Indication: For the treatment of adult patients with locally advanced unresectable metastatic non–small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) tyrosine kinase receptor exon 14 skipping alterations.
Sponsor: EMD Serono Canada, a division of EMD Inc.
Final recommendation: Do not reimburse
What Is the CADTH Reimbursement Recommendation for Tepmetko?
CADTH recommends that Tepmetko not be reimbursed by public drug plans for the treatment of locally advanced unresectable or metastatic non–small cell lung cancer (NSCLC) harbouring MET tyrosine kinase receptor exon 14 (METex14) skipping alterations.
Why Did CADTH Make This Recommendation?
The clinical evidence reviewed by CADTH was not strong enough to show whether treatment with Tepmetko benefits patients with locally advanced or metastatic NSCLC harbouring METex14 skipping alterations. It is not known if Tepmetko would lead to better outcomes for patients compared to treatments that are currently available.
Patients identified a need for treatments that stop or slow the progression of disease, prolong life, promote independence, improve symptoms and quality of life (QoL), and have minimal side effects. It is not clear whether Tepmetko meets these needs.
What is NSCLC With METex14 Skipping Alterations?
Lung cancer is the most diagnosed cancer and the leading cause of cancer deaths in Canada. It is estimated that in 2021, 29,600 people in Canada were diagnosed with lung cancer and 21,000 people in Canada died from lung cancer. NSCLC accounts for approximately 85% of lung cancer cases in the country. NSCLC can be driven by changes in a gene, such as METex14 skipping alterations which occur in approximately 3% of NSCLC cases.
Unmet Needs in NSCLC With METex14 Skipping Alterations
Not all patients’ tumours respond to currently available treatments for NSCLC and most patients will experience disease progression. As a result, there is a need for new oral, targeted therapy options for these patients.
How Much Does Tepmetko Cost?
Treatment with Tepmetko is expected to cost approximately $9,340 per patient per monthly cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that tepotinib not be reimbursed for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14 skipping alterations.
One phase II, open-label study (VISION; N = 151 in pivotal cohort A), evaluated the efficacy and safety of tepotinib in adult patients with locally advanced or metastatic NSCLC harbouring a METex14 skipping mutation; however, whether treatment with tepotinib results in added clinical benefit versus any relevant treatment comparators is unknown due to the single-arm design of this descriptive study and the lack of robust statistical testing. Furthermore, pERC noted the uncertainty regarding the health-related quality of life (HRQoL) data from the VISION trial due to the decreased sample sizes at later treatment cycles, open-label administration of tepotinib, and absence of a comparator arm. As a result, the effect of tepotinib on HRQoL remains unknown relative to currently available treatments. Indirect evidence submitted by the sponsor that compared the VISION trial’s cohort A to patients treated with other available therapies were limited by important methodological issues and several sources of bias that precluded pERC from concluding that treatment with tepotinib resulted in added clinical benefit in progression-free survival (PFS) or overall survival (OS) relative to immunotherapy, chemotherapy, and chemo-immunotherapy. Additionally, there was no comparative evidence on HRQoL or harms within the indirect treatment comparison (ITC). Given the totality of the evidence, pERC concluded there is a high degree of uncertainty regarding the clinical significance of the treatment benefit with tepotinib in patients with locally advanced or metastatic NSCLC harbouring a METex14 skipping mutation relative to standard of care therapies for NSCLC.
Patients identified a need for treatments that stop or slow the progression of disease, prolong life, promote independence, improve symptoms and QoL, and have minimal side effects. pERC noted that there is insufficient evidence that tepotinib meets these therapeutic needs because no definitive conclusion could be reached regarding the effects of tepotinib on these outcomes compared to standard of care therapies; however, pERC does recognize there is a need for new oral, targeted therapy options for these patients.
