CADTH Reimbursement Review

Tepotinib (Tepmetko)

Sponsor: EMD Serono, a division of EMD Inc., Canada

Therapeutic area: Locally advanced or metastatic non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada.¹ Survival from lung cancer of all stages and histologic subtypes is poor, with an overall 5-year net survival of 19%.¹ Lung cancer is classified into small cell lung cancer or non–small cell lung cancer (NSCLC), which accounts for approximately 88% of cases in Canada.¹ 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.² In patients with advanced NSCLC and distant metastasis, symptoms may include bone pain, headache, neurologic or psychiatric abnormalities, paraplegia, hepatomegaly, and pathological fractures.³

The mesenchymal-epithelial transition (MET) receptor tyrosine kinase is an oncogenic driver of NSCLC. Mutations that result in loss of exon 14 in the MET gene, called MET exon 14 (METex14) skipping alterations, lead to dysregulation and inappropriate signalling.⁴ METex14 skipping alterations occur in approximately 3% of NSCLC cases and are associated with poor prognosis, according to retrospective studies and the clinical experts consulted by CADTH.^4-7 A retrospective study has also found that patients with NSCLC harbouring METex14 skipping mutations may be less responsive to immunotherapy.⁸ Currently, patients in Canada with advanced (i.e., stage IV and stage IIIB not amenable to curative treatment approaches) NSCLC harbouring METex14 skipping mutations are usually treated according to guidelines for advanced NSCLC without driver mutations.^9,10 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.¹⁰

Tepotinib is an oral, ATP-competitive, and highly selective MET receptor tyrosine kinase inhibitor.¹¹ Tepotinib is indicated for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14skipping alterations. Documentation of METex14 skipping alteration status based on a validated METex14 assay is required before treatment with tepotinib. Tepotinib (225 mg tablets, as tepotinib hydrochloride) is taken orally, and the recommended dosage is 450 mg (2 tablets) once daily. Per the Health Canada product monograph, it is recommended that treatment be continued until disease progression or unacceptable toxicity.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of tepotinib for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14 skipping alterations.

After CADTH issued a draft CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommendation for tepotinib in March 2022, the following additional information was provided to CADTH.

• The sponsor provided additional unpublished data from the pivotal VISION study with a data cut-off date of February 2021.

• The sponsor provided an additional unanchored matching-adjusted indirect comparison (MAIC) comparing tepotinib to the combination of chemotherapy and immunotherapy. These data were not included in the submission to CADTH (the sponsor reported that the data became available only after the CADTH recommendation was issued). A comparison of tepotinib with a combination of chemotherapy and immunotherapy has been identified as an important gap in the evidence. The information has been summarized and critically appraised as an addendum to the CADTH report in Appendix 5.

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

Patient Input

CADTH received input from 2 patient advocacy groups: the Lung Health Foundation (LHF) and Lung Cancer Canada (LCC). The LHF collected information from an online survey with 13 patients and 1 caregiver, and from 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 a negative impact on 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 quality of life, and have minimal side effects. The patients expressed that it is important to maintain independence and functioning. 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 the equal access to biomarker testing across Canada at the time of diagnosis or early in treatment.

Input From the Clinical Experts Consulted by CADTH

CADTH received input from 2 clinical specialists with expertise in the diagnosis and management of NSCLC. The clinical experts reported that retrospective studies^7,8 have indicated patients with METex14 alterations have a poor prognosis, and there appears to be less benefit from immunotherapy in these patients. Moreover, the clinical experts noted that patients with METex14 skipping mutations tend to be an elderly population that often experiences increased side effects from chemotherapy. Thus, better-tolerated treatments are needed. The clinical experts noted that there is currently no targeted treatment for NSCLC with METex14 mutations 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 overall survival (OS), progression-free survival (PFS), and response rate, as well as maintain quality of life. 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 NSCLC with METex14 mutations would be identified by molecular biomarker testing using tumour tissue biopsy or liquid biopsy, followed by next-generation sequencing (NGS) 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 more who otherwise met the VISION trial eligibility criteria.

The clinical experts reported that, in standard practice, response to treatment is assessed using CT or bone scans every 2 to 4 months, as clinically indicated. In addition, if patients present with disease-related symptoms before starting treatment, clinical assessments are 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 quality of life. 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 involving a total of 21 clinicians: Northeast Cancer Centre – Thoracic Cancer Clinicians, Ontario Health – Cancer Care Ontario’s (OH-CCO) Lung and Thoracic Cancers Drug Advisory Committee, and LCC’s 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 as a subsequent therapy for those who had already received other treatments.

