treatment options. However, the clinical experts consulted by CADTH anticipated that based on the CHRYSALIS results and on poor results with existing treatment options in clinical practice, amivantamab would likely offer improved and clinically meaningful benefits compared with currently available therapies.

Indirect Comparisons

Adjusted Treatment Comparison

Description of Studies

The sponsor submitted an adjusted treatment comparison that compared the efficacy of amivantamab from individual patient data (IPD) from cohort D (N = 81) of the single-arm CHRYSALIS trial to current treatments using an external control arm derived from real-world data sources from the US, the UK, Germany, and France. The primary objective of the sponsor-submitted adjusted treatment comparison was to compare the efficacy (ORR, OS, PFS, time to next treatment [TTNT]) of amivantamab in the CHRYSALIS trial (cohort D) to current treatments from real-world settings in patients with advanced EGFR NSCLC with exon 20 insertion mutations following platinum-based chemotherapy.¹⁸

Amivantamab was compared to both a pooled basket of treatments, labelled as physician’s choice, and individual treatment classes (TKI, IO, non–platinum-based chemotherapy, vascular endothelial growth factor inhibitor [VEFGi] plus chemotherapy–, and other–based regimens). Data from the 4 European data sources were pooled to create a European Union (EU) cohort, and collectively compared against amivantamab. Data from the 3 US data sources were also pooled to create the US cohort. Additionally, all data sources were combined to create a US plus EU cohort.¹⁸

Efficacy Results

In all comparisons, CHRYSALIS was the index trial, consisting of the primary efficacy population (N = 81). In the comparison to physicians’ choice, the EU plus US cohort included 349 patients, with 206 from the US cohort and 143 from the EU cohort. In the comparison of CHRYSALIS to the different treatment classes in the EU plus US cohort, there were 60, 89, 76, 58, and 66 patients in the TKI, IO, non–platinum-based chemotherapy, VEFGi plus chemotherapy, and other groups, respectively.¹⁸

For the primary outcome of ORR, the adjusted ORR was 38.3% for amivantamab compared to █████ for physicians’ choice for the EU plus US cohort (odds ratio [OR] = █████████████████████]; relative risk ratio = ██████████████████████). The adjusted ORR for amivantamab versus physicians’ choice in the US cohort was 38.3% versus █████ (OR = ██████████████████████; relative risk ratio = █████████████████████), and 38.3% versus █████ in the EU cohort (OR = ████████████████████; relative risk ratio = ██████████████████████). Results for the individual treatment classes were consistent with the primary analysis; however, they were hindered by small sample sizes.¹⁸

For OS, amivantamab was favoured over physicians’ choice in the EU plus US cohort (hazard ratio [HR] = █████████████████████████), US cohort (HR = █████████████████████████), and EU cohort (HR = ████████████████████████) after adjustment. The median OS for amivantamab was at 22.77 months (95% CI, 17.48 to not estimable) compared to █████ months (██████████████████), █████ months (██████████████████), and █████ months (█████████████████) from the EU plus US cohort, the US cohort, and the EU cohort, respectively. Compared to the individual treatment classes, amivantamab was favoured after adjustment in all cases.¹⁸

For PFS, amivantamab was favoured over physicians’ choice in the EU plus US cohort (HR = █████████████████████████), US cohort (HR = ████████████████████████), and EU cohort (HR = █████████████████████████) after adjustment. The median PFS for amivantamab was 8.25 months (95% CI, 5.49 to 12.32) compared to ████ months (████████████████), ████ months ██████████████████, and ████ months ██████████████████ from the EU plus US cohort, the US cohort, and the EU cohort, respectively.¹⁸

Critical Appraisal

The choice to conduct an adjusted treatment comparison of amivantamab and external real-world data cohorts as a comparator arm was justified by the lack of a comparator arm for the CHRYSALIS trial. Data derived from 7 international real-world data sources were used for the comparison with amivantamab; therefore, there is a high risk of selection bias. Moreover, the methods and reasons for selecting these specific databases were unknown. Data analyzed retrospectively from databases and medical records are more prone to unique biases (e.g., selection bias, confounding, limited data availability) compared with those collected from prospective interventional studies that cannot be fully controlled for. In general, comparisons with externally generated cohorts also suffer from the potential of missing information.

There was notable heterogeneity in the populations included in the adjusted treatment comparison. Inclusion and exclusion criteria from cohort D of the CHRYSALIS trial were applied to all real-world data sources to select the appropriate population. Any criteria that could not be applied to patients from a given data source due to missing data were omitted, which may have resulted in unaccounted-for differences in patient populations. It was unclear how many potential patients were excluded following the application of inclusion and exclusion criterion from CHRYSALIS. Appropriately, all patients in the analysis had confirmation of EGFR exon 20 insertion mutation positivity. However, due to limited data availability, ECOG performance status, which was noted as an important prognostic factor by the clinical experts consulted by CADTH, was not included in the inverse probability weighting (IPW) adjustment for the EU plus US cohort or the EU cohort, potentially resulting in some unaccounted-for heterogeneity. No consideration or covariate adjustment was given to follow-up duration, and the time of assessment for end points was unknown. As a result, it is uncertain whether the follow-up times between CHRYSALIS and the real-world data sources are comparable, and may also contribute to heterogeneity, especially for survival analyses.

Multiple comparative analyses were performed for the CHRYSALIS population versus the various data sources. Individual real-world data sources from Europe and from the US were pooled to increase sample size. The sponsor noted that pooling of the EU and US cohorts into a single combined cohort was possible due to the high consistency between the results and a comparable treatment distribution of the EU and US cohorts; however, the observable differences in baseline characteristics of populations between the EU and US cohorts, as well as the significant missing data between databases, may have resulted in significant heterogeneity in the population, though this was not explored and remains uncertain. Additionally, amivantamab was compared to both a pooled basket of treatments (physicians’ choice), and various treatment class regimens (TKIs, IOs, non-platinum-based chemotherapy, VEGFi, and other). Pooling of treatments for the physicians’ choice group assumes equivalence of treatment benefit; however, it is unclear how exclusion of treatments irrelevant to the Canadian context such as VEGFis would have affected the results, because this was not explored.

The results of the adjusted treatment comparisons were consistent across end points and statistical methodologies, generally favouring amivantamab over physicians’ choice across end points, as well as for the individual treatment classes. However, there was notable imprecision in all cases, as demonstrated by the moderately to severely wide 95% CIs, though the reason for this imprecision was unknown and may be due to small sample sizes and unexplored heterogeneity.

In summary, given the phase I/Ib nature of the CHRYSALIS trial and the lack of a comparator arm, the ability to make definitive conclusions on the comparative efficacy of amivantamab was limited. Comparisons using the external control arms derived from real-world data sources were subject to substantial uncertainty and risk of bias due to the methods of data collection, small sample sizes, and high degree of heterogeneity due to pooling assumptions, as well as the limited data availability for important confounders and potential prognostic factors, including ECOG performance status in the EU and EU plus US cohorts. Additionally, outcomes important to patients including HRQoL and AEs were not analyzed in the adjusted treatment comparisons; thus, the comparative efficacy of amivantamab on these outcomes remains uncertain.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH.

Conclusions

One phase I/Ib, single-arm, open-label trial (CHRYSALIS; cohort D) provided evidence for the efficacy and safety of amivantamab in adult patients with metastatic or unresectable NSCLC who harboured EGFR exon 20 insertion mutations and failed on, or progressed after, platinum-based chemotherapy. The CHRYSALIS trial achieved the predetermined threshold for a positive outcome (lower limit of the 95% CI for ORR greater than 12%) in cohort D. The clinical experts consulted by CADTH felt that the achieved ORR per investigator assessment of 38.3% (43.2% per BICR) (March 30, 2021, DCO date) was clinically meaningful for the target population and durable (median DOR 12.45 months, 95% CI, 6.54 to 16.13). In the opinion of the clinical experts, the observed responses appeared higher than what is seen with currently used therapies in the target setting. There was uncertainty around the magnitude of the clinical benefit given the limitations in the evidence from the noncomparative phase I/Ib clinical trial. While time-to-event end points, OS, and PFS, appeared supportive of the observed ORR, the nonrandomized design of the CHRYSALIS trial made interpreting the PFS and OS events attributable to amivantamab challenging. The CADTH clinical assessment identified limitations with the sponsor’s adjusted treatment comparison (including small sample sizes, heterogeneity across study designs and pooled populations, and the inability to adjust for important potential confounders and prognostic variables), which substantially limited the ability to interpret the relative treatments effects observed between amivantamab and other treatments. The results for HRQoL and symptom severity were exploratory outcomes and remained inconclusive due to a number of important limitations. Harms associated with amivantamab were largely consistent with treatments based on EGFR inhibition and were considered manageable according to the clinical experts consulted by CADTH. Overall, the ability to draw firm conclusions on the magnitude of clinical benefit and safety of amivantamab was limited given the limitations in the evidence.

Introduction

Disease Background

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada. Survival from lung cancer of all stages and types is poor, with an overall 5-year net survival rate of 19%.¹ In 2022, it was estimated that there would be 30,000 new cases of lung cancer diagnosed and 20,700 deaths from lung cancer in Canada. It is estimated that 1 in 18 men, and 1 in 20 women, will die of lung cancer.¹

Lung cancer is classified as either NSCLC or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada.² NSCLC is further classified into 3 main histologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

To determine prognosis and treatment, NSCLC is staged using the American Joint Committee on Cancer staging criteria, which involves TNM (tumour, node, metastasis) classification of the disease based on the size and spread of the primary tumour (T), lymph node involvement (N), and occurrence of metastasis (M).¹⁹ Approximately half of all lung cancer cases in Canada are stage I to stage III at diagnosis.² Early-stage NSCLC is often asymptomatic.^3,19 If patients do present with symptoms, they are often unspecific and difficult to directly attribute to a lung cancer diagnosis. The most common symptoms include unspecific cough, chest and shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, and fever.³ Diagnostic procedures include imaging of the lungs, sputum cytology, and tissue biopsy.

Approximately 15% of Canadians with NSCLC have an EGFR-activating mutation in the region encoding the tyrosine kinase domain.^4-6 EGFR mutations are more frequently observed in those who have never smoked, people of Asian descent, patients with adenocarcinoma, and females.^4,20 The most common activating EGFR mutations arise from exon 19 deletions or exon 21 L858R point substitutions, accounting for 85% to 90% of EGFR mutations.^5-9 Exon 20 insertion mutations are the third most common EGFR mutations, occurring in less than or equal to 12% of all EGFR mutations, though a Canadian-based retrospective observational cohort study suggested that this may only occur in approximately 4% of NSCLC EGFR mutations in Canada,¹² It has been estimated that patients with EGFR exon 20 insertion make up between 0.1% and 4% of all NSCLC cases globally and approximately 0.4% to 0.6% of overall NSCLC cases in Canada.^13-15

Standards of Therapy

Progress has been made in treating EGFR-mutated NSCLC with the introduction of EGFR TKIs. First-, second-, and third-generation EGFR TKIs have activity in NSCLC tumours harbouring sensitizing EGFR gene mutations that demonstrate improved efficacy compared with chemotherapy in delaying disease progression in first-line treatment of locally advanced or metastatic NSCLC.⁶ However, though similar to other EGFR mutations in biology and epidemiology, patients with advanced NSCLC whose tumours harbour uncommon EGFR mutations (i.e., EGFR exon 20 insertion or de novo exon 20 T790M mutations) are TKI resistant as a result of an altered enzyme active site that sterically hinders TKI binding, resulting in low response rates (0% to 9%) with approved EGFR TKIs.^6,21-26 As such, the first-line SOC in Canada for patients with EGFR exon 20 insertion mutations remains platinum-based chemotherapy (cisplatin or carboplatin), generally in combination with pemetrexed followed by pemetrexed maintenance, although gemcitabine, vinorelbine, paclitaxel, or docetaxel may be used,⁶ with a median OS of 16 months, compared with 39 months in EGFR TKI-sensitive disease treated with TKIs.^24,27-32

Following failure of first-line platinum-doublet chemotherapy, second-line treatment options are limited to non–platinum-based chemotherapeutic drugs, primarily docetaxel. After first-line platinum-based chemotherapy, it is estimated that only about 50% of patients go on to subsequent lines of therapy.³³ For lack of a better option, EGFR TKIs, immunotherapy, or platinum rechallenge may be used based on chart reviews and real-world evidence collected in Canada. The sponsor suggested that variability in treatment patterns exists in Canadian clinical practice, with patients receiving EGFR TKIs, platinum-based chemotherapy, or IOs in combination with platinum-based chemotherapy or chemotherapy in the front-line setting. Patients who progress on first-line therapy may receive an alternative drug class (often either EGFR TKI or IO) and, if progression continues, the terminal therapy may be supportive care or docetaxel, if not previously received, due to its toxicity.¹⁵ The sponsor suggested that, based on a retrospective population-based cohort study in patients with metastatic NSCLC with EGFR mutations (n = 6,666) receiving second-line therapy in Alberta, Canada, real-world median OS of patients with EGFR exon 20 insertion mutations was 8.1 months (95% CI, 6.0 to not reached) compared to patients with EGFR exon 19 deletions (median OS = 17.8; 95% CI, 13.7 to 20.1) or exon 21 L858R mutations (median OS = 14.9; 95% CI, 11.4 to 21.9).^12,15

Drug

Amivantamab is indicated by Health Canada for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.¹⁶ The Health Canada Notice of Compliance with Conditions was granted on March 30, 2022, based on the October 2020 DCO, through Project Orbis. The conditions for authorization include the submission of the phase III PAPILLON study, which aims to evaluate the efficacy of amivantamab in combination with chemotherapy in the first-line treatment of locally advanced or metastatic EGFR exon 20 insertion NSCLC and is expected to complete in late 2025, and the final study report for CHRYSALIS, including efficacy results on at least 129 patients who have been followed for at least 6 months from the date of initial response. Additional progress reports of other ongoing trials are also required, as well as ongoing safety monitoring.¹⁵ The sponsor is requesting that amivantamab be reimbursed as per the indication from Health Canada. Amivantamab has not been previously reviewed by CADTH.

