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Indication: For the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer with activating epidermal growth factor receptor exon 20 insertion mutations whose disease has progressed on, or after platinum-based chemotherapy
CADTH recommends that Rybrevant be reimbursed by public drug plans for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy if certain conditions are met.
Rybrevant should only be covered to treat patients who have EGFR exon 20 insertion mutation–positive NSCLC that has spread to other parts of the body or cannot be removed by surgery, and who have already received treatment with a platinum-based chemotherapy. Patients receiving Rybrevant should be in relatively good health.
Rybrevant should only be reimbursed when it is used after platinum-based chemotherapy and if its cost is reduced. It should not be reimbursed if it is given in combination with other anticancer drugs. Rybrevant must be prescribed by specialists with experience managing NSCLC.
NSCLCs occur when healthy cells in the lungs become cancerous; they are considered metastatic when cancer cells have spread to other parts of the body. There are approximately 30,000 new cases of NSCLC diagnosed each year in Canada, and up to 0.6% of patients have EGFR exon 20 insertion mutations, which can cause cancers to grow and spread.
Patients with NSCLC with EGFR exon 20 insertion mutations are treated with chemotherapy and immunotherapy; however, most patients’ disease does not respond to these available treatments. There is a need for new, life-extending treatments that improve quality of life.
Based on public list prices, treatment with Rybrevant is expected to cost $20,112 to $26,816 per patient for the first 28-day treatment cycle, and $10,056 to $13,408 per patient for each subsequent 28-day treatment cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that amivantamab be reimbursed 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 only if the conditions listed in Table 1 are met.
One ongoing phase I and Ib, multicenter, multinational, open-label, single-arm study (CHRYSALIS, which included 81 patients with metastatic NSCLC for the primary efficacy population in cohort D) demonstrated a clinically meaningful benefit of amivantamab based on overall response rate (ORR) (ORR per blinded independent central review = 43.2%; 95% confidence interval [CI], 32.2 to 54.7) and durability of response (median duration of response [DOR] = 11.04 months0; 95% CI, 5.52 to 11.07) in 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. pERC considered that the harms reported in the CHRYSALIS trial seemed generally manageable and the clinical experts indicated that amivantamab’s tolerability profile may be similar to currently available targeted therapies in NSCLC. There is an important unmet need for additional treatment options in this rare patient population given the poor prognosis and high symptom burden. pERC noted that amivantamab addresses a therapeutic need as there are currently no targeted therapies funded for patients with EGFR exon 20 insertion mutation–positive NSCLC.
Patients identified a need for effective treatments that delay disease progression, have the potential to cure their disease, maintain quality of life, improve disease symptoms, and have manageable side effects. pERC concluded that amivantamab met some of the patients’ needs as it provides symptom control, has a manageable toxicity profile, and fulfills an unmet need for a targeted treatment option. Although patients expressed an unmet need for treatments that maintain quality of life, no definitive conclusion could be reached regarding the effects of amivantamab on health-related quality of life (HRQoL) due to the results being based on a small subset of 36 patients.
A submitted adjusted indirect treatment comparison that compared amivantamab versus physician’s choice of treatment and individual treatment classes (e.g., tyrosine kinase inhibitor [TKI], immunotherapy, nonplatinum chemotherapy [NPBC]) had numerous limitations and pERC concluded that no firm conclusions could be drawn on the relative efficacy of amivantamab versus relevant comparators. Given the uncertain comparative clinical evidence for amivantamab, the committee considered exploratory cost-effectiveness analyses conducted by CADTH. Using the sponsor’s submitted price for amivantamab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio was likely at least $253,131 per quality-adjusted life-year (QALY) gained compared with NPBC. A price reduction would be required for amivantamab to achieve an incremental cost-effectiveness ratio of $50,000 per QALY gained.
Reimbursement Conditions and Reasons.
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada. In 2022, it was estimated there would be 30,000 new cases of lung cancer diagnosed, and 20,700 deaths from lung cancer in Canada. Lung cancer is classified as either NSCLC or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada. The most common symptoms of lung cancer include nonspecific cough, chest and shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, and fever. Approximately 15% of people in Canada with NSCLC have an EGFR-activating mutation in the region encoding the tyrosine kinase domain. 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. Exon 20 insertion mutations are the third most common EGFR mutations, which occur in 12% or fewer of all EGFR mutations globally, though a Canadian-based retrospective observational cohort study suggested exon 20 insertion mutations may only occur in approximately 4% of NSCLC EGFR mutations in Canada. It has been estimated that patients with EGFR exon 20 insertion mutations make up between 0.1% to 4.0% of all NSCLC cases globally and approximately 0.4% to 0.6% of overall NSCLC cases in Canada.