As there was uncertainty with the clinical evidence, the committee deliberated on tepotinib considering the criteria for significant unmet need that are described in section 9.3.1 of the . The committee acknowledged the rarity of METex14 skipping alterations and severity of the condition; however, the committee concluded that the evidence available does not reasonably suggest that tepotinib could substantially reduce morbidity and/or mortality associated with the disease.
pERC recognized the need for an effective targeted treatment option for patients with NSCLC harbouring METex14 skipping alterations and that conducting a randomized controlled trial in this patient population could be challenging; however, the evidence reviewed for the initial submission and reconsideration was of low quality and evidence gaps remain. The sponsor may file a resubmission in the future should new evidence become available that fills the gaps identified by pERC.
In addition to the clinical evidence, pERC considered input and feedback from clinician and patient groups and the public drug plans. Although expert opinion and patient needs are used to inform the deliberation, pERC concluded that the available evidence did not demonstrate that tepotinib meets the needs identified by patients and clinicians. pERC discussed the need for new treatments with fewer or more manageable adverse effects than current standard of care. Since there was no evidence on the relative safety of tepotinib compared to standard of care therapies, pERC concluded that it remains unknown whether tepotinib addresses this patient need. Although the oral formulation of tepotinib may lead to increased patient independence and avoid IV administration, there was insufficient evidence to demonstrate that this would translate into benefits to patients such as improved HRQoL.
The current standard of care for the treatment of NSCLC with METex14 skipping alterations is immunotherapy with or without chemotherapy. pERC noted the absence of a direct comparison of tepotinib to a relevant treatment comparator and the important limitations of the indirect evidence. Limitations associated with the ITC submitted by the sponsor include a significant risk of bias in study selection, limited reporting of methods employed in the ITCs, important differences in the study design that could not be accounted for in the analyses, differences in definitions and assessments of study end points, incomplete assessment of heterogeneity, and the lack of adjustment for all important potential confounders in the analyses. In light of the substantial uncertainty in the ITC results, pERC could not draw any conclusions pertaining to the efficacy of tepotinib compared to chemotherapy or immunotherapy in patients with advanced NSCLC harbouring METex14 skipping alterations. In addition, important outcomes (i.e., duration of response [DOR], objective response rate [ORR], HRQoL, and harms) were not assessed and tepotinib was not compared to the combination of chemotherapy and immunotherapy in the indirect evidence analyses in the initial submission, which represent significant gaps in the evidence. The potential benefits and safety of tepotinib compared with other standard of care therapies remain unknown.
pERC discussed new indirect evidence that was submitted by the sponsor for the reconsideration. The new unanchored matching adjusted indirect comparison (MAIC) compared tepotinib to the combination of chemotherapy and immunotherapy using the KEYNOTE-189 study and assessed OS and PFS. The 95% confidence intervals (CIs) for the Cox proportional hazard ratios (HRs) included the null and there were no statistically significant differences between groups for each outcome. Furthermore, there were methodological limitations of the MAIC that made the results uncertain (e.g., the KEYNOTE-189 study enrolled patients with wild-type NSCLC, heterogeneity, lack of adjustment for all important potential confounders). Based on this data, it remains unknown whether treatment with tepotinib would result in survival benefit compared to chemo-immunotherapy.
pERC discussed the prevalence of the condition under review. METex14 skipping alterations occur in approximately 3% of NSCLC cases, which is not substantially lower than ALK alterations. pERC noted that drugs targeting the latter are associated with more robust evidence from phase III trials.
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 histology is poor, with an overall 5-year net survival of 19%. Lung cancer is classified into NSCLC or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada. The symptoms of advanced or metastatic NSCLC can be variable and often depend on the site of metastasis. At presentation, the most common signs and symptoms of NSCLC include persistent cough, shortness of breath, chest pain, wheezing, and hemoptysis. In patients with advanced disease and distant metastases, symptoms may include bone pain, headache, neurological or psychiatric abnormalities, paraplegia, hepatomegaly, and pathological fractures.
