An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Amivantamab (Rybrevant): CADTH Reimbursement Review: Therapeutic area: Non–small cell lung cancer [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 May.
The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.
Submitted for Review.
Summary of Economic Evaluation.
The CADTH Clinical Review highlighted the high degree of uncertainty associated with the results of CHRYSALIS. The single-arm, open-label, nonrandomized, phase I/Ib design of the CHRYSALIS trial makes interpreting the efficacy and safety events attributable to amivantamab challenging, because all patients received the same treatment. While objective response rate (ORR) may be directly attributable to the drug’s antitumour activity, interpreting progression-free survival (PFS) and overall survival (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. The CADTH assessment of the sponsor-submitted adjusted treatment comparison identified several key limitations including small sample sizes, heterogeneity across study designs and pooled populations, and the inability to adjust for all potential confounders and prognostic variables, all of which significantly limited the ability to interpret the relative treatments effects observed between amivantamab and other treatments. Overall, it was noted that the phase I nature of the CHRYSALIS trial limits the ability to make firm conclusions on comparative efficacy given the short duration of follow-up, which results in immature data, as well as the small sample size of the CHRYSALIS trial and comparator cohorts.
Due to the high degree of unresolved uncertainty with the clinical data, CADTH was unable to derive an economic base case.
CADTH performed an exploratory analysis in which a Weibull parametric extrapolation was used for the OS data for amivantamab. Based on CADTH sequential reanalysis, amivantamab is associated with an incremental cost-effectiveness ratio (ICER) of $253,131 per quality-adjusted life-year (QALY) compared to non–platinum-based chemotherapy (NPBC), with a 0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $50,000 per QALY. This estimate is based on the sponsor’s clinical assumptions, which predict an additional 0.79 life-years (LYs) and 0.60 QALYs for those receiving amivantamab compared with NPBC. A price reduction of at least 77% would be required for amivantamab to be considered cost-effective compared to NPBC at this threshold.
If the comparative clinical data — particularly the PFS and OS data — are considered sufficiently robust, then the exploratory analysis performed by CADTH may be informative. However, in light of the available clinical information, CADTH’s results are based on assumptions (e.g., survival extrapolations, which result in OS benefits for amivantamab both preprogression and postprogression) that cannot be validated at this time and hence are associated with a large degree of uncertainty. As such, additional price reductions may be required to ensure the cost-effectiveness of amivantamab.
Due to the limitations with the clinical evidence and substantial uncertainty associated with the comparative clinical effects of amivantamab with relevant comparators, CADTH performed a scenario cost comparison analysis in which only drug acquisition costs were included. Results of this analysis suggest that amivantamab would require a price reduction of 86.4% to achieve cost parity with the least costly comparator, docetaxel.
This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CADTH review process.
Patient input was received from 2 groups, the Lung Health Foundation and Lung Cancer Canada. Lung Cancer Canada conducted 4 telephone interviews with patients living in Ontario, Canada, who were part of the amivantamab clinical trial. All 4 of the interviewed patients were epidermal growth factor receptor (EGFR) positive and 2 had EGFR exon 20 insertion mutations. The Lung Health Foundation conducted 3 phone interviews with Canadian lung cancer patients and received 2 responses to an online survey (demographic data not collected). Patients interviewed by the Lung Health Foundation reported previous treatment with surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. The input indicated that most patients struggled with lingering side effects, including fatigue, nausea, weight loss, and hair loss, and that side effects from chemotherapy were specifically noted to affect patients’ quality of life, ability to work, and daily activities. The patient input noted a specific unmet need for targeted therapy to the exon 20 insertion mutation, which current chemotherapy does not address. The patients interviewed by Lung Cancer Canada were enrolled in the amivantamab clinical trial and had experience with the drug under review. Some patients experienced stability in tumours and metastases on amivantamab, while others experienced shrinkage. The most common adverse events (AEs) reported by patients were skin-related, including inflammation of the nail bed, rashes, acne, and dry and sensitive skin. All patients noted that side effects are manageable and that the potential benefits outweigh the negatives.