Amivantamab is a bispecific antibody that binds to the extracellular domains of the EGFR and mesenchymal-epithelial transition (MET) receptors, disrupting EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of these receptors. The presence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity and trogocytosis mechanisms, respectively.¹⁶

Amivantamab is administered via IV infusion once weekly via split infusion on days 1 and 2 of cycle 1, and then on days, 8, 15, and 22, followed by every 2 weeks starting at week 5 (cycle 2). The recommended dose of amivantamab is based on patient body weight at baseline. If patients weigh less than 80 kg, the recommended dose of amivantamab is 1,050 mg, representing 3 vials of amivantamab. In patients weighing greater than or equal to 80 kg at baseline, the recommended dose of amivantamab is 1,400 mg, representing 4 vials of amivantamab. Antihistamines, antipyretics, and glucocorticoids must be administered before the initial infusion (week 1, days 1 and 2) to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics must be administered before all infusions, and glucocorticoids administered as necessary. Amivantamab should be used until disease progression or unacceptable toxicity.¹⁶

Stakeholder Perspectives

Patient Group Input

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

Two patient groups, LCC and the Lung Health Foundation, submitted patient group input for this review. LCC gathered data through phone interviews with 4 EGFR-positive NSCLC patients, 2 of whom have EGFR exon 20 insertion mutations. All 4 patients were diagnosed with stage IV NSCLC and are currently enrolled in the clinical trial for amivantamab in Ontario. The Lung Health Foundation obtained input from patients with lung cancer via an online survey (2 respondents) and telephone interviews (3 respondents) conducted between September and December 2021, none of whom had experience with the treatment under review.

Input from LCC highlighted that conventional TKIs have poor efficacy in a majority of EGFR exon 20 insertion subtypes and therefore treatment options for these patients are limited, indicating a significant unmet need in this population. LCC respondents recalled their initial distress at receiving a stage IV NSCLC diagnosis, citing various psychosocial effects including anxiety and depression; given their mild symptoms of a persistent cough and back pain. Respondents to both patient groups reported that future lung cancer treatments should be effective in curing their disease rather than slowing progression (though delayed disease progression remains important), provide additional treatment options with improved management of disease symptoms, and have minimal or manageable side effects so that they can participate in regular activities while on treatment and allow them to maintain QoL. Regarding their experience with the treatment under review, the most common AEs were skin related, including inflammation of the nail bed, rashes on the face and legs, acne, and dry and sensitive skin. Other side effects that were reported include severe dry mouth, slight vision deterioration, severe muscle pain the first few days after treatment, fatigue, chronic constipation, and yeast infections. Some patients stated that although the side effect burden was more than what they had experienced with other targeted therapies, they would not consider discontinuing treatment because the hope of survival outweighed the side effects experienced. Two patients who began amivantamab as a first line of treatment stated that when they were feeling well, they were able to participate in physical activities and work they previously enjoyed and that they hoped to be able to continue to maintain their independence, functionality, and HRQoL. Two patients who were able to take amivantamab as a third-line treatment expressed the relief of having an additional treatment option after exhausting other alternatives. According to the Lung Health Foundation input, respondents found the psychosocial effects of having a disease with a poor prognosis challenging, as was maintaining relationships with families and friends. Patients noted that side effects related to some previous treatments severely affected their ability to participate in daily activities and their HRQoL.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH 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, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of NSCLC.

Unmet Needs

The clinical expert stated that although EGFR exon 20 insertion mutations are considered the third most common mutation, they are quite rare, effective current therapies are limited, and there is a need for molecularly targeted therapies in this patient population. The clinical experts emphasized that not all patients benefit from current therapies. Current second-line treatments after failure of platinum-based chemotherapy consist of docetaxel, though EGFR TKIs or IO may be used as a last line of therapy if available. However, they have limited activity for exon 20 insertion mutations.

The clinical experts expressed that there is an unmet need for effective new treatment options that improve QoL, delay progression or prolong survival, and reduce disease-related symptoms through demonstrated response to treatment.

Place in Therapy

Unless there is an appropriate clinical trial available, platinum-doublet chemotherapy, most commonly cisplatin or carboplatin plus pemetrexed followed by maintenance pemetrexed, is first-line SOC in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Following failure of first-line therapy, docetaxel or pemetrexed would be used, and patients may receive nivolumab, pembrolizumab, or atezolizumab as another line of therapy. The clinical experts stated that the ORR to first-line platinum-based doublet is approximately 30% and is only about 10% for second-line therapy. In general, unless patients have private insurance, EGFR TKIs are not funded as second-line therapy, and activity with IO or TKIs is limited.

The clinical experts believe that amivantamab would be used as monotherapy in patients with exon 20 insertion mutations following failure of platinum-doublet chemotherapy, displacing the current second- and third-line options, though it would also be reasonable to use amivantamab in any subsequent line of therapy. It was also noted that there are currently no data to support combinations of amivantamab with other drugs in this patient population; however, clinical trials investigating combinations are ongoing. The clinical experts also highlighted that there are several drugs currently in development for this patient population, some of which are unavailable in Canada, though optimal sequencing of this class of drugs and activity following failure or resistance are unclear.

Patient Population

Per the indication for amivantamab, patients are required to have locally advanced or metastatic NSCLC with confirmed EGFR exon 20 insertion mutations. Genetic testing for EGFR mutations is standard across Canada, most commonly through polymerase chain reaction or NGS. In line with the trial criteria, patients with brain metastases must have received treatment for these before commencing amivantamab. The clinical experts highlighted that there is no data to identify certain subgroups that do not benefit from therapy with amivantamab.

Assessing Response to Treatment

The clinical experts stated that the most meaningful outcomes in this patient population are delayed progression and improved OS; however, given that these outcomes are difficult to measure in individual patients, tumour response (or shrinkage) or disease stabilization resulting in improvements in disease-related symptoms is the most meaningful outcome in clinical practice.

In the clinical trial, response was assessed every 6 weeks. The clinical experts noted that, in clinical practice, response would be assessed every 9 to 12 weeks.

Discontinuing Treatment

The clinical experts suggested that treatment with amivantamab should be discontinued due to disease progression or unacceptable toxicity that cannot be managed. The experts noted that the trial allowed treatment beyond progression, in which patients who originally had meaningful improvement before progression may still experience some benefit. The experts also noted that patients with evidence of benefit in their systemic disease who develop central nervous system progression should have their central nervous system metastases treated appropriately and then be allowed to continue treatment with amivantamab if they are otherwise well.

Prescribing Conditions

The clinical experts noted that patients with NSCLC are typically under the care of expert medical and thoracic oncologists. The experts highlighted that given the method of administration and potential for adverse reactions, patients should receive treatment with amivantamab in cancer-specific institutions or infusion clinics under the supervision of an appropriately trained cancer specialist or unit with expertise in treating lung cancers and experience in managing infusion reactions, which are common and may be severe.

Additional Considerations

The clinical experts highlighted the paucity of available randomized data in this population given the rarity of EGFR exon 20 insertion mutations, clinical equipoise, and the strong unmet need.

Clinician Group Input

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

Clinician group input was received from 2 groups: LCC-MAC, with 21 clinicians contributing to the submission; and the OH-CCO Lung Cancer Drug Advisory Committee, with input from 5 clinicians. Based on global estimates, the LCC-MAC input noted that approximately 200 to 1,000 patients are diagnosed with EGFR exon 20 insertion NSCLC in Canada each year and experience resistance to the first-generation and second-generation EGFR TKIs. The clinician group also highlighted the rarity of the indication, stating that less than 2% of all EGFR exon 20 insertion NSCLC patients would be candidates for second-line amivantamab therapy, given the high number of patients considered to be too sick to receive first-line or second-line therapy for locally advanced or metastatic NSCLC. The clinician groups highlighted the poor prognosis for patients with locally advanced or metastatic NSCLC EGFR exon 20 insertion due to the lack of effective targeted therapies, and emphasized a significant unmet need for novel targeted therapies that prolong PFS and improve HRQoL. Clinician groups stated that the ideal treatment for these patients should directly inhibit the driver mutation; be well tolerated, with a predictable and low toxicity profile; have a durable response; and correlate with an improvement in QoL. Both clinician groups stated that patients most likely to respond to amivantamab are those with an EGFR exon 20 insertion mutation, and stated that NGS is routinely conducted in all patients with advanced NSCLC with a non-squamous and squamous histology, without a smoking history. In terms of place in therapy, the OH-CCO input notes that amivantamab would be used after all standard therapies acceptable to the patient have failed, usually following platinum-doublet chemotherapy with or without immunotherapy and maintenance pemetrexed, or after docetaxel therapy. The LCC-MAC also notes that such targeted therapies against driver mutations should ideally be offered in a first-line setting for maximal efficacy and that clinical trials are ongoing in this setting. Both submissions stated that a clinically meaningful end point is radiological response to treatment. The submissions indicated that the drug should be administered at a cancer centre, infusion clinic, or hospital (outpatient) setting by a specialist or personnel experienced in administering chemotherapy drugs.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s 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 by CADTH are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Response

BICR = blinded independent central review; CNS = central nervous system; CR = complete response; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; IO = immuno-oncology; NGS = next-generation sequencing; NSCLC = non–small cell lung cancer; PCR = polymerase chain reaction; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; TKI = tyrosine kinase inhibitor.

Clinical Evidence

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

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of amivantamab (50 mg/mL) 1,050 mg for patients weighing less than 80 kg, and 1,400 mg for patients weighing greater than or equal to 80 kg for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 4. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 4: Inclusion Criteria for the Systematic Review

AE = adverse event; DOR = duration of response; EGFR = epidermal growth factor receptor; HRQoL = health-related quality of life; ILD = interstitial lung disease; IO = immuno-oncology; IRR = infusion-related reactions; NSCLC = non–small cell lung cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; SAE = serious adverse event; TKI = tyrosine kinase inhibitor; TTNT = time to next treatment; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁴

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

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on May 19, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on September 14, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³⁵ Included in this search were the websites of regulatory agencies (the US FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

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

A focused literature search for indirect treatment comparisons (ITCs) dealing with EGFR-mutated NSCLC was run in MEDLINE All (1946–) on May 18, 2022. No limits were applied. The literature search for ITCs identified 93 articles; however, no articles evaluated the efficacy and safety of amivantamab in patients with NSCLC with EGFR exon 20 insertion.

Findings From the Literature

A total of 60 studies were identified from the literature, with 1 study selected for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 5. At the time of this review, the CADTH literature search did not identify any phase III studies that are planned or currently enrolling patients with EGFR exon 20 insertion NSCLC in the post–platinum-based chemotherapy setting. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 5: Details of Included Studies

AE = adverse event; CBR = clinical benefit rate; CHF = congestive heart failure; CR = complete response; ctDNA = circulating tumour DNA; DBP = diastolic blood pressure; DCO = data cut-off; DOR = duration of response; DVT = deep vein thrombosis; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; EQ-5D-5L = 5-level EQ-5D; ILD = interstitial lung disease; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; MET = mesenchymal-epithelial transition; MI = myocardial infarction; MUGA = multigated acquisition; NSCLC-SAQ = Non–small Cell Lung Cancer Symptom Assessment Questionnaire; NYHA = New York Heart Association; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PR = partial response; QTcF = corrected QT interval using Fridericia formula; RECIST = Response Evaluation Criteria in Solid Tumors; SBP = systolic blood pressure; SOC = standard of care; TKI = tyrosine kinase inhibitor; TTF = time to treatment failure.