Drug Program Input

The drug programs noted that the VISION trial eligibility included patients with ECOG PS of 0 or 1 and asked whether patients with ECOG PS of 2 or more should be eligible for tepotinib. The clinical experts consulted by CADTH indicated that it would be reasonable to offer tepotinib to patients with an ECOG PS of 2 and 3.

The drug programs noted that patients currently receiving alternative first-line or subsequent lines of therapy would have a time-limited opportunity to switch to tepotinib at the time of public funding. The clinical experts indicated that, if a patient was responding to their current treatment, they would not switch the patient to tepotinib at the time of public funding. The clinical experts would keep the patient on their current treatment until they experienced progressive disease and then use tepotinib for the next line of therapy.

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 line with previous pERC recommendations. 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 tepotinib may change the place in therapy of drugs reimbursed in subsequent lines. Last, the drug programs noted that testing for METex14 skipping alterations may not be routinely available in some jurisdictions and would need to be implemented.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One ongoing, phase II, single-arm, open-label, multi-centre trial (VISION) was included in the CADTH systematic review.^12-14 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 [CR] or partial response [PR]), 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 (ctDNA) derived from plasma (i.e., liquid biopsy). Patients with METex14 skipping alterations were enrolled in 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 for cohort B will not be presented 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 objective response rate (ORR) by independent review committee (IRC) assessment. Secondary outcomes included OS; PFS by IRC; PFS by investigator; ORR by investigator; duration of response (DOR) by IRC; DOR by investigator; change from baseline and time to deterioration (TTD) by 10 points in 5-Level EQ-5D (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 and quality of life score), and 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, 67.1% in cohort A plus C), had an ECOG PS of 1 (73.5% in cohort A, 72.2% in cohort A plus C), adenocarcinoma histology type (86.8% in cohort A, 81.2% in cohort A plus C), and stage IV disease at study entry (74.8% in cohort A, 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, 44.3% in cohort A plus C) and immunotherapy (25.8% in cohort A, 25.9% in cohort A plus C). Most patients had not had prior anticancer surgery (68.9% in cohort A, 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 VISION (data cut-off date of July 1, 2020) for the pivotal cohort A and pooled cohort A plus C (i.e., entire population with METex14 skipping alterations) are reported in this section. The results of key efficacy outcomes in the modified intention-to-treat (mITT) population are summarized in Table 2.

Overall Survival

Median OS was 17.6 (95% confidence interval [CI], 15.0 to 21.0) months in cohort A and 19.1 (95% CI, 15.3 to 22.1) months in cohort A plus C.

Progression-Free Survival

Median PFS by IRC was 8.9 (95% CI, 8.2 to 11.0) months in cohort A and 9.5 (95% CI, 8.2 to 11.2) months in cohort A plus C.

Objective Response Rate

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 PR.

Duration of Response

Median DOR by IRC was 11.1 (95% CI, 8.4 to 18.5) months in cohort A and 11.1 (95% CI, 9.5 to 18.5) months in cohort A plus C.

Health-Related Quality of Life and Patient-Reported Outcomes

In cohort A, 40.4% of patients experienced a deterioration in EQ-5D-5L VAS score by 10 points, and median TTD was 8.3 (95% CI, 5.8 to 17.7) months. In cohort A plus C, 31.9% of patients experienced a deterioration in EQ-5D-5L VAS score by 10 points and median TTD was 8.3 (95% CI, 5.9 to 17.7) months.

In cohort A, 35.8% of patients experienced a deterioration in EORTC QLQ-C30 global health status and quality of life score by 10 points, and median TTD was 15.2 (95% CI, 6.0 to 33.2) months. In cohort A plus C, 29.1% of patients experienced a deterioration in global health status and quality of life score by 10 points, and median TTD was 15.2 (95% CI, 6.2 to 33.2) months.

In cohort A, 29.8% of patients experienced a deterioration by 10 points in the EORTC QLQ-LC13 cough symptom scale. and median TTD was 11.1 (95% CI, 11.1 to NE) months. For chest pain, 29.8% of patients experienced a deterioration by 10 points, and median TTD was 17.7 (95% CI, 11.1 to NE) months. For dyspnea, 50.3% of patients experienced a deterioration by 10 points, and median TTD was 5.5 (95% CI, 4.1 to 6.9) months.