First-line standard of care for patients with locally advanced or metastatic NSCLC 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, or paclitaxel are approved but rarely used. Following the failure of first-line platinum-doublet chemotherapy, second-line treatment options are limited to single-drug non–platinum-based chemotherapeutic drugs, primarily docetaxel. Based on chart reviews and real-world evidence collected in Canada, the sponsor suggested that variability in treatment patterns exist in Canadian clinical practice with patients receiving EGFR TKIs, platinum-based chemotherapy, immuno-oncologics (IOs) in combination with platinum-based chemotherapy or chemotherapy in the front-line setting. Patients whose disease progresses on first-line therapy may receive an alternative drug class (often either an EGFR TKI or IO) and, if progression continues, further treatment may be supportive care or docetaxel, if not previously received, due to its toxicity. The sponsor suggested that based on a retrospective population-based cohort study in patients with metastatic NSCLC with EGFR mutations receiving second-line therapy in Alberta, Canada (n = 6,666), the 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).
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. Amivantamab has been approved by Health Canada, with conditions, 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. The Health Canada Notice of Compliance with conditions was granted on March 30, 2022, 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 mutated NSCLC, and the final report for CHRYSALIS to verify the clinical benefit of amivantamab. Amivantamab is available as a 50 mg/mL concentrate for solution for IV infusion, and the dosage recommended in the product monograph is 1,050 mg for patients weighing less than 80 kg, and 1,400 mg for patients weighing 80 kg or more once weekly for the first 4 weeks, and once every 2 weeks in all subsequent 28-day cycles.
To make its recommendation, the committee considered the following information:
Two patient groups, LCC and the Lung Health Foundation submitted patient group input for this review. LCC gathered data through phone interviews with 4 patients with EGFR-positive NSCLC and 2 patients who 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 the majority of EGFR exon 20 insertion mutation subtypes and therefore treatment options for these patients are limited, indicating a significant unmet need in this population. LCC respondents recalled their initial distress of receiving a stage IV NSCLC diagnosis, citing various psychosocial effects, including anxiety and depression, as 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 should have minimal or manageable side effects to allow participation in regular activities while on treatment and maintenance of quality of life (QoL). Regarding their experience with the treatment under review, the most common AEs were skin-related, including inflammation of the nail bed (paronychia), rashes on the face and legs, acne, and dry and sensitive skin. Other reported side effects included severe dry mouth, slight deterioration of vision, severe muscle pain during 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 as the hope of survival outweighed the side effects experienced. Two patients who began amivantamab as a first-line treatment stated that when feeling well, they were able to participate in physical activities and work they previously enjoyed and hoped to be able to continue to maintain their independence, functionality, and HRQoL. Two patients who were able to receive 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, as well as maintaining relationships with families and friends, challenging. Patients noted that side effects related to some previous treatments severely impacted their participation in daily activities and HRQoL.
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 this patient population.
Currently, the first-line treatment for patients with EGFR exon 20 insertion mutations is platinum-doublet chemotherapy, most commonly cisplatin or carboplatin plus pemetrexed, followed by maintenance pemetrexed. Docetaxel or pemetrexed would be used as second-line therapy following the 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 in this patient population. The clinical experts indicated that amivantamab would be used as monotherapy in patients with exon 20 insertion mutations following the failure of platinum-doublet chemotherapy, displacing the current second- 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 are no data to identify certain subgroups of patients who 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 could still experience some benefit. They also noted that patients with NSCLC are typically under the care of expert medical and thoracic oncologists. Due to the IV administration of amivantamab and the potential for adverse reactions, patients should be treated in cancer-specific institutions under the supervision of an appropriately trained cancer specialist who has expertise in treating lung cancers and managing infusion-related 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, tumour response would be assessed every 9 to 12 weeks.