Source: CHRYSALIS Clinical Study Report interim analysis 1.³⁶

Description of Studies

One study was included in the review. Study EDI1001 (CHRYSALIS) is an ongoing, phase I/Ib, open-label, single-arm, multicentre study of amivantamab as monotherapy in patients with advanced NSCLC that includes both a dose-escalation phase (part 1), and a dose-expansion phase (part 2). The primary objective of part 1 of the CHRYSALIS study was to determine the maximally tolerated dose (MTD), if 1 existed (part 1 monotherapy dose escalation only), and the RP2D for patients with NSCLC treated with amivantamab. For part 2, the primary objective was to determine the safety, tolerability, and antitumour activity of amivantamab at the RP2D, and to estimate the antitumour activity of amivantamab at the RP2D in selected populations of patients with documented EGFR or MET mutation(s) who have progressed after treatment with SOC.³⁶

A diagram of the study design for the monotherapy cohorts is provided in Figure 3. In part 1, a 3 plus 3 design was utilized to determine the MTD and the RP2D regimen(s) for amivantamab in patients with advanced NSCLC. Initially, 3 to 6 patients received amivantamab to achieve at least 3 dose-limiting toxicities (DLTs). If none of the first 3 DLT evaluable patients experienced a DLT, dose escalation proceeded with a new cohort. If 1 out of the first 3 DLT evaluable patients experienced a DLT, at least 3 additional patients were enrolled and treated at that dose level for safety. Under these circumstances, all additional patients in the cohort must have completed cycle 1 of treatment and if there was no occurrence of DLT in any additional DLT evaluable patients (i.e., less than 33% of patients at the current dose level have experienced DLT), then further dose escalation may have proceeded. Otherwise, the dose level with less than 33% of patients experiencing a DLT was considered the MTD.

Figure 2: Dose-Escalation Scheme of the CHRYSALIS Trial

DLT = dose-limiting toxicity; MTD = maximally tolerated dose.

Source: CHRYSALIS Clinical Study Report interim analysis 1.³⁶

In part 1, the starting dose of amivantamab was 140 mg, administered as an IV infusion once weekly for 4 weeks (cycle 1), then every 2 weeks thereafter during subsequent cycles until DLT. In the absence of DLT, dose escalation included planned dose cohorts of 140 mg, 350 mg, 700 mg, 1,050 mg, 1,400 mg, and 1,750 mg. Only toxicities that occurred during the period from the start of the first amivantamab infusion on cycle 1, day 1 through day 28 were used for the purpose of defining a DLT. Dose escalation was stopped when the MTD, defined as the highest dose level at which less than 33% of patients treated at that level experienced a DLT, was reached.³⁶

Intrapatient dose escalation was allowed in part 1, with patients able to move from a lower dose level to the next higher dose level, if that dose has been previously declared safe according to the safety review process, after consultation with the sponsor’s medical monitor and in the absence of disease progression. Patients must tolerate at least 2 cycles at the dose at which they were enrolled (and at least 1 cycle at subsequent dose levels, if applicable) and receive approval from the medical monitor before being escalated to the next dose level.

In part 2, patients with advanced or metastatic NSCLC who had a previously diagnosed activating EGFR and/or MET mutation, measurable disease, and disease progression following prior systemic anticancer therapy were enrolled into 2 separate molecularly defined tumour subgroups (Cohorts A and B). Cohorts A and B were closed with study amendment 4 (further defined in the following section), and Cohorts C, D, MET-1, and MET-2 were added with Amendment 4.³⁶ Note that only cohort D is of interest to this review because its patient population aligns with the requested reimbursement criteria. The current analysis presents the results of amivantamab monotherapy after platinum-based chemotherapy in patients who harboured EGFR exon 20 insertion mutations. Results for other cohorts will not be summarized and appraised.

Figure 3: Design of the CHRYSALIS Study: Monotherapy Cohorts

EGFR = epidermal growth factor receptor; MET = mesenchymal-epithelial transition; RP2D = recommended phase II dose; TKI = tyrosine kinase inhibitor.

Source: Sponsor submission.¹⁵

Across part 1 and part 2, patients with previously diagnosed activating EGFR exon 20 insertion mutation who had not been previously treated with a TKI with known activity in exon 20 insertion disease (e.g., poziotinib) but who had received treatment with a platinum-based chemotherapy regimen were enrolled into cohort D, in which patients were treated with the RP2D identified in part 1. This cohort was closed globally to further enrolment on May 29, 2020, except for in Japan and China,^17,36 though the reason was not provided.¹⁵

The end of study was planned to occur 6 months after the last patient had completed study treatment with 6 or more months of follow-up.¹⁵

As of the first interim analysis, with a clinical cut-off of June 8, 2020 (median follow-up of 5.1 months), a total of 362 patients received at least 1 dose of amivantamab across part 1 and part 2, including 114 patients enrolled into cohort D. The primary efficacy population included 81 patients, and the safety analysis set consisted of 114 patients. There was 1 Canadian study site, which enrolled 6 patients into cohort D.³⁶

At the third interim analysis, with a clinical cut-off of March 30, 2020 (median follow-up of 14.5 months), a total of 489 patients were enrolled into the CHRYSALIS trial, including 153 patients in cohort D, 81 patients in the primary efficacy population, 124 patients in the additional efficacy population, and 153 patients in the safety analysis set. As of this DCO, there was 1 Canadian study site that enrolled 21 patients.¹⁷ Details on the populations evaluated in cohort D of the CHRYSALIS trial are summarized in Table 6 and Figure 4. Data from the March 30, 2020, DCO are included in the main body of this report and data from the second interim analysis, October 8, 2020, are included in Appendix 3.

Table 6: Populations Evaluated in Cohort D of the CHRYSALIS Trial

NA = not applicable.

^aN = 81 had a median follow-up time of 6.5 months; N = 114 had a median follow-up time of 5.1 months.

^bN = 81 had a median follow-up time of 9.7 months; N = 114 had a median follow-up time of 8.3 months

^cN = 81 had a median follow-up time of 14.5 months; N = 124 had a median follow-up time of 11.9 months.

^dAll patients had greater than or equal to 6 months of follow-up from the onset of response, or had discontinued treatment as of the data cut-off.

^eAll patients had greater than or equal to 6 months of follow-up from the onset of response, or had discontinued treatment as of the data cut-off.

^fThis population of 114 patients had each initiated amivantamab therapy by June 4, 2020. All patients had greater than or equal to 6 months of follow-up from the onset of response, or had discontinued treatment as of the data cut-off.

^gThis population of 124 patients had greater than or equal to 6 months of follow-up from the last-patient-enrolled date (September 29, 2020) at the data cut-off. Also, all patients had greater than or equal to 6 months of follow-up from the onset of response, or had discontinued treatment as of the data cut-off.

Figure 4: Visual Representation of Patient Populations Evaluated in Cohort D of the CHRYSALIS Trial

Source: Sponsor submission.¹⁵

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for the CHRYSALIS trial are summarized in Table 5. Briefly, eligible patients consisted of adults (aged 18 years or older) diagnosed with metastatic or unresectable NSCLC who had either progressed after prior SOC therapy (prior platinum-based chemotherapy for cohort D) for metastatic disease, or were ineligible for or had refused all other currently available therapeutic options. For part 2, cohort D, patients also had to have marketed TKI-resistant mutations such as exon 20 insertion mutations, and specifically for cohort D, patients not previously treated with a TKI with known activity in exon 20 insertion disease (e.g., poziotinib) were eligible. Patients were also required to have evaluable disease (part 1) or measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (part 2), and ECOG performance status less than or equal to 1. Patients were excluded if they had untreated or active brain metastases and a history of ILD.³⁶

Baseline Characteristics

The baseline characteristics of patients in cohort D of the CHRYSALIS trial are summarized in Table 7. At baseline, per the March 30, 2021, DCO, 153 and 81 patients made up the safety analysis set and efficacy analysis set, respectively. In the safety analysis set, the median age of patients enrolled was 61.0 years, with the majority of patients younger than 65 years (62.1%). Most patients were Asian (62.1%) and female (61.4%), and had an ECOG performance status of 1 (72.5%). Most patients had stage III (8.6%) or IV (78.9%) disease, adenocarcinoma (96.1%), and no history of smoking (61.4%). The median number of prior lines of therapy was 2, with as many as 10 lines of therapy received. All patients (100%) had received prior platinum-based chemotherapy (mostly carboplatin; 65.4%), as well as non–platinum-based chemotherapy (mostly pemetrexed; 60.8%).³⁶

Baseline characteristics for the primary efficacy population and the additional efficacy population were consistent with the safety analysis set.

Table 7: Summary of Baseline Characteristics for Cohort D (Safety Analysis Set; March 30, 2021, DCO)

BMI = body mass index; DCO = data cut-off; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; NR = not reported; NSCLC = non–small cell lung cancer; SD = standard deviation; TKI = tyrosine kinase inhibitor.

^aPatients can be counted in more than 1 category.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021);¹⁷ sponsor submission.¹⁵

Interventions

Amivantamab

Amivantamab was administered via IV infusion at a dose of 1,050 mg for less than 80 kg and 1,400 mg for greater than 80 kg of body weight and was given once weekly for the first 4 weeks (i.e., cycle 1) and once every 2 weeks in all subsequent 28-day cycles, over a minimum 60-minute infusion. Amivantamab was supplied as a sterile liquid in either 3 mL or 7 mL glass vials of 50 mg/mL for dilution for IV infusion. To minimize the risk of IRRs, the first dose was split over 2 days (cycle 1, days 1 and 2), required steroid premedication, and was administered using an accelerated infusion strategy.³⁶

In part 1, amivantamab was given in doses of 140 mg, 350 mg, 700 mg, 1,050 mg, and 1,400 mg, as assigned to each dose-escalation cohort, dosed according to the 28-day cycle. After identifying body weight as a primary covariate explaining interindividual pharmacokinetic variability, the recommended RP2D for part 2 was determined to be 1,050 mg for patients weighing less than 80 kg and 1,400 mg for patients weighing greater than or equal to 80 kg, administered at the dosing schedule. Treatment was administered until disease progression, unacceptable toxicity, or withdrawal of consent. Patients who continued to receive clinical benefit despite documented disease progression were permitted to remain on study treatment at the discretion of the investigator.³⁶

Protocol defined treatment discontinuation criteria included:

• documented clinical or radiographic (RECIST v1.1) disease progression

• unacceptable toxicity

• general or specific changes in the patient’s condition that render the patient unacceptable for further treatment in the judgment of the investigator

• pregnancy

• intercurrent illness that prevents further administration of treatment

• refusal of further treatment with study drug

• receipt of concurrent (nonprotocol) systemic anticancer treatment

• noncompliance with study drug or procedure requirements.

Prior and Concomitant Therapy

Prophylactic and predose medications were to be administered to all patients to prevent or lessen the severity of IRRs, rash, and nausea. Prophylactic treatment for IRRs included:³⁶

• IV administration of a glucocorticoid (i.e., dexamethasone 10 mg or methylprednisolone 40 mg) 45 to 60 minutes before study drug infusion on cycle 1, day 1, and 2

• administration of antihistamine (diphenhydramine 25 to 50 mg or equivalent) given either IV 15 to 30 minutes or orally 30 to 60 minutes before each amivantamab infusion

• administration of paracetamol (650 to 1,000 mg or equivalent) given either IV 15 to 30 minutes or orally 30 to 60 minutes before each amivantamab infusion.

Optional prophylactic treatments included glucocorticoid (IV or oral) given from cycle 1, day 8 and onward; histamine H2 antagonist (ranitidine 50 mg or equivalent) given IV at any cycle; or antiemetics (ondansetron 16 mg IV or 8 mg oral or equivalent) given at any cycle.³⁶

Postinfusion medications could have been prescribed and continued for up to 48 hours after infusion of study drug if clinically indicated for the management of IRRs or other infusion-related symptoms. These included IV or oral glucocorticoids, antihistamines, antipyretics (paracetamol), opiates (meperidine), and antiemetics.³⁶

Dose Modifications

In addition to prophylactic and reactive treatment regimen for rash, investigators were instructed to consider reducing the dose for grade 2 events and to interrupt treatment for grade 3 events (or grade 2 events that did not resolve after 2 weeks) until the event improved to less than or equal to grade 1. If rash worsened or did not improve after 2 weeks, treatment discontinuation was recommended.³⁶

Investigators were instructed to withhold amivantamab for patients with drug-related toxicity (of any grade) whose symptoms were intolerable (per investigator assessment) until the toxicity returned to less than or equal to grade 1 or baseline. Investigators were instructed to interrupt dosing in the event of grade 3 or 4 toxicity. Following resolution of the event(s) (i.e., return to baseline or to less than or equal to grade 1 for nonhematologic toxicity), dosing could have been restarted according to the following guidance:³⁶

• Interruption of less than or equal to 7 days: restart at current dose level (grade 3 toxicity) or at next lower dose level (grade 4 toxicity)

• Interruption of greater than 7 to less than or equal to 28 days: restart at next lower dose level

Investigators were instructed to consider permanently discontinuing amivantamab for patients whose dose was withheld for more than 28 days (i.e., 2 consecutive doses) due to toxicity, and for patients with grade 4 toxicity whose treatment was interrupted for greater than 7 to less than or equal to 28 days unless the patient was considered to be benefiting from the drug and with agreement from the sponsor’s medical monitor.³⁶

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized in the following sections.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

DOR = duration of response; HRQoL = health-related quality of life; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; TTF = time to treatment failure.