Clinician input was received from 2 groups, the Ontario Health – Cancer Care Ontario Lung Cancer Drug Advisory Committee and the Lung Cancer Canada Medical Advisory Committee. Clinicians indicated that current standard of care for patients in first-line therapy is platinum-based doublet chemotherapy, followed by docetaxel in second-line therapy, though response rates are poor. EGFR tyrosine kinase inhibitors (TKIs) may also be used for patients with EGFR mutations but patients with EGFR exon 20 insertion mutations are resistant to EGFR TKIs and have a low response rate to immunotherapy. Feedback from Ontario Health suggested that amivantamab would be used after all standard therapies acceptable to the patient have failed, suggested to be platinum-based doublet chemotherapy with maintenance pemetrexed and, potentially, docetaxel as well. The input from Lung Cancer Canada highlighted that targeted therapies against driver mutations should ideally be offered in a first-line setting, and that clinical trials in this setting are ongoing.
Drug plan input received for this review noted that additional resource use would be required with amivantamab due to its split first dose and escalating infusion-rate schedule. Additional labour will be required for drug preparation, and premedications are required to prevent infusion-related reactions (IRRs). The plans noted the presence of confidential prices for nivolumab, pembrolizumab, and atezolizumab.
The following concern was addressed in the sponsor’s model:
CADTH was unable to address the following concerns raised from the stakeholder input:
The current review is for amivantamab (Rybrevant) for adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with activating EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.
The sponsor submitted a cost-utility analysis of amivantamab compared to IO drugs, TKIs, and NPBC. The modelled population is consistent with the Health Canada indication and the reimbursement request, and these populations are aligned with the sponsor’s CHRYSALIS trial population.1-3
Amivantamab is supplied in single-use vials containing 350 mg amivantamab in 7 mL solution (50 mg/mL).2 The recommended dose of amivantamab is 1,050 mg (3 vials) for patients weighing less than 80 kg and 1,400 mg (4 vials) for patients weighing greater than or equal to 80 kg.2 The recommended dosing schedule for amivantamab is once weekly for the first 4 weeks (first dose split on days 1 and 2) and every 2 weeks starting at week 5.2 Amivantamab should be reconstituted and administered by a health care professional with appropriate medical support to manage IRRs if they occur. Premedications consisting of antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. Amivantamab should be administered until disease progression or unacceptable toxicity.2 The cost for amivantamab is $1,676.00 per vial, leading to costs per dose of $5,028 and $6,704 for patients weighing less than 80 kg or greater than or equal to 80 kg, respectively.3 The cost in the first cycle is $20,112 for patients weighing less than 80 kg and $26,816 for patients weighing greater than or equal to 80 kg; the cost in subsequent cycles is $10,056 and $13,408, respectively.3
The sponsor selected 3 therapy classes as comparators: IO drugs consisting of atezolizumab (33.3%), nivolumab (33.3%), and pembrolizumab (33.3%); EGFR TKIs consisting of gefitinib (50%), afatinib (25%), and osimertinib (25%); and NPBC consisting of docetaxel (100%). Costs and effects for these comparators were weighted by these proportions, which were derived based on Canadian market share estimates and clinician input.3 The costs per cycle calculated by the sponsor were $10,052 for IO drugs, $3,471 for TKIs, and $2,775 for NPBC.3
The clinical outcomes of interest were QALYs and LYs over a lifetime horizon (10 years). Discounting (1.5% per annum) was applied to both costs and outcomes and a cycle length of 4 weeks was used along with a half-cycle correction. The base-case perspective was that of the Canadian publicly funded health care payer.