The MET receptor tyrosine kinase is an oncogenic driver of NSCLC. Mutations that result in loss of exon 14 in the MET gene, called METex14 skipping alterations, lead to dysregulation and inappropriate signalling. METex14 skipping alterations occur in approximately 3% of NSCLC cases. Currently, patients in Canada with advanced NSCLC (i.e., stage IV and stage IIIB not amenable to curative treatment approaches) harbouring METex14 skipping mutations are usually treated per guidelines for advanced NSCLC without driver mutations. In the first-line setting, current treatments include immunotherapy with or without chemotherapy. In the second- or later-line setting, single-agent chemotherapy, single-agent immunotherapy, or platinum-based chemotherapy doublets may be used.
Tepotinib has been approved by Health Canada for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14 skipping alterations. Tepotinib is a MET receptor tyrosine kinase inhibitor. It is available as tablets and the dosage recommended in the product monograph is 450 mg once daily.
To make its recommendation, the committee considered the following information:
a review of 1 phase II, single-arm clinical study in patients with advanced (locally advanced or metastatic) NSCLC
patients’ perspectives gathered by 2 patient groups, the Lung Health Foundation (LHF) and Lung Cancer Canada (LCC)
input from public drug plans and cancer agencies that participate in the CADTH review process
input from 2 clinical specialists with expertise diagnosing and treating patients with NSCLC
input from 3 clinician groups, including the Northeast Cancer Centre – Thoracic Cancer Clinicians, Ontario Health – Cancer Care Ontario’s Lung and Thoracic Cancers Drug Advisory Committee, and the LCC Medical Advisory Committee
a review of the pharmacoeconomic model and report submitted by the sponsor.
After the draft pERC recommendation for tepotinib was issued in March 2022, the sponsor provided additional unpublished data from the pivotal VISION study with a data cut-off date of February 2021. In addition, the sponsor provided an additional unanchored MAIC comparing tepotinib to the combination of chemotherapy and immunotherapy. These data were not included in the initial submission to CADTH and the sponsor reported that the data only became available after the draft CADTH recommendation was issued. A comparison of tepotinib to a combination of chemotherapy and immunotherapy has been identified as an important gap in the evidence.
CADTH received input from 2 patient advocacy groups: LHF and LCC. LHF collected information from an online survey with 13 patients and 1 caregiver, and phone interviews with 2 patients. LCC collected data from phone and video interviews with 4 patients and 1 caregiver. Patients’ experiences with lung cancer varied from no symptoms to having the disease negatively impact their ability to perform instrumental activities of daily living. The most frequently reported symptoms were shortness of breath, fatigue, and depression. Other notable concerns were anxiety and stigma related to their diagnosis that prevented them from fully engaging with their families and participating in social activities.
Patients indicated that they want treatments that stop or slow the progression of disease, prolong life, improve symptoms and QoL, and have minimal side effects. The patients expressed that it is important to maintain independence and functionality. Patients reported that they struggled to navigate the health care system and access biomarker testing for MET mutations in Canada. The patients indicated that they want equal access to biomarker testing across Canada at the time of diagnosis or early in treatment.
CADTH received input from 2 clinical specialists with expertise in the diagnosis and management of NSCLC. The clinical experts reported that retrospective studies have shown that patients with METex14 alterations have a poor prognosis and there appears to be less benefit with immunotherapy in these patients. Moreover, the clinical experts noted that patients with METex14 skipping mutations tend to be an elderly population that often experience increased side effects with chemotherapy, thus better-tolerated treatments are needed. The clinical experts noted that there is currently no targeted treatment for METex14-mutated NSCLC that is publicly funded. The clinical experts indicated that the goals of treatment in locally advanced (not amenable to curative treatment) or metastatic NSCLC are to improve OS, PFS, and response rate, as well as to maintain the patient’s QoL. In addition, the clinical experts thought that new treatment options should minimize adverse events (AEs).