Primary Efficacy End Point

The primary outcome of the CHRYSALIS trial was ORR, defined as the proportion of patients with a best overall response of a confirmed complete response (CR) or PR as assessed by the investigator and BICR based on RECIST v1.1 criteria. Best overall response was recorded from the start of the study drug until disease progression, withdrawal of consent, or start of a subsequent anticancer therapy, whichever came first.³⁶

Disease assessments were performed every 6 (plus or minus 1) weeks during part 1 and part 2.³⁶

Secondary Efficacy End Points

The secondary outcomes of the CHRYSALIS trial for cohort D were based on investigator and BICR and included:³⁶

• CBR was defined as the percentage of patients achieving a best overall response of confirmed CR, confirmed PR, or durable stable disease (SD; duration of at least 11 weeks) as defined by RECIST v1.1. CBR was not defined as an outcome of interest in the CADTH review protocol. Results for CBR are presented in Appendix 3.

• DOR was defined as the time from first documentation of a PR or CR to the date of first documented evidence of disease progression or death due to any cause, whichever occurred first. Patients who were progression-free and alive or had unknown status were censored at last tumour assessment, and patients who started a subsequent anticancer therapy in the absence of progression were censored at the last disease assessment before the start of subsequent therapy.

• PFS was defined as the time from the first dosing date to the first date of disease progression or death due to any cause, whichever occurred first. Patients who were progression-free and alive or have unknown status were censored at last tumour assessment. Patients with no postbaseline disease assessment were censored on day 1. Patients who started a subsequent anticancer therapy in the absence of progression were censored at the last disease assessment before the start of subsequent therapy, and patients whose diseases have not progressed and who were still alive at the end of the study or clinical cut-off were censored at the last adequate disease assessment.

• OS was defined as the time interval from the first dosing date to the date of death from any cause. If the patient was alive or the vital status was unknown, then the patient’s data were censored at the date the patients was last known to be alive.

• TTF was defined as the time interval from the first dosing date to study drug discontinuation for any reason. Patients who are treatment failure-free or have unknown status was censored at last tumour assessment, and patients with no postbaseline disease assessment were censored on day 1.

Four PRO assessments were included in this study with implementation of Amendment 7. Instruments included the Non–small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC), and the 5-level EQ-5D (EQ-5D-5L). The NSCLC-SAQ contains 7 items that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period. The EQ-5D-5L is a validated tool to measure health status and health utility, including mobility, self-care, usual activities, pain, discomfort, and anxiety/depression on a scale of 0 (worst) to 100 (best). The PGIS and PGIC are single-item questionnaires with PGIS scores ranging from 1 (not at all severe) to 5 (very severe), and PGIC scores ranging from 1 (a lot better now) to 7 (a lot worse now).¹⁵ Due to the limited follow-up time and small sample, PRO data were only included as supportive data in the sponsors’ clinical package.³⁶

Safety End Points

Safety analyses were performed based on the safety analysis set. Safety monitoring was the same for both part 1 and part 2 and included evaluation of incidence, severity, and type of AEs and laboratory abnormalities (hematology, clinical chemistry), which were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03. Other safety measures include monitoring of vital signs (temperature, pulse rate, blood pressure, respiratory rate, pulse oximetry), ECGs, and physical examinations.

Statistical Analysis

Sample Size and Power Calculation

For part 1, cohorts of 3 to 6 patients were typically treated at each dose level based on the 3 plus 3 dose-escalation scheme (described previously). For part 2, the maximum total sample size at an RP2D was set to be approximately 460 patients. This included approximately 40 patients in Cohort A, 20 patients in Cohort B, and up to 100 patients each if sufficient efficacy was observed in Cohorts C, D, MET-1, and MET-2 at an RP2D of amivantamab monotherapy.³⁶

The sample size calculation for CHRYSALIS was based on the primary end point of ORR, assuming a null hypothesis of ORR for amivantamab per RECIST v1.1 of less than or equal to 15%, and alternative hypothesis of ORR greater than or equal to 30%. With a 1-sided alpha of 2.5%, and a power of 87.5%, the total number of patients needed for each cohort was 86 response-evaluable patients. Assuming a nonevaluable rate of 15%, approximately 100 patients were to be enrolled within each cohort, though the number of patients could be expanded beyond 100 patients (maximum of approximately 150) to further characterize activity for subpopulations within a cohort.³⁶

The sample size consideration for the subgroup in cohort D who were required to have had previous therapy with a combination platinum-doublet chemotherapy regimen was based on the null hypothesis of ORR for amivantamab per RECIST v1.1 of less than or equal to 12%, and the alternative hypothesis of ORR greater than 25% based on response rates for platinum-doublet or single-drug chemotherapy regimens. To have a power of 80% to reject the null hypothesis with a 1-sided alpha of 2.5%, at least 60 patients were required to be enrolled in the subgroup of patients with exon 20 insertion mutations previously treated with platinum chemotherapy; approximately 100 patients were targeted for enrolment to characterize the activity of amivantamab in this population.³⁶

Interim Analyses

For cohorts C, D, MET-1, and MET-2 in part 2, within each cohort, a 2-stage design was employed.

A planned interim monitoring for futility was carried out separately for cohorts C, D, MET-1, and MET-2 when there were at least 30 response-evaluable patients. With 30 patients evaluable for response within cohorts C, D, MET-1, and MET-2, if 5 or fewer responses were observed, the null hypothesis (ORR ≤ 15%) was to be accepted and enrolment for the cohort may have been terminated for futility by the safety evaluation team (SET). Otherwise, additional patients were enrolled for total 100 patients in the cohort for the final analysis. This stopping criterion led to a probability of early termination of at least 71.1% for Cohorts C, D, MET-1, and MET-2.¹⁵ No further information or results of the interim monitoring for futility was provided.

The first interim analysis was conducted based on a clinical cut-off date of June 8, 2020, representing 6.5 months of follow-up for the primary efficacy population. According to the sponsor, hypothesis testing for the primary end point was conducted at the June 8, 2020, DCO.³⁷ The second interim analysis considered an addendum to the first interim analysis had a clinical cut-off date of October 8, 2020, and had a median follow-up of 9.7 months. The third interim analysis was based on a clinical cut-off of March 30, 2021, representing 14.5 months of follow-up. According to the sponsor, both the June 8, 2022, and October 8, 2020, DCO dates were based on agreements with the FDA.

The primary efficacy population (described below) represented the same group of patients followed up over time. The safety analysis set increased with additional enrolment beyond the cut-off for the primary efficacy population.

Analysis Populations

Results of efficacy and safety data are presented for the following populations in this report:^17,36,38

• Primary efficacy population: Includes exon 20 insertion plus prior chemotherapy patients (N = 81) enrolled in part 1 (dose escalation) or part 2 (dose expansion) who have received their first dose with RP2D amivantamab monotherapy by February 5, 2020. These 81 consecutively treated patients had undergone 3 or more postbaseline disease assessments or discontinued treatment for any reason, including disease progression/death, before the clinical cut-off of June 8, 2020.

• Additional efficacy population:

  • Includes exon 20 insertion plus prior chemotherapy patients (N = 114) enrolled in part 1 and part 2 who had received prior platinum-based chemotherapy and were treated at the RP2D, and had undergone 3 or more postbaseline disease assessments or discontinued treatment for any reason, including disease progression/death, as of the clinical cut-off of October 8, 2020. All patients had initiated treatment before June 8, 2020, and this population was inclusive of the 81 patients in the primary efficacy population.³⁸

  • Includes exon 20 insertion plus prior chemotherapy patients (N = 124) enrolled in part 1 or part 2 who had received prior platinum-based chemotherapy and 1 or more dose of amivantamab monotherapy at the RP2D, and who had 6 or more months of follow-up from the last-patient-enrolled date (September 29, 2020) at this clinical cut-off of March 30, 2021. This population was inclusive of the patient efficacy set described previously (i.e., N = 114).

• Primary safety population: Includes exon 20 insertion plus prior chemotherapy at RP2D patients (N = 153) with EGFR exon 20 insertion NSCLC enrolled in part 1 or part 2 who had received prior platinum-based chemotherapy and 1 or more doses of amivantamab monotherapy at the RP2D as of the March 30, 2021, clinical cut-off.

Efficacy Analyses

All efficacy analyses were performed using the primary and the additional efficacy populations. In addition to the investigator assessment, scans were centrally collected for potential assessment of response by BICR using RECIST v1.1 criteria.³⁶

Primary Efficacy End Point

The primary efficacy analysis of ORR with confirmed best overall responses was performed approximately 12 weeks after the last patient received the first infusion or at the end of study.¹⁵ The observed ORR and its 95% 2-sided exact CI were presented based on the primary efficacy population. Assessment of responses was performed according to RECIST v1.1 criteria by the investigator. Subsequently, assessment of efficacy within exon 20 insertion patients was completed by BICR.³⁶

The following response criteria (according to RECIST v1.1) were acceptable: CR, PR, SD, PD, and not evaluable. A response of PR or CR must have been confirmed by repeat assessments 4 or more weeks from the initial observation. For a response to qualify as SD, follow-up measurements must have met SD criteria at least once at a minimum interval not less than 6 weeks after the first dose of study drug. If symptomatic deterioration (on the basis of global deterioration of health status) was recorded as the basis for determining disease progression, every effort was to be made to document radiographic progression even after discontinuation of treatment for symptomatic deterioration, but before initiation of subsequent anticancer therapy.³⁶

Subgroup Analyses

Prespecified subgroup analyses for the primary end point of ORR (and 95% CI) per investigator assessments were analyzed for the following subgroups of the exon 20 insertion at RP2D efficacy populations: age (aged < 65 years versus ≥ 65 years and < 75 years versus ≥ 75 years), sex (male versus female), race (those who identified as Asian versus those who did not), baseline ECOG performance status (0 versus ≥ 1), smoking history (yes versus no), prior immunotherapy (yes versus no), and key exon 20 insertion variants.³⁶ Only subgroups identified a priori in the CADTH review protocol (Table 4) were presented in the results section of this report.

Secondary Efficacy End Points

Secondary outcomes of the CHRYSALIS trial included CBR, DOR, PFS, OS, and TTF. CBR and its 95% 2-sided exact CI were presented based on the efficacy analysis set. DOR was summarized descriptively using the Kaplan-Meier method for responders in efficacy analysis set. The median PFS, OS, and TTF and 95% CI were estimated using the Kaplan-Meier method.

Safety Analyses

Safety monitoring was the same for both part 1 and part 2 and was based on the safety analysis population. The baseline value for safety assessment is defined as the value collected at the time closest to, but before, the first dose of study drug. Exposure to investigational product and reasons for discontinuation of study drug were tabulated. Unless otherwise specified, no inferential statistical analyses were performed in analyzing the safety data.³⁶

Safety data obtained during the study were reviewed on a routine basis by the SET, consisting of participating principal investigators, the sponsor’s medical monitor and clinical pharmacologist, and the sponsor’s safety management team chair. Among the SET’s responsibilities were the recommendation of modification(s) to the study drug dose, schedule, and/or regimen in the dose-escalation phase (part 1); the RP2D regimen(s) to be investigated in the dose-expansion phase (part 2); and continued enrolment or termination of cohorts in the dose-expansion phase (part 2).³⁶

Protocol Amendments and Deviations

There were 10 global amendments to the original protocol dated October 15, 2015, as well as several country-specific amendments. Key global amendments are summarized in Table 9. Patient enrolment into cohort D initiated with Amendment 4 on March 9, 2018, in which 6 additional amendments followed enrolment.

In Amendment 5 (September 6, 2018), timing of assessment for response was updated in accordance with RECIST v1.1: assessed at baseline, at week 6 (plus 1), and then every 6 (plus 1) weeks until disease progression by imaging, start of new anticancer therapy, or withdrawal of consent, as opposed to baseline, week 6, week 15, and then every 8 weeks, which may have affected the assessment of time to response or time to progression; however, given that the number of patients enrolled before this amendment was not provided, the effect remains uncertain.

Amendment 6 (May 29, 2019) clarified that characterization of tumour tissues for EGFR and MET via NGS was to be conducted during the prescreening period and of circulating tumour DNA via NGS during the screening period. As such, the target group was better identified from this point, though it was uncertain how many patients were enrolled before this change.

Table 9: Key Changes Implemented with Global Protocol Amendments for CHRYSALIS

ALK = anaplastic lymphoma kinase; CBR = clinical benefit rate; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; ILD = interstitial lung disease; IRR = infusion-related reaction; MET = mesenchymal-epithelial transition; NGS = next-generation sequencing; NSCLC = non–small cell lung cancer; ORR = overall response rate; OS = overall survival; RP2D = recommended phase II dose; SET = safety evaluation team; SOC = standard of care; TKI = tyrosine kinase inhibitor; WT = wild type.

Source: CHRYSALIS Clinica Study Report interim analysis 1;³ CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

A total of 28 major protocol deviations occurred in 25 (16.3%) patients in cohort D of the CHRYSALIS trial (Table 10). A total of 6 (3.9%) patients developed withdrawal criteria but were not withdrawn. All 6 patients had confirmed disease progression and continued study treatment before obtaining sponsor approval for treatment beyond progression.

None of these deviations led to exclusion of data from the safety or efficacy analyses or were considered to have affected the conduct or integrity of the study.