The sponsor submitted a partitioned survival model (PSM) consisting of 3 mutually exclusive health states: preprogression, postprogression, and death. All patients entered the model in the preprogression state and received amivantamab or a comparator. The allocation of patients into health states is based on treatment-specific PFS and OS functions. The proportion of patients in the preprogression health state followed the PFS curve for amivantamab from the CHRYSALIS trial, and the PFS curve generated from Kaplan-Meier (KM) data from a sponsor-commissioned real-world evidence (RWE) study for comparators.3 In the CHRYSALIS trial, PFS was derived based on investigator assessment and independent review committee assessment; in the RWE study, PFS was defined as human abstraction of physician evaluation of tumour progression.3 The proportion of patients in the postprogression health state was equal to the difference between the OS and the PFS curves. Patients in the postprogression state can receive subsequent-line therapy. Patients transitioning into the death state remained there until the end of the model time horizon. A figure of the sponsor’s model structure is available in Figure 1, Appendix 3.
The target population of the economic evaluation was based on cohort D of the phase I/Ib single-arm CHRYSALIS trial, which included NSCLC patients with activating EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. The mean age of the population was 62.3 years, mean weight was 67.5 kg, and 41% were male.1 The key clinical inputs (i.e., PFS, OS, and treatment discontinuation) for amivantamab were obtained from the primary efficacy population (n = 81), while safety data were informed from the expanded safety population (n = 153) of the trial. Data were based on the March 30, 2021, data cut-off date.4
In the absence of direct comparative evidence, comparative effectiveness data were derived from a sponsor-commissioned adjusted treatment comparison of CHRYSALIS versus an RWE cohort (n = 349). The sponsor-commissioned RWE study cohort was created using various RWE sources from the US (Flatiron Health Spotlight, ConcertAI, COTA) and Europe (Public Health England, 2 from Germany, and 1 from France). The adjusted treatment comparison used inverse probability of treatment weights derived from a propensity score model to account for variables including, but not limited to, age, sex, race, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, and time from initial diagnosis to advanced diagnosis.3 It was assumed that unobserved confounders did not have an impact on the comparator treatment-effect estimate. The covariates used to estimate the weights in the analysis of the European plus US cohort included age, gender, presence of brain metastases, and number of previous lines of therapy in the metastatic disease setting.3 For PFS, OS, and time to next treatment, time-to-event analyses were performed using weighted Cox proportional hazard models. KM curves were generated and used to estimate median time-to-event estimates for each treatment group.5
Extrapolations of the PFS, OS, and time to treatment discontinuation data were performed for amivantamab and comparators. For amivantamab, the PFS, OS, and time to treatment discontinuation data were fit with a lognormal, gamma, and exponential parametric fit, respectively. Full details of the parametric extrapolations are available in Table 10, Appendix 3.3
Regarding the safety of amivantamab, the model included grade 3 or 4 AEs occurring in 5% or more of patients in cohort D of CHRYSALIS, as well as grade 1 to 2 IRRs.4 Product monographs for individual treatments were used to inform safety data, with AE incidence rates for selected index drugs used to represent the corresponding treatment class.3
Utility values were derived from Labbé et al., who performed a longitudinal cohort study of metastatic lung cancer; the values obtained were from the EGFR-mutated NSCLC population.6 The publication reported a utility value of 0.81 for progression-free disease and 0.70 for postprogression disease, which were employed in the sponsor’s model. Disutilities due to AEs were derived from various sources and were also applied in the model as a one-time disutility decrement.3
The economic model included costs related to drugs (acquisition, administration), AEs, monitoring and disease management, subsequent treatment, and terminal care. Dosing for amivantamab was as previously described, with weighted acquisition costs for the initial and subsequent cycles of $21,850 and $10,925, respectively, based on data from CHRYSALIS, which found that 74.1% of patients weighed less than 80 kg at baseline. Drug acquisition costs for comparators are as previously described. An administration cost of $201 per hour of chair time was assumed based on a published study;7 amivantamab administrations were assumed to require 2 to 6 hours of chair time, while comparators required 1 hour. Monitoring and disease management costs consisted of costs for outpatient visits, chest radiography, CT scans, nurse visits, and routine blood work, which were obtained from the Ontario Schedule of Benefits for Physician and Laboratory Services.8,9 Resource utilization frequency was assumed to be the same across all treatments, but differed for patients in the preprogression and postprogression health states. Costs for most AEs were derived from the Ontario Case Costing Initiative, while the cost of IRRs and febrile neutropenia came from published sources.7,10,11 Half of modelled patients were assumed to receive subsequent therapy upon progression, which consisted of IO drugs, TKIs, and NPBC, though patients were assumed not to receive the same therapy twice. Duration of subsequent therapy ranged from 2.8 months for NPBC to 4.2 months for IO drugs and amivantamab.12 Finally, a one-off terminal care cost of $53,008 was applied based on a published study.13
All analyses were run probabilistically (1,000 iterations for the base case and scenario analyses). The deterministic and probabilistic results were similar. The probabilistic findings are presented in the following sections.