The clinical experts indicated that tepotinib would preferentially be used in the first-line setting for patients with METex14 skipping alterations because it is a targeted therapy. If patients received tepotinib or another MET receptor tyrosine kinase inhibitor as first-line treatment, later lines of therapy would consist of chemotherapy, immunotherapy, or chemotherapy plus immunotherapy based on established provincial funding algorithms. If tepotinib was not used as first-line therapy, it would be used as second- or later-line therapy.
The clinical experts thought tepotinib should be used in patients with locally advanced or metastatic NSCLC harbouring a METex14 skipping mutation who meet the eligibility criteria used in the VISION trial. Patients with METex14-mutated NSCLC would be identified by molecular biomarker testing using tumour tissue biopsy or liquid biopsy followed by next-generation sequencing or panel testing. The clinical experts noted that it would be ideal for this testing to be done at the time of diagnosis of advanced NSCLC. The clinical experts would also consider using tepotinib in patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or greater that otherwise met the VISION trial eligibility criteria.
The clinical experts reported that, in standard practice, response to treatment is assessed using CT and/or bone scans every 2 to 4 months as clinically indicated. In addition, if patients presented with disease-related symptoms before starting treatment, clinical assessments were conducted at regular intervals (e.g., every 3 months) to assess symptom control. The clinical experts reported that a clinically meaningful response to treatment would be improved survival and maintenance or improvement in QoL. The clinical experts indicated that treatment with tepotinib would be discontinued if a patient experienced disease progression or intolerable treatment-related side effects.
CADTH received input from 3 clinician groups with a total of 21 clinicians: the Northeast Cancer Centre – Thoracic Cancer Clinicians, Ontario Health – Cancer Care Ontario’s Lung and Thoracic Cancers Drug Advisory Committee, and the LCC Medical Advisory Committee. The clinician groups generally agreed with the input provided by the clinical experts consulted by CADTH. The clinician groups indicated that there is an unmet need for targeted therapy and improved outcomes in patients with advanced NSCLC harbouring METex14 skipping alterations. They thought that tepotinib would be preferentially offered as first-line therapy and offered as a subsequent therapy to those who had already received other treatments.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for tepotinib:
The drug programs noted that the VISION trial eligibility criteria included patients with an ECOG PS of 0 or 1 and asked whether patients with an ECOG PS of 2 or greater should be eligible for tepotinib if reimbursed.
The drug programs noted that patients currently receiving alternate first-line or subsequent lines of therapy would have a time-limited opportunity to switch to tepotinib at the time of public funding if reimbursed.
The drug programs noted that in patients with advanced NSCLC with driver mutations (e.g., EGFR, ALK, ROS, BRAF) who receive targeted treatment in the first-line setting, chemotherapy is required before accessing immunotherapy, in alignment with previous pERC recommendations. If tepotinib were reimbursed, the drug programs indicated that jurisdictions would use the same sequencing principles for therapies used after tepotinib, regardless of programmed death-ligand 1 (PD-L1) tumour proportion score.
The drug programs noted that if it was reimbursed, tepotinib may change the place in therapy of drugs reimbursed in subsequent lines.
The drug programs noted that METex14 skipping alteration testing may not be routinely available in some jurisdictions and would need to be implemented if reimbursed.