Table 10: Summary of Major Protocol Deviations (Safety Analysis Set; March 30, 2021, DCO)

DCO = data cut-off.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021).¹⁷

Results

Patient Disposition

As of the March 30, 2021, DCO, a total of 489 patients received amivantamab monotherapy in the CHRYSALIS trial, of which 380 patients received amivantamab monotherapy at RP2D (n = 30 in part 1, and n = 350 in part 2), and 153 patients with exon 20 insertion who had received prior platinum-based chemotherapy received monotherapy at RP2D (n = 5 in part 1, and n = 148 in part 2). For cohort D, a total of 43 (28.1%) patients completed the study (patients are considered to have completed the study if the patient died before the end of study), 95 (62.1%) were still in the study, and 15 (9.8%) had terminated the study prematurely. The most common reason for premature termination was withdrawal by the patient (12; 7.8%).¹⁷

As of the March 30, 2021, DCO, 56 (36.6%) patients were still receiving amivantamab and 97 (63.4%) had discontinued treatment. The most common reason for treatment discontinuation was PD (73; 47.7%). The primary efficacy analysis population consisted of 81 patients enrolled in cohort D, while the safety analysis set consisted of 153 patients.¹⁷

Table 11: Patient Disposition (March 30, 2021, DCO)

DCO = data cut-off; RP2D = recommended phase II dose.

^aA patient is considered to have completed the study if the patient died before the end of study.

Source: CHRYSALIS Clinical Study Report interim analysis 1 and 2.^17,36

Exposure to Study Treatments

The extent of exposure for patients treated with amivantamab in cohort D is summarized in Table 12. The median duration of treatment with amivantamab was 5.6 months (range, 0.03 to 23.89), with 71 (46.4%) patients having received treatment for 6 or more months. The median number of treatment cycles was 7.0, with 52 (34.0%) patients having received treatment for 10 or more cycles.

The median relative dose intensity, defined as the ratio of total received dose versus total prepared dose, was 100%. Infusion modifications were reported in 93 (60.8%) patients, with most amivantamab modifications during infusion due to IRRs (90; 58.8%). Dose reductions were reported for 22 (14.4%) patients, mostly due to dermatitis acneiform (7; 4.6%) and paronychia (6; 3.9%).¹⁷ Dose interruptions occurred in 55 (35.9%) patients due to AEs. Details on the duration of infusions for amivantamab in the safety analysis population are summarized in Table 36, Appendix 3.

Overall, 8 (5.2%) patients missed scheduled doses of amivantamab due to COVID-19–related issues.¹⁷

Table 12: Summary of Treatment Exposure (Safety Analysis Set; March 30, 2021, DCO)

AE = adverse event; IRR = infusion-related reaction; SD = standard deviation.

^aTreatment duration is defined as the duration from the date of the first dose of study drug to the date of last dose of study drug plus 1 divided by 30.4375.

^bA patient is considered as treated in a cycle if the patient received any nonzero dose of study drug in that cycle.

^cInfusion modification of study drug is based on infusion interrupted, infusion rate decreased, and infusion aborted.

^dExcludes infusion-related reactions.

^eWhen infusion skipped and COVID-19 protocol deviation or AE occur concurrently, the infusion skipped is considered to be COVID-19 related.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021).¹⁷

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below. Refer to Appendix 3 for detailed efficacy data.

Clinical Response

Overall Response Rate

ORR was the primary end point of the CHRYSALIS trial. Results for ORR for both efficacy populations as assessed by the investigator and BICR are summarized in Table 13. In the primary efficacy population (N = 81), a total of 31 (38.3%; 95% CI, 27.7% to 49.7%) patients achieved an ORR per investigator assessment, and 35 (43.2%; 95% CI, 32.2% to 54.7%) patients achieved an ORR per the BICR assessment.¹⁷

According to the investigators, no patients achieved a CR, and all patients who contributed to ORR were partial responders (31; 38.3%). In the BICR assessment, there were 3 (3.7%) patients who achieved a CR, and 32 (39.5%) who had PR. Most patients had SD in both the investigator and BICR assessments (37 [45.7%] and 35 [43.2%], respectively).¹⁷ Results for CBR are presented in Table 34, Appendix 3.

Results for the additional efficacy analysis set (N = 124) were consistent with the primary analysis (Table 13).

Results for the October 8, 2020, DCO for the primary efficacy population (N = 81; median follow-up = 9.7 months) and the additional efficacy population (N = 114; median follow-up = 8.3 months) are available in Table 35, Appendix 3. Results at the October 8, 2020, DCO were overall consistent with the results at the March 30, 2021, DCO.³⁸

Results at the June 8, 2020, DCO date are not presented in this report but were, overall, consistent with the results at the March 30, 2021, DCO.

Table 13: Summary of ORR Based on RECIST v1.1 in Patients With Measurable Disease at Baseline — Investigator and BICR Assessment (March 30, 2021, DCO)

BICR = blinded independent central review; BOR = best overall response; CI = confidence interval; CR = complete response; NE = not evaluable; ORR = overall response rate; PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021).¹⁷

Subgroup Analysis

Subgroup analyses for ORR in the CHRYSALIS trial as assessed by the investigator and BICR for the primary and additional efficacy populations are summarized in Table 14. Results for the subgroup analyses were generally consistent with the primary analysis.

Table 14: Subgroup Analysis of ORR Based on RECIST v1.1 in Patients With Measurable Disease at Baseline (March 30, 2021, DCO)

BICR = blinded independent central review; CI = confidence interval; DCO = data cut-off; IO = immunotherapy; ORR = overall response rate.

Source: CHRYSALIS Clinical Study Report interim analysis (March 30, 2021).¹⁷

Progression-Free Survival

Results for PFS are summarized in Table 15 and displayed graphically in Figure 5, Appendix 3. At the time of the DCO (March 30, 2021), a total of 57 PFS events had occurred in the primary efficacy population. With a median follow-up of 14.5 months, the median PFS was 8.25 months (95% CI, 5.49 to 12.32) based on the investigator assessment, and 8.31 months (95% CI, 5.52 to 11.07) based on the BICR assessment. The PFS rate with amivantamab at 3, 6, and 12 months per investigator assessment was 75% (95% CI, 64% to 83%), 58% (95% CI, 47% to 68%), and 40% (95% CI, 29% to 50%), respectively.¹⁷

With a median follow-up of 11.9 months, the median PFS for the additional efficacy population (N = 124) per investigator and BICR assessment was ███████████████████████████████████████████████████████████), respectively.¹⁷ The PFS rate for the additional efficacy population was consistent with the primary efficacy population.

Results for the October 8, 2020, DCO for the primary efficacy population (N = 81; median follow-up: 9.7 months) and the additional efficacy population (N = 114; median follow-up: 8.3 months) are available in Table 35, Appendix 3. Results at the October 8, 2020, DCO were overall consistent with the results at the March 30, 2021, DCO.³⁸

Results at the June 8, 2020, DCO date are not presented in this report but were overall consistent with the results at the March 30, 2021, DCO date.

Table 15: Summary of PFS per Investigator and BICR Assessment (March 30, 2021, DCO)

BICR = blinded independent central review; CI = confidence interval; NE = not estimable; PFS = progression-free survival.

Source: CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

Results for treatments received postprogression are summarized in Table 37, Appendix 3.

Overall Survival

Results for OS as of the March 30, 2021, DCO are summarized in Table 16 and displayed graphically in Figure 6, Appendix 3. With a median follow-up of 14.5 months for the primary efficacy population (N = 81), and 11.9 months for the additional efficacy population (N = 124), the median OS was 22.77 months (95% CI, 17.48 to not estimable) in both the primary and additional efficacy populations. The estimated 6-, 12-, and 24-month survival rates for the primary efficacy population were 90% (95% CI, 81 to 95), 74% (95% CI, 63 to 83), and 41% (95% CI, 21 to 59), respectively. The estimated 6-, 12-, and 24-month survival rates for the additional efficacy population were ████████████████████████████████████████████████████████, respectively.¹⁷

Results for the October 8, 2020, DCO for the primary efficacy population (N = 81; median follow-up: 9.7 months) and the additional efficacy population (N = 114; median follow-up: 8.3 months) are available in Table 35, Appendix 3. Results at the October 8, 2020, DCO were overall consistent with the results at the March 30, 2021, DCO.³⁸

Results at the June 8, 2020, DCO date are not presented in this report but were overall consistent with the results at the March 30, 2021, DCO date.

Table 16: Summary of OS (March 30, 2021, DCO)

CI = confidence interval; NE = not estimable; OS = overall survival.

Chinese patients enrolled beyond the initial global cohort enrolment are excluded.

Source: CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

Duration of Response

Results for DOR based on investigator and BICR assessment for both the primary (N = 81) and additional efficacy populations (N = 124) are summarized in Table 17. Among the 31 responders as assessed by the investigator in the primary efficacy population, the median duration of treatment was 14.03 months and the median DOR was 12.45 months (95% CI, 6.54 to 16.13), and 21 (67.7%) patients had a DOR greater than or equal to 6 months. Per BICR, the median duration of treatment was 13.90 months, the median DOR assessed by BICR was 11.04 months (95% CI, 6.90 to not estimable), and 60% of patients had a DOR greater than or equal to 6 months.¹⁷

Results for DOR in the additional efficacy population were generally consistent with the primary analysis; however, the BICR assessment was associated with a ███████████████████████████████████████████████████████████████████████████████████████████████████████████████. The median duration of study treatment was also ████████████████████████████████████████████████████████████ per the investigator and BICR assessment.¹⁷

Results for the October 8, 2020, DCO for the primary efficacy population (N = 81; median follow-up: 9.7 months) and the additional efficacy population (N = 114; median follow-up: 8.3 months) are available in Table 35, Appendix 3. Results at the October 8, 2020, DCO were overall consistent with the results at the March 30, 2021 DCO.³⁸

Table 17: Summary of DOR in Responders per Investigator and BICR Assessment (March 30, 2021, DCO)

BICR = blinded independent central review; CI = confidence interval; DCO = data cut-off; DOR = duration of response; NE = not estimable; SD = standard deviation.

^aTreatment duration is defined as the duration from the date of the first dose of study drug to the date of last dose of study drug plus 1 divided by 30.4375.

Source: CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

Health-Related Quality of Life

Four patient-reported HRQoL assessments were used in the CHRYSALIS trial, including the NSCLC-SAQ, PGIS, PGIC, and EQ-5D-5L. The Clinical Study Report for the CHRYSALIS trial did not include results of HRQoL due to limited sample size and short duration of follow-up. Data on HRQoL and PROs from the CHRYSALIS trial were included as additional information within the sponsor’s submission. As of the March 30, 2021, DCO, 36 patients had available HRQoL data at baseline. Results were summarized descriptively.

For the NSCLC-SAQ, the mean total score at baseline was 7.4. Change from baseline at each cycle is shown in Figure 7, Appendix 3, with initial decreases in total score observed until cycle 4, followed by changes from baseline upwards of 1.5 points until cycle 13.

Results for the EQ-5D-5L visual analogue scale for the PRO population are summarized in Figure 8, Appendix 3. No observable trend was demonstrated, with score improving (increasing) until cycle 5, followed by a decrease (worsening) until cycle 10 before increasing again.

Symptom Severity

Symptom severity was measured via the PGIS and PGIC. Results were summarized descriptively. Results of the 36 patients who had evaluable PRO data from the PGIS and PGIC are summarized in Figure 9 and Figure 10, Appendix 3, respectively. Minimal changes were observed across measures in terms of symptom severity and change in symptoms.

Time to Treatment Failure

TTF, defined as the time interval from the first dosing date to study drug discontinuation for any reason, was a secondary outcome of the CHRYSALIS trial. Results for TTF in both the primary and additional efficacy populations are summarized in Table 18. As of the March 30, 2021, DCO, the median TTF was 7.7 months (95% CI, 5.62 to 10.61) months, and the 6-, 12-, and 24-month TTF rates were 60% (95% CI, 49 to 70), 37% (95% CI, 27 to 47), and 7% (95% CI, 1 to 22), respectively.¹⁷

Results for the additional efficacy population (N = 124) were consistent with the primary efficacy population.

Table 18: Summary of TTF per Investigator Assessment (March 30, 2021, DCO)

CI = confidence interval; DCO = data cut-off; NE = not estimable; TTF = time to treatment failure.

Chinese patients enrolled beyond the initial global cohort enrolment are excluded.

Source: CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

Harms

Only those harms identified in the review protocol are reported below. Refer to Table 19 for detailed harms data.