In the sponsor’s base case, amivantamab was associated with an estimated cost of $233,445 and 1.81 QALYs over a lifetime horizon. In sequential analysis, amivantamab was associated with an ICER of $210,591 compared to NPBC (incremental cost: $142,316, incremental QALYs: 0.68). IO drugs were dominated by NPBC in the sponsor’s base case, resulting in fewer QALYs and higher cost. In the sponsor’s sequential analysis, amivantamab had a 0% probability of being cost-effective at a WTP threshold of $50,000 per QALY. Results of the base case suggest that 0.34 incremental QALYs were accrued after the maximum follow-up in CHRYSALIS of 30 months — that is, approximately 51% of the incremental benefit was obtained after the trial period. Less than 1% of patients on amivantamab remained alive after 10 years. Additional results from the sponsor’s submitted economic evaluation base case are available in Appendix 3.
Summary of the Sponsor’s Economic Evaluation Results.
The sponsor conducted several scenario analyses involving an expanded efficacy population from CHRYSALIS (n = 114), definition of progression (based on independent review committee or investigator assessed), amivantamab PFS and OS extrapolations, treatment discontinuation, 5-year time horizon, and vial sharing. Results were generally similar among the scenarios tested, though sequential analysis was not performed on the scenarios. The ICER for amivantamab versus NPBC was most influenced by the choice of OS extrapolation for amivantamab, with ICERs ranging from $144,147 to $237,700 per QALY depending on the extrapolation chosen. The analysis with a 5-year time horizon resulted in an ICER of $238,659.
CADTH identified several key limitations to the sponsor’s analysis that have notable implications on the economic analysis:
One additional limitation was identified but was not considered to be a key limitation. The sponsor did not include the cost of preinfusion medications in its analysis despite the stipulation in the product monograph that these medications must be administered between 15 and 60 minutes before amivantamab.2 These medications, which consist of diphenhydramine, acetaminophen/paracetamol, and dexamethasone/methylprednisolone, would represent additional drug acquisition costs that are only incurred for patients on amivantamab; however, the cost of these drugs is minimal and unlikely to affect the base case.16
Additionally, the following key assumptions were made by the sponsor and have been appraised by CADTH (refer to Table 4).
Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission).
Due to the myriad of limitations outlined previously involving both the direct and indirect clinical evidence, CADTH was unable to derive a base case.
CADTH undertook a correction to the sponsor’s model to address a dosing error, and an exploratory analysis involving 1 change to the sponsor’s OS assumptions for amivantamab (refer to Table 5).
CADTH Revisions to the Submitted Economic Evaluation.
The results of the CADTH exploratory analysis suggested that amivantamab is associated with higher costs and QALYs than NPBC, the next comparator on the frontier (Table 6). The ICER for amivantamab compared to NPBC was $253,131, indicating that amivantamab is not cost-effective at a $50,000 WTP threshold, and had a 0% probability of being cost-effective at this threshold. Results are driven by the high drug acquisition and administration cost of amivantamab. Full results are available in Appendix 4.