One ongoing, phase II, single-arm, open-label, multicentre trial (VISION) was included in the CADTH systematic review. The primary objective of the VISION study was to assess the efficacy of tepotinib in patients with advanced (locally advanced or metastatic) NSCLC, as per objective response (confirmed complete response or partial response) determined according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, based on independent review in patients that tested positive for METex14 skipping alterations or MET amplification. There were 3 cohorts in the VISION study (cohorts A, B, and C). Patients were selected for each cohort based on defined MET alterations or MET amplification identified in tumour tissue and/or in circulating tumour DNA derived from plasma (i.e., liquid biopsy). Patients with METex14 skipping alterations were enrolled into cohort A and cohort C under the same eligibility criteria and underwent the same study procedures. Cohort A was the pivotal cohort; cohort C was a confirmatory cohort added as a protocol amendment to extend and confirm the existing results for cohort A, and to expand the METex14 population in the study. After accrual for cohort A was complete, enrolment at sites was shifted from cohort A to cohort C (cohort A: N = 151; cohort A plus C: N = 254). Cohort B does not align with the Health Canada indication or reimbursement request; therefore, data will not be presented for cohort B in this review. All patients received 500 mg tepotinib hydrochloride hydrate containing 450 mg tepotinib orally once daily in 21-day cycles. Treatment was continued until disease progression, death, an AE leading to discontinuation, or withdrawal of consent. The primary outcome was ORR by independent review committee (IRC) assessment. Secondary outcomes included OS; PFS by IRC; PFS by investigator; ORR by investigator; DOR by IRC; DOR by investigator; change from baseline and time-to-deterioration (TTD) by 10 points in EQ-5D Five-Level (EQ-5D-5L) Visual Analogue Score (VAS), European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) (global health status/QoL score), EORTC Quality of Life Questionnaire Lung Cancer 13 (QLQ-LC13) (coughing, dyspnea, and chest pain symptom scales); and safety. Data were analyzed descriptively; no statistical testing was performed.
The mean age of study patients in cohort A and cohort A plus C was 73 years. Most patients were White (70.9% in cohort A and 67.1% in cohort A plus C), had an ECOG PS of 1 (73.5% in cohort A and 72.2% in cohort A plus C), had an adenocarcinoma histology type (86.8% in cohort A and 81.2% in cohort A plus C), and stage IV disease at study entry (74.8% in cohort A and 64.3% in cohort A plus C). Approximately half of the patients in cohort A and cohort A plus C had received prior anticancer drug therapy for advanced or metastatic disease (54.3% and 51.0%, respectively). The most common types of prior anticancer therapies were cytotoxic therapy (49.7% in cohort A and 44.3% in cohort A plus C) and immunotherapy (25.8% in cohort A and 25.9% in cohort A plus C). Most patients did not have prior anticancer surgery (68.9% in cohort A and 67.5% in cohort A plus C). Per IRC assessment, 9.9% of patients in cohort A and 12.2% of patients in cohort A plus C had brain metastases at baseline.
Data from an interim analysis of the VISION trial (data cut-off date of July 1, 2020) for the pivotal cohort A and pooled cohort A plus C (i.e., entire METex14 skipping population) are reported in the following. The results of key efficacy outcomes in the modified intention-to-treat population are summarized in Table 2.
Median OS was 17.6 months (95% CI, 15.0 to 21.0) in cohort A and 19.1 months (95% CI, 15.3, 22.1) in cohort A plus C.
Median PFS by IRC was 8.9 months (95% CI, 8.2 to 11.0) in cohort A and 9.5 months (95% CI, 8.2 to 11.2) in cohort A plus C.
The ORR by IRC was the primary end point in the VISION trial. The ORR by IRC was 45.0% (95% CI, 36.9 to 53.3) in cohort A and 46.4% (95% CI, 39.8 to 53.2) in cohort A plus C. All observed responses by IRC assessment were partial responses.
Median DOR by IRC was 11.1 months (95% CI, 8.4 to 18.5) in cohort A and 11.1 months (95% CI, 9.5 to 18.5) in cohort A plus C.
In cohort A, 40.4% of patients experienced a deterioration in EQ-5D-5L VAS score of 10 points and median TTD was 8.3 months (95% CI, 5.8 to 17.7). In cohort A plus C, 31.9% of patients experienced a deterioration in EQ-5D-5L VAS score of 10 points and median TTD was 8.3 months (95% CI, 5.9 to 17.7).