Clinician group input was received from 2 groups: LCC-MAC, with 21 clinicians contributing to the submission and from the Ontario Health – Cancer Care Ontario 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 mutation NSCLC in Canada each year and they experience resistance to the first- and second-generation EGFR TKIs. The clinician group also highlighted the rarity of the indication, estimating that less than 2% of all patients with EGFR exon 20 insertion mutation NSCLC may be candidates for second-line amivantamab therapy, given the high number of patients considered to be too sick to receive first- 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 mutations due to the lack of effective targeted therapies and emphasized a significant unmet need for novel targeted therapies that prolong PFS and improve the 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 the patients most likely to respond to amivantamab are those with an EGFR exon 20 insertion mutation and they noted that next-generation sequencing is routinely conducted in all patients with advanced NSCLC with a nonsquamous 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 patients have failed, usually following platinum-doublet chemotherapy with or without immunotherapy and maintenance pemetrexed, or after docetaxel therapy. The LCC-MAC also noted 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) by a specialist or person experienced in administering chemotherapy drugs.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One study was included in the review. Study EDI1001 (CHRYSALIS) is an ongoing, phase I and Ib, single-arm, open-label, multicenter 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) where patients were treated with the RP2D of 1,050 mg amivantamab for patients who weighed less than 80 kg and 1,400 mg for patients who weighed 80 kg or more. Treatment in part 2 was delivered once weekly by IV infusion 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 parts 1 and 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 ORR per investigator and blinded independent central review (BICR) assessment in the primary efficacy population (81 patients who had undergone ≥ 3 postbaseline disease assessments), with secondary outcomes consisting of clinical benefit rate and best overall response, PFS, OS, DOR, and time to treatment failure.
In the safety analysis set (153 patients who received ≥ 1 dose of amivantamab), 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 identified as Asian (62.1%), female (61.4%), and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (72.5%); 36 patients (23.5%) 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%). Baseline characteristics for the primary efficacy population and the additional efficacy population were consistent with the safety analysis set.
At the time of the March 30, 2021, data cut-off (DCO), the median follow-up time was 14.5 months. In the primary efficacy population (N = 81), a total of 31 patients (38.3%; 95% CI, 27.7% to 49.7%) achieved an ORR per investigator assessment, and 35 patients (43.2%; 95% CI, 32.2% to 54.7%) achieved an ORR per BICR. Best response to the treatment per investigator assessment consisted of only partial responses in 31 patients (38.3%), while 12 patients (14.8%) had their best response as progressive disease. 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).
As of the March 30, 2021, DCO, the median PFS per investigator assessment 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 median PFS per BICR was 8.31 months (95% CI, 5.52 to 11.07), and a total of 54 (66.7%) PFS events had occurred. The progression-free rate for amivantamab per BICR was 79% (95% CI, 68% to 87%) at 3 months, 61% (95% CI, 49% to 71%) at 6 months, and 36% (95% CI, 25% to 47%) at 12 months. The median OS per investigator assessment 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.
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 patients (41.8%), the most frequent being pulmonary embolism, hypokalemia, diarrhea, dyspnea, hypoalbuminemia, paronychia, pneumonia, IRRs, and neutropenia. A total of 44 patients (28.8%) experienced serious AEs; the most frequently reported being pneumonia, dyspnea, pulmonary embolism, back pain, muscular weakness, and pneumonitis.
IRRs were the most frequent reason for infusion modifications, reported in 90 patients (58.8%). Dose reductions were reported in 22 patients (14.4%), mostly due to dermatitis acneiform and paronychia, while dose interruptions were reported in 55 patients (35.9%), mainly due to IRRs (15.0%). In total, 18 patients (11.8%) withdrew from treatment with amivantamab due to TEAEs, most frequently pneumonia, IRRs, pleural effusion, and pneumonitis.
Overall, 11 patients (7.2%) treated with amivantamab experienced a TEAE leading to death, with respiratory, thoracic, and mediastinal disorders the most common TEAEs leading to death in 6 patients (3.9%). As of the March 30, 2021, DCO, 45 patients (29.4%) in the CHRYSALIS trial died, primarily due to progressive disease (31 patients; 20.3%).
The most frequent notable harm associated with amivantamab included IRRs in 97 patients (63.4%), most of which were nonserious (grade 1 or 2) and occurred 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 (6 patients; 3.9%), paronychia (81 patients; 52.9%), and ophthalmologic disorders (19 patients; 12.4%).
CHRYSALIS was a first-in-human phase I and 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 and Ib or phase II trial may not accurately predict harm and/or effectiveness of treatments relative to other available therapeutic options. 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. 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 limit higher than 12%. Interpretation of time‐to‐event end points such as OS or PFS is limited in single‐arm studies; as all patients in cohort D received the same treatment, the extent to which the observed survival is due to the natural history of this subset of NSCLC, or the treatment received, remains unclear. The results for patient-reported outcomes 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 consulted by CADTH indicated that although the inclusion and exclusion criteria were appropriate, the exclusion criteria may have been restrictive, selecting for 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 identified as Asian (62.1%) enrolled, though the clinical experts did not feel this was likely to affect the generalizability of the results.