Adverse Events

The incidence of TEAEs in the CHRYSALIS trial is summarized in Table 19. Overall, 100% of patients experienced at least 1 TEAE in the CHRYSALIS trial as of the March 30, 2021, DCO. The most frequently reported TEAEs with amivantamab included IRRs (97; 63.4%), paronychia (81; 52.9%), rash (66; 43.1%), dermatitis acneiform and hypoalbuminemia (60 each; 39.2%), and stomatitis (34; 22.2%).¹⁷

A total of 64 (41.8%) patients experienced 1 or more TEAE that was greater than or equal to grade 3. The most frequently reported greater than or equal to grade 3 TEAEs included pulmonary embolism (7; 4.6%), hypokalemia (6; 3.9%), diarrhea, dyspnea, hypoalbuminemia, paronychia, and pneumonia (5 each; 3.3%), and IRRs and neutropenia (4 each; 2.6%).¹⁷

Serious Adverse Events

The incidence of SAEs is summarized in Table 19. A total of 44 (28.8%) patients experienced SAEs. The most common SAEs with amivantamab were pneumonia (5; 3.3%), dyspnea and pulmonary embolism (4 each; 2.6%), and back pain, muscular weakness, and pneumonitis (3 each; 2.0%).¹⁷

Grade 4 SAEs were reported for 3 (2.0%) patients, and grade 5 (fatal) SAEs were reported in 11 (7.2%) patients.¹⁷

Withdrawals Due to Adverse Events

As of the March 30, 2021, DCO, a total of 18 (11.8%) patients withdrew from treatment with amivantamab due to TEAEs. The most common reason for withdrawals due to AEs was pneumonia (4; 2.6%), and IRRs, pleural effusion, and pneumonitis (2 each; 1.3%).¹⁷

Mortality

Deaths occurring within the treatment period (up to 30 days after last dose of amivantamab) were reported as grade 5 TEAEs regardless of whether death resulted from PD, TEAEs, or any other cause. TEAEs resulting in death during the study are summarized in Table 19. Overall, 11 (7.2%) patients treated with amivantamab experienced a TEAE leading to death, with respiratory, thoracic, and mediastinal disorders the most common TEAE leading to death. As of the March 30, 2021, DCO, 45 (29.4%) patients died. The most common cause of death on study was PD (31; 20.3%).¹⁷

Notable Harms

Notable harms of IRRs, ILD, skin disorders, paronychia, and ophthalmologic disorders are summarized in Table 19.

Infusion-Related Reactions

IRRs occurred for 97 (63.4%) patients treated with amivantamab. The majority of IRRs were grade 1 (16; 10.5%) or 2 (77; 50.3%) severity, and grade 3 IRRs were reported for only 4 (2.6%) patients, 2 of which were considered serious.¹⁷

The median time to onset of greater than or equal to grade 1 TEAEs was 47.0 minutes. The grade 3 IRRs had a median time to onset of 327.5 minutes after the first dose of amivantamab. IRRs occurred almost exclusively on cycle 1, day 1 (66.32%), decreasing for cycle 1, day 2 (3.51%).¹⁷

IRRs were managed prophylactically as described previously. IRRs leading to infusion modification of an ongoing infusion were reported for 90 (59.5%) patients; 11 (7.2%) patients had the cycle 1, day 1 infusion aborted due to an AE; and IRRs leading to discontinuation of amivantamab were reported for 2 (1.3%) patients. Postinfusion medications to manage IRRs and symptoms were uncommon, with postinfusion administration of systemic antihistamines (9; 5.9%), systemic corticosteroids (4; 2.6%), and paracetamol (3; 2.0%).¹⁷

Interstitial Lung Disease

AEs of ILD were reported in 6 (3.9%) patients: 5 (3.3%) with pneumonitis and 1 (0.7%) with ILD. Of these, 2 were grade 1, 3 were grade 2, and 1 was grade 3 (pneumonitis). Of the ILD events, 4 were considered serious. Amivantamab was discontinued due to TEAEs of pneumonitis in 2 patients.¹⁷

The median time to first onset of ILD from the first dose of amivantamab was 50.5 days.¹⁷

Skin Reactions

Skin and subcutaneous tissue disorders were the most frequently reported class of TEAEs in the CHRYSALIS trial. Rash events (grouped term) occurred in 130 (85.0%) patients. Rash and dermatitis acneiform were the most frequently reported skin reactions, occurring in 66 (43.1%) and 60 (39.2%) patients, respectively.¹⁷

In general, rash events were of grade 1 (96; 73.8%) or 2 (34; 26.2%) severity and nonserious. Grade 3 TEAEs included acne and rash (2 each; 1.3%), and dermatitis acneiform, erythema, papular rash, and toxic epidermal necrolysis (1 each; 0.7%). Of the grade 3 TEAEs, 2 (1.3%) patients had rash that was considered serious, and 1 (0.7%) patient had toxic epidermal necrolysis that was considered serious. Rash events resulted in dose interruption and in dose reduction for 14 (10.8%) patients each.¹⁷

Most of the rash events occurred within cycle 1, with the median time to first onset of 11.5 minutes, and a median time of onset for greater than or equal to grade 3 rash events of 28.5 minutes.¹⁷

Of the 130 patients with rash events, the most frequent treatments included systemic antibacterials (83; 63.8%), most frequently tetracyclines (71; 54.6%), dermatological corticosteroid preparations (59; 45.4%), and systemic corticosteroids (55; 42.3%).¹⁷

Paronychia

Paronychia was an AE of clinical importance in the CHRYSALIS trial. It was reported for 81 (52.9%) patients. Most events were grade 1 or 2. Grade 3 events were reported for 5 (3.3%) patients, none of which were serious. One patient discontinued treatment with amivantamab due to grade 2 paronychia.¹⁷

Ophthalmologic Disorders

Ophthalmologic disorders were considered an EGFR-mediated event in the CHRYSALIS trial. Overall, eye disorders were reported for 19 (12.4%) patients. The most frequently reported ophthalmologic TEAEs were dry eye (4; 2.6%) and eyelid edema (3; 2.0%). All ophthalmologic TEAEs were considered grade 1 or 2, and none were serious.

Table 19: Summary of Harms (Safety Analysis Set; March 30, 2021, DCO)

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DCO = data cut-off; IRR = infusion-related reaction; SAE = serious adverse event; TEAE = treatment-emergent adverse event; WDAE = withdrawal due to adverse event.

Note: Deaths during treatment are presented for patients who died within 30 days of last study drug dose.

^aAEs leading to death are based on AE outcome of fatal. Patients are counted only once for any given event, regardless of the number of times they experienced the event. AEs are coded using MedDRA (Medical Dictionary for Regulatory Activities) Version 23.0.

Source: CHRYSALIS CSR interim analysis (March 30, 2021).¹⁷

Critical Appraisal

Internal Validity

Primary purpose of phase I/Ib design: CHRYSALIS was a first-in-human phase I/Ib clinical study with the primary purposes of determining the RP2D (part 1) and subsequently assessing the safety of the selected dose in part 1 and estimating the clinical activity of amivantamab (part 2). A phase I/Ib or phase II trial may not accurately predict harm and/or effectiveness of treatments. There are numerous examples of phase III trials in which the results did not support the phase II trial results.³⁹ There are currently no randomized phase III trials under way for this review’s target population. The clinical experts consulted by CADTH noted that, despite the high unmet need, conducting an RCT in this setting with a targeted therapy, such as amivantamab, compared with the available therapies currently used in Canadian clinical practice would likely not be feasible. According to the clinical experts, developing phase III RCTs is hindered by the overall low number of patients who meet the current indication and because equipoise between amivantamab and other chemotherapy drugs does not exist. A phase III RCT, PAPILLON, is currently under way; it is investigating the efficacy and safety of amivantamab in combination with carboplatin-pemetrexed compared to carboplatin-pemetrexed alone for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. After first-line therapy for locally advanced or metastatic NSCLC, it is estimated that only about 50% of patients go on to subsequent lines of therapy.³³

Limited interpretation of time-to-event end points: The single-arm, nonrandomized design of the CHRYSALIS trial makes interpreting the efficacy and safety events attributable to amivantamab challenging, because all patients received the same treatment. While ORR may be directly attributable to the drug’s antitumour activity, interpreting PFS and OS events is significantly limited. The extent to which the observed survival is due to the natural history of the tumour or the intervention remains unclear.⁴⁰ The FDA’s multidisciplinary review for the assessment of amivantamab in the present indication included the following reviewer comment: “FDA considers time-to-event end points to be uninterpretable in a single-arm study.”⁴¹ Consequently, the efficacy outcomes contributing to the FDA’s accelerated approval of amivantamab in the current setting included response outcomes and no survival end points.⁴¹

Open-label design: The CHRYSALIS trial had an open-label design whereby the investigator and the study participants are aware of their treatment status, which increases the risk of detection bias and performance bias. Overall, the magnitude and direction of this bias remains unclear. However, to mitigate the impact of this bias, the response outcomes were also assessed by BICR using standardized criteria (i.e., based on RECIST 1.1 with confirmation of a CR and PR at least 4 weeks after the initial assessment). Discordance between investigator assessment and BICR for responders and nonresponders was 22.22%, suggesting some disagreement between investigator and central review, with sites providing slightly more conservative interpretations of the scans. Given the open-label design of the trial, it is likely that the BICR assessment of response provided more unbiased response assessments compared with the investigator’s assessments. FDA and Health Canada assessments of response focused on the BICR assessments of response.^41,42 Furthermore, subjective outcomes (i.e., adverse outcomes and PROs) may be biased due to the open-label design. For example, if study personnel and patients knew that the treatment was amivantamab, this could have influenced the reporting of harms. In addition, the nonrandomized design of the CHRYSALIS trial makes interpreting the safety events attributable to amivantamab challenging, because all patients received the same treatment. Overall, the magnitude and direction of this bias remain unclear.

Statistical analyses: No inferential statistical testing was performed for the efficacy outcomes in cohort D; thus, no P values were reported. Point estimates with 95% CIs were reported to estimate the magnitude of treatment effect. The threshold for a positive study outcome for cohort D was observing a 95% CI for ORR with a lower limited larger than 12%. This threshold for tumour activity was based on historical response rates observed in phase III trials in patients who were treated with single-drug chemotherapy upon failure of platinum-based chemotherapy and was overall considered acceptable in signalling promising treatment effect.⁴² Results for ORR appeared consistent with the sample size assumptions, and the study recruited the intended number of patients.

Small sample size: A limited number of patients were included in the primary (N = 81) and additional (N = 124) efficacy sets of cohort D. The magnitude of the treatment-effect estimates observed in a small study sample may not be replicable in a larger study sample.

Subgroup analysis: Methodological issues limited the ability to interpret the results from subgroup analyses. Wide CIs reflected uncertainty in the effect estimates, and small sample sizes limited the generalizability to a broader population.

HRQoL and symptom severity assessments: PROs were a late inclusion in the trial; they were included as an amendment and were not part of the regulatory submission package. Due to the small sample size (N = 36), a substantial decline in patients available to provide assessments over time, and the descriptive nature of the analysis, the potential effect of amivantamab on HRQoL and symptom severity remains inconclusive.

Multiple protocol amendments: There were multiple amendments to the protocol of the CHRYSALIS study, including changes to the primary and secondary end points and that the overall population cohorts enrolled were discontinued or altered (Amendments 3 and 4), though no patients were believed to have been enrolled into cohort D before the change in end points, with the exception of HRQoL outcomes. Because multiple revisions to the protocol are commonly seen in exploratory phase I studies, this does not necessarily raise concerns with regards to the conduct of the study. It was noted in the Health Canada reviewer report that the assessment of protocol amendments did not raise major concerns in regards to interpreting the results of cohort D.⁴²

External Validity

The CHRYSALIS trial was an international, multicentre study that included sites in Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, the US, and the UK. One Canadian treatment centre enrolled 6 patients as of the June 2020 interim analysis, and 21 at the March 30, 2021, DCO. The treatment regimen used in part 2 of the CHRYSALIS trial aligns with the Health Canada recommended dose of 1,050 mg for patients weighing less than or equal to 80 kg, and 1,400 mg for patients weighing greater than or equal to 80 kg. The clinical experts conducted by CADTH indicated that although the inclusion and exclusion criteria were appropriate, they hypothesized that the exclusion criteria may have been restrictive, selecting for ideal, less severely ill patients. In line with the exclusion criteria, patients with untreated central nervous system metastases were not enrolled. Overall, 23.5% of patients enrolled in cohort D had previously treated brain metastases at baseline. The clinical experts consulted by CADTH agreed that results for amivantamab are likely generalizable to patients with treated brain metastases.

The clinical experts also noted that the baseline characteristics of the included population was generally reflective of Canadian clinical practice; however, there was a high proportion of patients who were Asian (62.1%) enrolled. The clinical experts noted that the higher proportion of patients who were Asian in the trial may be due to the fact that people of Asian descent are genetically more susceptible to mutations involving EGFR. Mutations of EGFR in NSCLC adenocarcinoma occur in 40% to 50% of patients of Asian descent compared to 15% of patients from Western countries.^43,44 Additionally, in part 2, cohort D was closed globally to further enrolment on May 29, 2020, except to complete country-specific enrolment requirements in Japan and China, likely resulting in a greater proportion of patients who were Asian enrolled in the trial. Furthermore, the clinical experts did not anticipate seeing differential treatment effects between patients who were Asian and those who were not. Therefore, the high proportion of patients of Asian descent enrolled in cohort D is unlikely to affect the generalizability of the results.