In cohort A, 35.8% of patients experienced a deterioration in EORTC QLQ-C30 global health status/QoL score of 10 points and median TTD was 15.2 months (95% CI, 6.0 to 33.2). In cohort A plus C, 29.1% of patients experienced a deterioration in global health status/QoL score of 10 points and median TTD was 15.2 months (95% CI, 6.2 to 33.2).
In cohort A, 29.8% of patients experienced a deterioration of 10 points in the EORTC QLQ-LC13 cough symptom scale and median TTD was 11.1 months (95% CI, 11.1 to not estimable [NE]). For chest pain, 29.8% of patients experienced a deterioration of 10 points and median TTD was 17.7 months (95% CI, 11.1 to NE). For dyspnea, 50.3% of patients experienced a deterioration of 10 points and median TTD was 5.5 months (95% CI, 4.1 to 6.9).
In cohort A plus C, 20.5% of patients experienced a deterioration of 10 points in the EORTC QLQ-LC13 cough symptom scale and median TTD was 13.8 months (95% CI, 11.1 to NE). For chest pain, 22.0% of patients experienced a deterioration of 10 points and median TTD was 17.7 months (95% CI, 11.8 to NE). For dyspnea, 40.9% of patients experienced a deterioration of 10 points and median TTD was 5.6 months (95% CI, 4.1 to 6.9).
In cohort A, 99.3% of patients experienced at least 1 treatment-emergent AE. The most frequently reported AE was peripheral edema (75.0%). Grade 3 or higher peripheral edema was reported in 18 (11.8%) patients in cohort A. Other frequently reported AEs in cohort A included nausea (35.5%), diarrhea (31.6%), hypoalbuminemia (29.6%), and increased blood creatinine (28.9%). In cohort A plus C, 96.5% of patients experienced at least 1 treatment-emergent AE. The most frequently reported AE was peripheral edema (60.0%). Grade 3 or higher peripheral edema was reported in 20 (7.8%) patients. Other frequently reported treatment-emergent AEs in cohort A plus C were nausea (26.3%), diarrhea (26.3%), increased blood creatinine (25.1%), and hypoalbuminemia (23.1%).
In cohort A, 55.9% of patients experienced at least 1 serious adverse event (SAE) as of the July 1, 2020, data cut-off date. The most frequently reported SAEs were pleural effusion (8.6%), disease progression (6.6%), and pneumonia (6.6%). In cohort A plus C, 45.1% of patients experienced at least 1 SAE. The most frequently reported SAEs were pleural effusion (6.7%), disease progression (4.7%), and pneumonia (4.7%).
In cohort A, a total of 42 (27.6%) patients permanently discontinued study treatment due to an AE. The most frequently reported AEs leading to treatment discontinuation were peripheral edema (4.6%), pleural effusion (3.3%), and general physical health deterioration (2.6%). In cohort A plus C, 20.4% of patients permanently discontinued study treatment due to an AE. The most frequently reported AEs leading to treatment discontinuation were peripheral edema (3.5%) and pleural effusion (2.0%).
In cohort A, 50.0% of patients had died as of the July 1, 2020, data cut-off date. Causes of death were reported to be disease progression in 39.5% of patients and an AE in 7.9% of patients. In cohort A plus C, 33.7% of patients had died as of the data cut-off date. Causes of death were reported to be disease progression in 25.9% of patients and an AE in 5.9% of patients.
The most frequently reported hepatotoxicity-related AEs in cohort A and cohort A plus C were increased alanine transaminase (11.8% and 11.4%, respectively), increased aspartate transaminase (8.6% and 7.5%, respectively), increased blood alkaline phosphatase (7.2% and 7.8%, respectively), and increased gamma-glutamyl transferase (5.9% and 5.5%, respectively). The most frequently reported renal toxicity-related AE in cohort A and cohort A plus C was increase in blood creatinine (28.9% and 25.1%, respectively). A total of 2 patients experienced interstitial lung disease and 6 patients experienced pneumonitis in cohort A. As of the data cut-off date, 75.0% of patients in cohort A and 60.0% of patients in cohort A plus C experienced peripheral edema.