Summary of the CADTH Exploratory Analysis.
CADTH undertook price reduction analyses based on the sponsor’s results and the CADTH exploratory analysis. The CADTH exploratory analysis suggested that a price reduction of 77% would be required to achieve cost-effectiveness of amivantamab relative to NPBC at a $50,000 per QALY threshold (Table 7).
CADTH Price Reduction Analyses.
CADTH undertook 1 scenario analysis involving setting adverse event rates equal to amivantamab for all comparators. This scenario, detailed in Table 15, Appendix 4, resulted in similar results as the CADTH exploratory analysis. In addition, in light of the uncertainty about the magnitude of clinical benefit, CADTH performed a cost comparison analysis in which drug acquisition costs only were considered. Drug costs from the CADTH cost table were multiplied by the median PFS from the CHRYSALIS trial, 8.3 months, and compared to the least costly option within a given drug class.1 The sponsor’s base case assumptions about the proportion of patients weighing less than 80 kg were not modified. Results of this analysis are available in Table 15, Appendix 4. This analysis suggests that a price reduction of 86.4% would be required to achieve cost parity with docetaxel, the least costly comparator in this disease space.
The CADTH Clinical Review highlighted the high degree of uncertainty associated with the results of CHRYSALIS. The single-arm, open-label, nonrandomized, phase I/Ib 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, the ability to interpret 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. The CADTH assessment of the sponsor-submitted adjusted treatment comparison identified several key limitations, including small sample sizes, heterogeneity across study designs and pooled populations, and the inability to adjust for all potential confounders and prognostic variables, all of which significantly limited the ability to interpret the relative treatments effects observed between amivantamab and other treatments. Overall, it was noted that the phase I nature of the CHRYSALIS trial limits the ability to make firm conclusions about comparative efficacy given the short duration of follow-up, which resulted in immature data, and the small sample size of the CHRYSALIS trial and comparator cohorts.
Therefore, there exists a high degree of unresolved uncertainty with the clinical data, preventing CADTH from deriving an economic base case. In addition to the clinical uncertainty, the sponsor’s PSM model structure was not appropriate given that PFS and OS have not been established in this patient population, and there is no robust evidence to confirm that response measures (such as ORR) are a prognostic marker of PFS or OS.
CADTH performed an exploratory analysis in which a Weibull parametric extrapolation was used for the OS data for amivantamab. Based on CADTH sequential reanalysis, amivantamab is associated with an ICER of $253,131 per QALY compared to NPBC, with a 0% probability of being cost-effective at a WTP threshold of $50,000 per QALY. This estimate is based on the sponsor’s clinical assumptions, which predict an additional 0.79 LYs and 0.60 QALYs for those receiving amivantamab, compared to NPBC. A price reduction of at least 77% would be required for amivantamab to be considered cost-effective compared to NPBC at this threshold.
If the comparative clinical data — particularly the PFS and OS data — are considered sufficiently robust, then the exploratory analysis performed by CADTH may be informative. However, in light of the available clinical information, CADTH’s results are based on assumptions — for example, survival extrapolations that result in OS benefits for amivantamab in both the preprogression and postprogression states [(79 LYs gained), which cannot be validated at this time — and hence are associated with a large amount of uncertainty. As such, additional price reductions may be required to ensure the cost-effectiveness of amivantamab.