Noncomparative design: The noncomparative design of the CHRYSALIS trial precludes the ability to assess the relative therapeutic benefit or safety of amivantamab against currently available therapies in Canadian clinical practice. As noted previously, the clinical experts consulted by CADTH agreed that direct randomized comparisons between amivantamab and currently used therapies are unlikely to take place for advanced or metastatic NSCLC with exon 20 insertion that has progressed after platinum-based chemotherapy. In the absence of a direct comparison of amivantamab with relevant treatment options, the sponsor submitted an adjusted treatment comparison using external control arms derived from real-world data sources. The results of the adjusted treatment comparison favoured amivantamab for ORR, PFS, and OS in comparison with treatment of physician’s choice. The CADTH review team identified several limitations (e.g., concerns regarding heterogeneity across the study designs and populations, and the inability to adjust for important potential confounders and prognostic variables across each cohort) and concluded that no firm conclusions could be drawn about how amivantamab compared to other relevant treatment options. However, the clinical experts consulted by CADTH anticipated that, based on the CHRYSALIS results and on poor results with existing treatment options in clinical practice, amivantamab would offer improved and clinically meaningful clinical benefits compared to currently available therapies.

Relevance of trial efficacy outcomes: The primary outcome in the CHRYSALIS trial was ORR and 1 of the secondary outcomes was DOR. According to the clinical experts consulted by CADTH, ORR and durability of response are clinically meaningful end points for patients with advanced or metastatic NSCLC who have progressed on prior therapy. Responses in this patient population are important because of accompanying delay in the worsening of symptoms and a slower decline in ECOG performance status. According to the clinical experts, it is rare to see CRs to treatment in this setting. While the clinical experts agreed that, based on the available evidence, it was not possible to firmly conclude whether the antitumour activity expressed as responses would translate into clinical benefits in terms of PFS and OS, they felt that durable responses could potentially delay tumour progression and result in prolonged survival benefit in this patient population.

Indirect Evidence

A focused literature search for ITCs dealing with EGFR-mutated NSCLC was run in MEDLINE All (1946–) on May 18, 2022. No limits were applied. The literature search for ITCs identified 93 articles; however, no articles evaluated the efficacy and safety of amivantamab in patients with NSCLC with EGFR exon 20 insertion.

Methods of the Adjusted Treatment Comparison

Objectives and Methods for the Summary of the Sponsor-Submitted Adjusted Treatment Comparison

Due to the lack of direct evidence comparing amivantamab to relevant treatment options for the management of advanced EGFR-mutated NSCLC with exon 20 insertion, the sponsor submitted an adjusted treatment comparison of trial data against real-world evidence that was used to inform the pharmacoeconomic analysis, and an additional report by Minchom et al. (2022) comparing amivantamab with real-world therapies in the US.^15,18 The objective of this section is to summarize and critically appraise the methods and findings of the sponsor-submitted adjusted treatment comparison of amivantamab and relevant drug comparators for the treatment of adult patients with advanced EGFR-mutated NSCLC with exon 20 insertion following platinum-based chemotherapy.

Description of the Sponsor-Submitted Adjusted Treatment Comparison

The sponsor submitted an adjusted treatment comparison that compared the efficacy of amivantamab from IPD from cohort D of the single-arm CHRYSALIS trial to current treatments using an external control arm derived from real-world data sources from the US, the UK, Germany, and France. Data from the real-world sources were identified by applying inclusion criteria from the CHRYSALIS trial.

An additional report by Minchom et al. (2022) was submitted as part of the sponsors’ clinical data package, which followed a similar methodology as the submitted adjusted treatment comparison. The primary objective of this study was to evaluate the effectiveness of amivantamab versus physicians’ choice in real-world settings among patients with advanced NSCLC harbouring EGFR exon 20 insertion who failed platinum-based chemotherapy. Similar to the adjusted treatment comparison, cohort D from the CHRYSALIS trial was used as the index trial for comparison. The external control cohort comprised patients in 3 real-world data sources from the US (ConcertAI, COTA, and Flatiron Health Inc.) who met clinically relevant eligibility criteria for CHRYSALIS. One of the key differences between the primary report and the report by Minchom et al. (2022) were the dates of data collection for the US cohorts (report by Minchom et al. (2022) versus the primary report for the adjusted treatment comparison: 2011 to 2020 versus 2009 to 2020), which affected the number of patients included from the US data sources (N = 125 versus N = 206). As well, the primary report used a DCO for CHRYSALIS of March 30, 2021, that represented the most mature data available, while the report by Minchom et al. (2022) used data from the October 8, 2020, DCO, with a refresh of the OS data from April 19, 2021. Results comparing amivantamab to the external cohorts for the report by Minchom et al. were overall consistent with those from the submitted ITC for all outcomes of ORR (amivantamab versus external cohorts: 40% versus 16%), PFS (median = 8.3 months versus 2.9 months; HR = 0.47 [95% CI, 0.34 to 0.65]), and OS (median = 22.8 months versus 12.8 months; HR = 0.49 [95% CI, 0.31 to 0.77]).¹⁵ Given the similarities in design and methodology, as well as the overlap with the US cohort from the submitted adjusted treatment comparison and results trending in the same direction, this additional report will not be further summarized.

Methods of the Sponsor-Submitted Adjusted Treatment Comparison

Objectives

The primary objective of the sponsor-submitted adjusted treatment comparison was to conduct adjusted treatment comparisons on the efficacy (ORR, OS, PFS, TTNT) of amivantamab in the CHRYSALIS trial (cohort D) to current treatments from real-world settings in patients with advanced EGFR-mutated NSCLC with exon 20 insertion following platinum-based chemotherapy.

Study Selection Methods

The index trial in all analyses was based off IPD from cohort D of the CHRYSALIS trial (n = 81). This cohort included adult patients with EGFR-mutated NSCLC with exon 20 insertion who had progressed on, or after, receiving platinum-based therapy. All efficacy analyses included patients who received the RP2D dose of amivantamab as monotherapy and had undergone at least 3 scheduled postbaseline disease assessments or discontinued treatment for any reason, including disease progression/death, before the clinical cut-off.

An external control arm for cohort D of the CHRYSALIS trial was generated via real-world data sources by applying the inclusion and exclusion criteria from CHRYSALIS to patients from the following real-world data sources:

• Flatiron Health Spotlight: US

• ConcertAI: US

• COTA: US

• Public Health England (PHE): UK

• The national Network Genomic Medicine (nNGM): Germany

• The Clinical Research Platform Into Molecular Testing, Treatment and Outcome Registry of (Non-)Small Cell Lung Carcinoma Patients (CRISP): Germany

• Epidemiological Strategy and Medical Economics (ESME): France

Any criteria that could not be applied to patients due to missing data were omitted from the list of inclusion and exclusion criteria applied to that data source.

The index date for patients in cohort D of the CHRYSALIS trial was the date on which the first dose of amivantamab was received. For patients from the real-world data sources, the index date was the start of any line of therapy at the start of which inclusion and exclusion criteria were met. Only treatment lines in which patients received EGFR exon 20 insertion testing before initial treatment were included. Some real-world patients satisfied inclusion criteria at multiple times during their follow-up. Therefore, to achieve an unbiased comparison in this situation, patients receiving qualifying treatment in more than 1 line setting were included multiple times in an analysis, once for each qualifying line setting. Correlation of outcomes across treatments within each patient was accounted for using the robust sandwich estimator.

All data sources were pooled to create an EU plus US cohort, representing the base-case analysis due to the increased sample size. The Flatiron, ConcertAI, and COTA databases were combined and presented for a pooled US population analysis, and the PHE, nNGM, ESME, and CRISP were pooled and are presented as an EU cohort. Data collection occurred at the following time periods for each database: 2009 and 2020 for US databases, 2016 for PHE, 2013 to 2021 for nNGM, and 2015 to 2021 for CRISP and ESME.

The primary patient population consisted of patients enrolled in cohort D of the CHRYSALIS trial (n = 81), with locally advanced or metastatic EGFR-mutated NSCLC with an exon 20 insertion, who had received their first dose of amivantamab monotherapy on or before February 5, 2020, and were treated with the RP2D (i.e., patients that had undergone at least 3 scheduled postbaseline disease assessments or discontinued treatment for any reason, including disease progression/death, before the clinical cut-off). Data from the latest DCO of CHRYSALIS (March 30, 2021) were used for all analysis sets.

Treatments across comparator real-world data sources were variable. Comparative analyses of amivantamab versus the whole population of patients treated with physicians’ choice (i.e., comparison versus a single basket of treatments) were carried out. Additional comparisons versus relevant treatments classes were also conducted: TKI-based regimens, IO-based regimens, non-platinum-based chemotherapy regimens, VEGFi-based regimens, and other regimens (platinum-based chemotherapy, investigational drugs, drugs not considered to be part of the SOC, and treatments that included a combination of the other treatment classes).

End points of interest for the adjusted treatment comparison were ORR, PFS, OS, and TTNT. For the adjusted treatment comparison, ORR was defined as the proportion of all patients who achieved a best response of partial response or better; OS was defined as the interval between index date and date of death; PFS was defined as the interval between the index date and the date of disease progression or death, whichever occurred first; and TTNT was defined as the interval between the index date and initiation of subsequent systemic anti-cancer therapy or death, whichever occurred first. In CHRYSALIS, ORR and PFS were assessed by both investigator and BICR. Because only investigator results are available in the real-world data sources, this was the key method of assessment for these end points and was used as the base case. For completeness, ORR and PFS end points with CHRYSALIS results based on BICR assessment were presented as sensitivity analyses. No ORR or PFS data were available from the PHE cohort, and no ORR data were available from ESME.

Adjusted Treatment Comparison Analysis Methods

Multiple methodological approaches were implemented to adjust for differences in observed baseline characteristics between the CHRYSALIS cohort and the real-world data sources, which were considered potential confounders. Adjusted comparative analyses were implemented using IPW and covariate adjustment for the comparison of amivantamab versus physicians’ choice. In cases where IPW was considered the primary analysis, covariate adjustment results were used to demonstrate consistency in results. Covariate adjustment was considered when IPW did not achieve a good covariate balance, led to extreme weights which overrepresent a small portion of patients in the treatment group, or when IPW estimates were unstable due to small sample size.

When comparing amivantamab to treatment classes in the pooled EU and pooled US cohorts, the whole real-world data population was compared to CHRYSALIS with covariate adjustment adjusting for treatment class and baseline characteristics (as opposed to comparing the populations of each treatment class from real-world evidence separately to CHRYSALIS via IPW methods). This was due to the number of observations available for the individual treatment classes often being low, meaning that IPW was not feasible or stable. However, due to the larger sample size of the EU plus US cohort, IPW methods were feasible and so are presented in the report alongside covariate adjustment results. Comparisons versus treatment classes are not presented for individual data sources, as the results were underpowered due to the small sample sizes. Analysis results are presented as an effect measure with a 2-sided 95% CI and corresponding P value.

In CHRYSALIS, ORR and PFS were assessed by both investigator and BICR. Because only investigator results are available in the real-world data sources, this was the key method of assessment for ORR and was used as the base case. For completeness, ORR and PFS end points with CHRYSALIS results based on BICR assessment were presented as sensitivity analyses.

IPW: Propensity Score–Based Adjusted Analysis

IPW is a propensity score–based method used to mimic randomization by creating a balance between 2 treatment groups with respect to prognostic baseline covariates. Where IPW was conducted, the following weighting schemes were applied:

• The average treatment effect on the treated (ATT) approach generated a comparative arm reflecting the population enrolled in CHRYSALIS by reweighting the real-world cohort to match the amivantamab patients of CHRYSALIS. ATT-based estimates represent the relative treatment effect in the CHRYSALIS population, and for these analyses, a scaled ATT approach was taken. To maintain the original sample size for the weighted populations and to properly reflect the associated uncertainty, the ATT weights were multiplied by the ratio of the original sample size versus the sum of the ATT weights, making the sum of these recalculated weights equal to the original sample size. This approach is referred to as the “ATT approach” throughout the report.

• The average treatment effect approach estimated the ATE across both cohorts, because it weights up both propensity score distributions toward the middle. Weights are assigned to patients in the amivantamab cohort and the real-world cohort, creating a more similar distribution of the covariates between the 2 cohorts.

• The average treatment effect for the overlap population (ATO) approach was more weighted toward patients whose characteristics could appear with substantial probability in either population. This approach downweighs patients at both extremes of the distributions.

The ATT approach was the primary analysis and was preferred because it preserved the sample size of the amivantamab population. This also matched the outcome of interest being the real-world data treatment’s adjusted effect on amivantamab’s treatment effect rather than treatment effect on the entire population. Furthermore, the sponsor considered the ATT approach to be preferred over the ATE approach due to the higher degree of heterogeneity in the real-world population, as that data came from multiple databases.