For the primary end point and most secondary end points, an IRC was appropriately used. The primary limitations of the VISION trial were the absence of a comparator group, no statistical testing, and open-label administration of tepotinib. The time-to-event analyses were appropriate, although the data are difficult to interpret in a single-arm trial without a control group. Open-label administration of tepotinib may have impacted subjectively measured outcomes, such as HRQoL and patient-reported outcomes, assessment of response, and AEs, although the direction of the potential bias is unknown. In addition, there is uncertainty in the HRQoL and patient-reported outcomes data due to reduced samples sizes contributing to the analysis at later treatment cycles, which is likely to overestimate treatment effects. Due to the absence of a comparator group and statistical hypothesis testing, no definitive conclusions can be drawn on the efficacy of tepotinib based on the VISION trial.
The treatment regimen used in the VISION trial aligns with the Health Canada–recommended dose. The VISION trial was an international, multicentre study but there were no sites in Canada. The clinical experts consulted by CADTH indicated that the eligibility criteria used in the VISION trial were appropriate and commonly used in NSCLC trials. The VISION trial restricted enrolment to patients with an ECOG PS of 0 or 1, and patients with NSCLC in Canada often have an ECOF PS of 2 or greater. The VISION trial used liquid biopsy and/or tumour tissue biopsy to determine study patients’ METex14 skipping alteration status and the clinical experts indicated that both methods could be used in Canada.
The sponsor-submitted ITC consisted of 2 parts: an indirect comparison of individual patient data from the VISION trial to pooled real-world data (RWD) using propensity scoring, and an indirect comparison of individual patient data from the VISION trial to retrospective observational studies using an unanchored MAIC.15 In the indirect comparison using propensity scoring, tepotinib data from the VISION trial were compared to chemotherapy (without immunotherapy) and immunotherapy as monotherapy using a dataset derived from 4 real-world evidence cohort studies and a database. For the indirect comparison using an unanchored MAIC, the VISION trial was compared to 3 retrospective observational studies including patients who were treated with chemotherapy or immunotherapy. The relative efficacy of tepotinib to immunotherapy in combination with chemotherapy in patients with NSCLC harbouring METex14 skipping alterations was not assessed. Efficacy was assessed in terms of PFS and OS. Safety outcomes were not assessed.
Overall, the authors of the ITC concluded that patients treated with tepotinib had a longer PFS interval compared to patients treated with chemotherapy or immunotherapy. The authors also concluded that tepotinib conferred a benefit in OS compared to chemotherapy or immunotherapy, albeit of smaller magnitude than for PFS. For the indirect comparisons of the VISION trial to pooled RWD using propensity scoring, the Cox proportional HR for OS was 0.91 (95% CI, 0.62 to 1.35) in favour of tepotinib for the chemotherapy group and 0.91 (95% CI, 0.59 to 1.42) in favour of tepotinib for the immunotherapy group. For PFS, the Cox proportional HR was 0.49 (95% CI, 0.35 to 0.69) in favour of tepotinib for the chemotherapy group and 0.59 (95% CI, 0.39 to 0.90) in favour of tepotinib for the immunotherapy group. No HRs or other statistics were reported for the MAIC; the MAIC results were comprised of Kaplan-Meier curves for visual comparison.
Harms outcomes were not assessed in the sponsor-submitted ITC.