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 EGFR exon 20 insertion mutations 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 this comparison favoured amivantamab for ORR, PFS, and OS in comparison with physician’s choice of treatment. The CADTH review team identified several limitations (e.g., small sample sizes, concerns regarding heterogeneity across the study designs and populations, limited data availability, and the inability to adjust for important potential confounders and prognostic variables across each cohort) and concluded that no firm conclusions could be drawn on how amivantamab compared with other relevant treatment options. However, the clinical experts consulted by CADTH anticipated that based on the CHRYSALIS trial’s 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.
The sponsor submitted an adjusted treatment comparison that compared the efficacy of amivantamab from individual patient data 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 (using ORR, OS, PFS, and time to next treatment) of amivantamab in the CHRYSALIS trial (cohort D) to current treatments from real-world settings in patients with advanced NSCLC with EGFR exon 20 insertion mutations who are following treatment with platinum-based chemotherapy.
Amivantamab was compared to both a pooled basket of treatments, labelled as physicians’ choice, and individual treatment classes (TKI, IO, NPBC, vascular endothelial growth factor inhibitor [VEGFi] plus chemotherapy, and “other” regimens). Data from the 4 European data sources were pooled to create an 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. The eligibility criteria from the CHRYSALIS trial were applied to the real-world data sources to compare patients from the CHRYSALIS trial to similar patients from the external data sources.
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 the CHRYSALIS trial to the different treatment classes in the EU plus US cohort, there were || | ||||||||||| ||| patients in the TKI, IO, NPBC, VEGFi plus chemotherapy, and “other” groups, respectively.
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 [RR] = |||||||| ||||||||||||||). The adjusted ORR for amivantamab versus physicians’ choice in the US cohort was 38.3% versus ||||| (OR = ||||||||||||||| |||||||||||; RR = ||||||||||||||| ||||||||||), and 38.3% versus ||||| in the EU cohort (OR = ||||||||||||||| |||||||RR = ||||||||||||||| |||||||||||). Results for the individual treatment classes were consistent with the primary analysis; however, they were hindered by small sample sizes.
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 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.
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.
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 the CHRYSALIS trial. 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 adjustment for the EU plus US cohort or the EU cohort, which potentially resulted 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 the CHRYSALIS trial and the real-world data sources are comparable, which 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 the EU and US cohorts into a single combined cohort was possible due to the high consistency between the results and their comparable treatment distributions. 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, nonplatinum-based chemotherapy, VEGFi, and “other” treatments). 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 impacted the results as 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 and 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, the high degree of heterogeneity due to pooling assumptions, and 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.
No other relevant evidence was identified for this review.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: the market share of amivantamab was underestimated, the population size is uncertain, and amivantamab may be used in addition to current therapies. CADTH reanalysis increased the market share of amivantamab in years 2 and 3. In the CADTH base case, the estimated budget impact of the reimbursement of amivantamab 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 for the treatment of || ||||, and || | patients per year, respectively. Scenario analyses involving the population size and lack of displacement of comparators by amivantamab resulted in higher budget impact estimates, suggesting the true budget impact may be higher than predicted by both the sponsor’s and CADTH’s reanalysis.
The sponsor filed a request for reconsideration for the draft recommendation for amivantamab (Rybrevant) 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. The sponsor indicated that despite the uncertainty due to the single-arm design of the CHRYSALIS trial, the totality of the evidence and stakeholder input submitted to CADTH reasonably suggested that there is a substantial benefit of amivantamab in improving patient’s morbidity and mortality. In their request, the sponsor identified the following issues:
In the meeting to discuss the sponsor’s request for reconsideration, pERC considered the following information:
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Initial meeting date: September 13, 2022
Regrets: Four expert committee members did not attend.
Conflicts of interest: None
Reconsideration meeting date: January 11, 2023
Regrets: Three expert committee members did not attend.
Conflicts of interest: None
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Indication: For the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer with activating epidermal growth factor receptor exon 20 insertion mutations whose disease has progressed on, or after platinum-based chemotherapy
Sponsor: Janssen Inc.
Final recommendation: Reimburse with conditions
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