Multivariable Regression Approach with Direct Adjustment for Covariates

Covariate adjustment based on a multivariable regression (Cox regression for time-to-event end points and logistic regression for binary end points) was considered as an alternative to propensity score–based adjustment in adjusting for covariate imbalance and potential confounding. This was of particular use when comparing CHRYSALIS to real-world data sources with small sample sizes (physicians’ choice or individual treatment classes). Small sample sizes often led to sudden drops in the Kaplan-Meier estimates after IPW adjustment, which lacked clinical validity and indicated the requirement for an alternative approach. With the multivariable regression approach, the treatment effects were estimated using a multivariable model that included all relevant prognostic variables as covariates together with the treatment group indicator. An advantage of covariate adjustment over the propensity score approach described in the previous section is that it provides a predictive model (including treatment) for the risk (hazard) of the outcome, which gives insight as to which covariates have the strongest influence on risk.

Statistical Analysis

For the binary end point (ORR) adjusted treatment effects, in terms of OR and the corresponding 95% CIs, were generated using logistic regression models. For the IPW approach, a weighted logistic regression model including treatment only was used. For covariate adjustment, an unweighted logistic regression model that includes treatments and relevant covariates was used. To estimate treatment effects in terms of response rate (RR) ratio, the same framework was implemented using a generalized linear model with the appropriate link (instead of logistic regression).

For each time-to-event end point (PFS, OS, TTNT), the following approaches were considered:

• Unadjusted comparison without inclusion of potential confounders was used.

• The IPW approach provided weights for estimating the treatment effect of amivantamab versus comparators in a weighted Cox proportional hazards model, to estimate the treatment effect in terms of the HR with 95% Wald-type CI and corresponding P values. A robust sandwich variance estimator was also used. Kaplan-Meier curves were generated, based on which median survival with 95% CI was reported for each treatment group.

• The covariate adjustment approach used a multivariable Cox proportional hazards model, including treatment and prognostic variables as covariates, with a robust sandwich variance estimator.

Handling of Missing Data and Data Pooling

No imputation method was applied to account for missing data, except for partial dates. If a substantial amount of data were missing for a specific covariate, that covariate was not included in the logistic regression model for propensity score weight generation. For both the EU and EU plus US cohorts, individual data sources were excluded from end point comparisons if no data were available. As previously mentioned, for both cohorts, no ORR data were included from PHE and ESME and no PFS data were included for PHE.

Data from the 4 European data sources (CRISP, nNGM, ESME, and PHE) were pooled to create an EU cohort and collectively compared against amivantamab using the same methods (IPW and covariate adjustment) as for the individual data sources’ analyses. Data from the 3 US data sources (Flatiron, ConcertAI, and COTA) were pooled to create the US cohort in the same manner as for the EU cohort. Direct access to IPD allowed the pooling of data from CRISP, nNGM, and PHE; however, this was not possible for ESME data, which were only remotely available on the servers of the data owners. Only aggregated outcomes data were made available by ESME. For the comparison versus physician’s choice, aggregated outcomes data from ESME were used to reconstruct the unadjusted and ATT-weighted IPD outcome data, which were then combined with the unadjusted and ATT-weighted IPD, respectively, from the other data sources. This is only feasible for the comparison versus physicians’ choice, and not versus treatment classes, for which, in ESME, no IPW-based analyses were performed. Furthermore, adjusted comparisons versus treatment classes that required access to pooled IPD with baseline characteristics (i.e., covariate adjustment and pairwise IPW adjustment per treatment class) were not possible when including ESME. Therefore, for the pooled EU and pooled EU plus US cohorts, comparisons versus treatment classes always excluded ESME.

Due to the high consistency between the results and a comparable treatment distribution of the EU and US cohorts, data from all available data sources were pooled to create an EU plus US cohort. The large sample size of the EU plus US cohort enabled ATT weighting adjustment to be applied for comparisons with individual treatment classes, which is consistent with the preferred approach taken for the comparison between amivantamab and physicians’ choice.

For the US cohort, because multiple real-world data sources were used, some patients were captured multiple times due to overlap of the data sources. Deduplication was used in these instances. For the US cohort, patients in Flatiron were removed from ConcertAI and COTA, and patients in ConcertAI were removed from COTA.

Confounding Factors

A systematic literature review (SLR) was conducted to identify potential prognostic patient and disease characteristic confounders in NSCLC. A comprehensive list of potential confounders was validated and narrowed down by clinical experts. The following confounders were considered relevant to each end point: ECOG performance status, number of prior lines of treatment, overall number of metastatic locations, localization of metastases, age, Asian ethnicity, body mass index, EGFR co-mutation TP53, baseline anemia, smoking history, cancer stage at initial diagnosis, surgery, gender, rebiopsy, programmed cell death 1 ligand 1 (PD-L1) status, liver insufficiency, and renal insufficiency. Some potential confounders were identified by the SLR but could not be considered in confounder adjustment for the present analyses because they were not available at baseline from the relevant data sources, though these confounders were not reported. Other potential confounders identified by the SLR were considered irrelevant by the clinical experts so were not included in confounder adjustment. These included neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and leukocyte-relevant telomere length.

Because patients in all cohorts may not be comparable and/or exchangeable due to lack of randomization, all comparative analyses were adjusted for imbalances in prognostic baseline characteristics between both treatment cohorts. The characteristics adjusted for in each real-world data source were based on the confounders identified by the SLR, clinical expert opinion, and data availability. The resulting characteristics adjusted for in each real-world data source analysis are presented in Table 20, while baseline characteristics excluded from comparative analyses are summarized in Table 21.

Table 20: Baseline Characteristics Adjusted for in Comparative Analyses

CRISP = Clinical Research Platform Into Molecular Testing, Treatment and Outcome Registry of (Non-)Small Cell Lung Carcinoma Patients; ECOG = Eastern Cooperative Oncology Group; ESME = Epidemiological Strategy and Medical Economics; EU = European Union; NA = not available; nNGM = national Network Genomic Medicine; PHE = Public Health England.

Source: Sponsor-submitted indirect treatment comparison.¹⁸

Table 21: Baseline Characteristics Excluded From Comparative Analyses and Their Justification

CRISP = Clinical Research Platform Into Molecular Testing, Treatment and Outcome Registry of (Non-)Small Cell Lung Carcinoma Patients; ECOG = Eastern Cooperative Oncology Group; ESME = Epidemiological Strategy and Medical Economics; EU = European Union; nNGM = national Network Genomic Medicine; PHE = Public Health England.

Source: Sponsor-submitted indirect treatment comparison.¹⁸

Results of the Sponsor-Submitted Adjusted Treatment Comparison

Summary of Included Studies

Unadjusted baseline and IPW-adjusted characteristics of treatment lines of patients from CHRYSALIS across the pooled data sources compared to physicians’ choice are summarized in Table 22 and compared to treatment class in Table 23.

In the comparison to physicians’ choice, the CHRYSALIS trial included 81 patients, while the EU plus US cohort included 349 patients, with 206 from the US cohort and 143 from the EU cohort. There was some variation in the baseline characteristics of patients in CHRYSALIS and the individual cohorts, and there was a high degree of missing baseline characteristics overall. All common variables across these data sources were included in the adjustment. Before adjustment, age range and gender were generally similar between the CHRYSALIS trial and the overall cohort; however, there was a greater variation in the prior number of lines of treatment received, with a lower proportion of patients receiving 1 prior line of treatment (38.3% versus 44.4%) in CHRYSALIS, and a higher proportion with 4 or more prior lines of treatment (18.5% versus 9.7%). Additionally, more patients did not have brain metastases at baseline in CHRYSALIS compared to the EU plus US cohort (77.8% versus 62.2%). Baseline characteristics were well balanced after IPW. There were further individual differences between the baseline characteristics of the CHRYSALIS trial and the US cohort, including the presence of brain metastases (22.2% versus 38.8%), the number of metastatic locations (1 location: 40.7% versus 29.6%; 2 locations: 37.0% versus 19.4%; 3 locations: 16% versus 21.4%; and 4 locations: 6.2% versus 22.8%), and normal or high hemoglobin levels (58% versus 46.6%); and the EU cohort, including prior lines of treatment (1 line: 38.3% versus 51.0%, and 4-plus lines: 18.5% versus 4.9%), and the presence of metastases in the brain (22.2% versus 36.4%) and liver (9.9% versus 22.4%). Baseline characteristics were well balanced after IPW.

In the comparison of CHRYSALIS to the different treatment classes in the EU plus US cohort, there were 81 patients in CHRYSALIS, and 60, 89, 76, 58, and 66 patients in the TKI, IO, non–platinum-based chemotherapy, VEGFi plus chemotherapy, and “other” groups, respectively. There were some baseline differences between age groups, particularly for the “other” treatment group, where there were more patients aged below 55 years, and more patients aged above 60 years. The same differences listed previously for the comparison between CHRYSALIS and physicians’ choice with regards to prior lines of treatment and the presence of brain metastases before adjustment applied to the comparison between CHRYSALIS and individual treatment classes.

Table 22: Baseline Characteristics of Treatment Lines for Patients in CHRYSALIS and the EU Plus US Cohort, US Cohort, and EU Cohort Before and After Adjustment (Physicians’ Choice)

ATT = average treatment effect on the treated; ECOG = Eastern Cooperative Oncology Group; EU = European Union; IPW = inverse probability weighting; NR = not reported; PS = performance score.

^aExcluding Epidemiological Strategy and Medical Economics.

^bBaseline characteristics included in adjustment: prior lines of treatment, brain metastases, age, gender.

^cBaseline characteristics included in adjustment: prior lines of treatment, brain metastases, age, ECOG performance status, number of metastatic locations, hemoglobin, gender, and cancer stage at diagnosis.

^dBaseline characteristics included in adjustment: prior lines of treatment, brain metastases, liver metastases, age, gender.

Source: Sponsor-submitted indirect treatment comparison.¹⁸

Results

Results using the ATT IPW approach were considered the base-case analysis across cohorts. Results for analyses using the ATE and ATO IPW approaches were not described in detail in the sponsor-submitted report.

Overall Response Rate

Results for the observed (unadjusted) and adjusted ORR per investigators assessment in all cohorts versus physicians’ choice is summarized in Table 24. Compared to the EU plus US cohort, the adjusted (via the IPW ATT approach adjustment) ORR was 38.3% versus █████ for amivantamab and physicians’ choice, respectively. The OR following adjustment via the IPW ATT approach was ████████████████████), with an RR of ████████████████████). Results using covariate adjustment based on multivariable proportional hazards regression were consistent with the primary analysis, with an adjusted OR for amivantamab versus physicians’ choice of ████████████████████), and a corresponding RR of ████████████████████).

Results for the US and EU cohort were similar. In the comparison against physicians’ choice, ORR adjusted via the IPW ATT approach was █████ in the US cohort and █████ in the EU cohort, versus 38.3% with █████████████████ US cohort, the IPW ATT approach resulted in an OR of █████████████████████ and RR of █████████████████████, while the EU cohort resulted in an OR of █████████████████████ and an RR of ██████████████████████

Results for analyses using the ATE and ATO IPW approaches were only reported for the US cohort, in which they were consistent with the ATT approach.

Table 24: Unadjusted and Adjusted ORR, OR, and RR for ORR for CHRYSALIS vs. EU Plus US Cohort, US Cohort, and EU Cohort (Amivantamab vs. Physicians’ Choice)

ATT = average treatment effect among the treated; CI = confidence interval; EU = European Union; IPW = inverse probability weighting; OR = odds ratio; ORR = overall response rate; PC = physician’s choice; RR = response rate; vs. = versus.

Source: Sponsor-submitted indirect treatment comparison.¹⁸

Results for ORR comparing amivantamab to individual treatment classes are summarized in Table 25. The sponsor considered the results for this analysis exploratory and underpowered due to the small sample sizes in individual treatment classes.

Table 25: Adjusted ORR, OR, and RR for ORR for CHRYSALIS vs. EU Plus US Cohort, US Cohort, and EU Cohort (Amivantamab vs. Individual Treatment Classes)

ATT = average treatment effect among the treated; CI = confidence interval; EU = European Union; IO = immuno-oncology; IPW = inverse probability weighting; NE = not estimable; OR = odds ratio; ORR = overall response rate; RR = response rate; TKI = tyrosine kinase inhibitor; VEGFi = vascular endothelial growth factor inhibitor.

^aGeneralized linear model for RR did not converge. RR is derived as the ratio of the overall response rates generated from the logistic regression model for the odds ratios.

Source: Sponsor-submitted indirect treatment comparison.¹⁸

Results of the sensitivity analysis for ORR using BICR from CHRYSALIS were consistent with the base-case analysis, though the point estimates were generally greater in the sensitivity analysis in favour of amivantamab.

Overall Survival

Results for IPW ATT–adjusted HR for OS for amivantamab versus physicians’ choice, and versus treatment classes in the EU plus US cohort, US cohort, and EU cohorts, are summarized in Table 26 and Table 27, respectively. In all cases, amivantamab was favoured over physicians’ choice for OS in the EU plus US cohort (HR = ████████████████████████), US cohort (HR = ████████████████████████), and EU cohort (HR = 0 ███████████████████████). The median OS for amivantamab was estimated at 22.77 months (95% CI, 17.48 to not estimable) compared to ███████████████████████████████ for the physicians’ choice group from the EU plus US cohort, ███████████████████████████████ for the physicians’ choice group from the US cohort, and ██████████████████████████████ for the physicians’ choice group from the EU cohort.