The description of the methods used in the ITC analyses lacked important details, which creates uncertainty in the data. The methods used to identify relevant studies and the criteria used for study selection were unclear. The sponsor submitted a systematic literature review that identified 2 of the 3 studies included in the MAIC; the third study included in the MAIC and the 4 RWD sources included in the indirect comparison using propensity scoring were not identified in this systematic literature review; thus, it remains unclear how these studies were identified and selected for inclusion in the indirect comparisons. No a priori protocol for selecting studies for inclusion in the indirect comparisons specifically was reported. Furthermore, it is unclear why other studies that were identified in the sponsor’s systematic literature review were not included in the ITC. The quality of the RWD sources was not assessed by the authors of the ITC and therefore not considered in the ITC analysis. The quality of 2 studies included in the MAIC was determined to be low, and the quality of the third study was not assessed. Any potential risks of bias of the included data sources (i.e., methodological limitations) were not assessed and not reported. A limited assessment of heterogeneity was reported. Key gaps in the evidence provided by the ITC were that no safety outcomes were assessed and chemotherapy in combination with immunotherapy was not included as a comparator.
Overall, substantial bias is expected in the results given the inherent limitations of the study design. The results observed in the indirect treatment analyses are unlikely to be valid, and the true effect may be substantially different than the results observed in the ITC. A number of key limitations related to the selection and assessment of studies and patients, as well as the methods used that could potentially bias the results, were identified. First, fundamental differences in study design between the VISION trial, RWD sources, and retrospective observational studies were noted, as were concerns over differences in the definition, assessment, and timing of the clinical end points. These differences could not be accounted for in the indirect comparisons. Second, there was limited assessment and reporting of clinically important heterogeneity, and the statistical analyses completed are unlikely to have accounted for all major differences. The generation of propensity scores and the unanchored MAIC did not include all important potential confounders, effect modifiers, and prognostic factors. In the unanchored MAIC, a large reduction in effective sample size was observed, which suggests there was likely significant heterogeneity between the VISION study and comparator studies. The results for comparisons with major reductions of effective sample size are not reliable. In addition, the indirect comparisons may have been biased by the differential distribution of invalid or missing data between the VISION clinical trial and retrospective datasets. Given these issues, there is substantial concern for the risk of bias in the sponsor-submitted ITCs and no conclusions can be drawn from the data.
Regarding external validity, the majority of the patient data were from sites in the US. It is likely that a number of important differences between the US and Canada exist with regard to the management of these patients, including differences in available treatments, health insurance coverage, and overall health care system structures, which would be expected to impact treatment eligibility and patient outcomes. In addition, the studies included patients enrolled more than a decade ago and these patients are unlikely to be representative of current patients, for whom better therapies and supportive care are available, which would be expected to bias the study results in favour of tepotinib.
No long-term extension studies or additional relevant studies were included in the sponsor’s submission to CADTH.
Type of economic evaluation
Partitioned survival model
Adult patients with locally advanced unresectable or metastatic NSCLC harbouring MET tyrosine kinase receptor exon 14 skipping alterations
Tepotinib, 225 mg, tablet: $153.96
$8,622 per 28 days at a dose of 450 mg once daily
Second-line or later population
Canadian publicly funded health care payer
Lifetime (10 years)
Key data source
CADTH reanalysis results
ICER = incremental cost-effectiveness ratio; ITC = indirect treatment comparison; LY = life-year; NSCLC = non–small cell lung cancer harbouring; PDC = platinum-based doublet chemotherapy; QALY = quality-adjusted life-year; vs. = versus.
The sponsor estimated the budget impact of tepotinib over 3 years. Several key limitations were identified related to treatment duration assumptions, pembrolizumab dosage, tepotinib market capture assumptions, comparator market shares, METex14 testing assumptions, and comparator drug costs. While the sponsor’s results suggested that the introduction of tepotinib would lead to a budgetary savings of $16,965,241 over a 3-year time horizon, CADTH reanalyses estimated a budget impact of $1,073,988 in year 1, $4,302,036 in year 2, and $8,122,224 in year 3, with a 3-year budget impact of at least $13,498,247. When testing costs were corrected and included, the 3-year budget impact increased substantially to $69,931,737, though it should be noted that these results were associated with substantial uncertainty.
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: February 9, 2022
Conflicts of interest: None
Reconsideration meeting date: August 10, 2022
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
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