In light of the uncertainty with the available evidence, CADTH performed a scenario cost comparison analysis in which only drug acquisition costs were included, based on costs from the CADTH cost table and a median duration of treatment of 8.3 months. This analysis assumes equal efficacy and duration of treatment for all comparators. Results of this analysis suggest that amivantamab would require a price reduction of 86.4% to achieve cost parity with the least costly comparator, docetaxel. If amivantamab is deemed to be no more efficacious than other currently reimbursed alternatives, this price reduction will be required to ensure that costs to the health care system do not increase.
adverse event
epidermal growth factor receptor
incremental cost-effectiveness ratio
immunotherapy
infusion-related reaction
Kaplan-Meier
life-year
non–platinum-based chemotherapy
non–small cell lung cancer
objective response rate
overall survival
progression-free survival
partitioned survival model
quality-adjusted life-year
real-world evidence
tyrosine kinase inhibitor
willingness to pay
Note that this appendix has not been copy-edited.
The comparators presented in the following table have been deemed to be appropriate based on feedback from clinical experts. Comparators may be recommended (appropriate) practice or actual practice. Existing Product Listing Agreements are not reflected in the table and as such, the table may not represent the actual costs to public drug plans.
CADTH Cost Comparison Table for Locally Advanced or Metastatic NSCLC.
Note that this appendix has not been copy-edited.
Submission Quality.
Note that this appendix has not been copy-edited.
Model Structure.
PFS, OS, and TTD Kaplan-Meier Curves for Amivantamab (CHRYSALIS; n = 81).
Predicted Survival and Reference Case Parametric Fittings for Amivantamab and Comparators.
Note that this appendix has not been copy-edited.
Disaggregated Summary of the CADTH Exploratory Analysis.
Probabilistic Cost-Effectiveness Sequential Analysis From CADTH Exploratory Analysis.
Summary of Scenario Analyses Conducted on CADTH Exploratory Analysis.
Note that this appendix has not been copy-edited.
Summary of Key Takeaways.
The submitted budget impact analysis (BIA) assessed the introduction of amivantamab for the treatment of post-platinum patients with EGFR Exon20ins mutated NSCLC. The analysis was taken from the perspective of the Canadian public drug plans using an epidemiology-based approach, with drug acquisition and administration costs included in the base case. A 3-year time horizon was used, from 2024 to 2026, with 2023 as a base year. The population size was estimated starting with incident lung cancer cases followed by a series of attritions. Key inputs to the BIA are documented in Table 17.
The reference case scenario included EGFR TKIs, IO drugs, and NPBC. The market share estimates were derived from Canadian chart review and a published conference proceeding.33 The new drug scenario included the same comparators along with amivantamab.
Summary of Key Model Parameters.
The estimated budget impact of funding amivantamab for the treatment of post-platinum patients with EGFR Exon 20ins mutated NSCLC was $1,757,694 in year 1, $2,118,425 in year 2, and $1,963,051 in year 3, for a 3-year total budget impact of $5,839,170.
CADTH identified several key limitations to the sponsor’s analysis that have notable implications on the results of the BIA:
Based on the identified limitations, CADTH’s base case included 1 correction to docetaxel dosing and 1 change to the market shares of amivantamab in the new drug scenario.
CADTH Revisions to the Submitted BIA.
The results of the CADTH step-wise reanalysis are presented in summary format in Table 19 and a more detailed breakdown is presented in Table 20. Based on the CADTH base case, the estimated budget impact of the reimbursement of amivantamab for the treatment of post-platinum patients with EGFR Exon20ins mutated NSCLC is expected to be $1,762,759 in year 1, $2,521,485 in year 2, and $2,782,311 in year 3, for a 3-year total of $7,066,555.
Scenario analyses conducted by CADTH indicate that the BIA results are sensitive to the population size, with the scenario assuming 100 incident patients per year resulting in a 3-year budget impact of $15,919,831. Results of the analysis in which only amivantamab costs are considered resulted in a 3-year budget impact of $8,403,136. Thus, the sponsor’s base case results may have underestimated the true budget impact.
Summary of the CADTH Reanalyses of the BIA.
Detailed Breakdown of the CADTH Reanalyses of the BIA.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
Your browsing activity is empty.
Activity recording is turned off.
See more...