In cohort A plus C, 20.5% of patients experienced a deterioration by 10 points in the EORTC QLQ-LC13 cough symptom scale, and median TTD was 13.8 (95% CI, 11.1 to NE) months. For chest pain, 22.0% of patients experienced a deterioration by 10 points, and median TTD was 17.7 (95% CI, 11.8 to NE) months. For dyspnea, 40.9% of patients experienced a deterioration by 10 points, and median TTD was 5.6 (95% CI, 4.1 to 6.9) months.

Harms Results

The results of key harms outcomes in the cohort A and cohort A plus C safety analysis sets as of the July 1, 2020, data cut-off date are reported here and summarized in Table 2.

Table 2: Summary of Key Results From VISION as of the July 1, 2020, Data Cut-Off Date

AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; CI = confidence interval; CR = complete response; DOR = duration of response; EORTC QLQ-C30 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13; EQ-5D-5L VAS = 5-Level EQ-5D visual analogue scale; GGT = gamma-glutamyl transferase; IRC = independent review committee; mITT = modified intention-to-treat; NE = not estimable; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; TTD = time to deterioration; WDAE = withdrawal due to adverse event.

^a95% CI calculated using the Brookmeyer and Crowley method.

^bMedian estimated using the Kaplan-Meier method.

^c95% CI calculated using the Clopper-Pearson method.

Source: VISION Clinical Study Report.¹⁴

Adverse Events

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%).

Serious Adverse Events

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%).

Withdrawals Due to Adverse Events

In cohort A, a total of 42 (27.6%) of 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%).

Mortality

In cohort A, 50.0% 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. Causes of death were reported to be disease progression, in 25.9% of patients, and an AE, in 5.9% of patients.

Notable Harms

The most frequently reported hepatotoxicity-related AEs in cohort A and cohort A plus C were increased alanine transaminase (ALT) (11.8% and 11.4%, respectively), increased aspartate transaminase (AST) (8.6% and 7.5%, respectively), increased blood alkaline phosphatase (ALP) (7.2% and 7.8%, respectively), and increased gamma-glutamyl transferase (GGT) (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.

Critical Appraisal

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 and of 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 affected subjectively measured outcomes, such as health-related quality of life (HRQoL) and patient-reported outcomes (PROs), response, and AEs, although the direction of the potential bias is unknown. In addition, there is uncertainty in the HRQoL and PRO data due to reduced sample sizes in later treatment cycles, which is likely to bias results in favour of tepotinib and overestimate treatment effects. Due to the absence of a comparator group and statistical 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 dosage. The VISION trial was an international, multi-centre 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 more. The VISION trial used liquid biopsy and/or tumour tissue biopsy to determine study patients’ METex14 skipping alteration status; the clinical experts indicated that both methods could be used in Canada.

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) consisting 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 (RWE) 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 versus immunotherapy in combination with chemotherapy in NSCLC patients harbouring METex14 skipping alterations was not assessed. Efficacy was assessed in terms of PFS and OS. Safety outcomes were not assessed.

Efficacy Results

Overall, the authors of the ITC concluded that patients treated with tepotinib had a greater PFS time 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 PFS. For the indirect comparisons of VISION to pooled RWD using propensity scoring, the Cox proportional hazard ratio (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 composed of Kaplan-Meier curves for visual comparison.

Harms Results

Harms outcomes were not assessed in the sponsor-submitted ITC.

Critical Appraisal

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 review¹⁶ 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 that 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. As a consequence, the results observed in the indirect treatment analyses are unlikely to be valid. 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 or effect modifiers and prognostic factors. In the unanchored MAIC, a large reduction in effective sample size (ESS) was observed, which suggests there was likely significant heterogeneity between the VISION study and comparator studies. The results for comparisons with major reductions of ESS 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, most patient data were from sites in the US. A number of important differences between the US and Canada likely exist with regard to the management of these patients, including differences in treatments available, health insurance coverage, and overall health care system structures, which would be expected to affect treatment eligibility and, thus, outcomes. In addition, the multiple studies included patients enrolled more than a decade ago, and these patients are unlikely to be representative of contemporary patients, as better therapies and supportive care are now available. This 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.

Conclusions

One ongoing phase II, single-arm trial (VISION) of tepotinib in patients with advanced (locally advanced or metastatic) NSCLC harbouring METex14 skipping alterations was identified in the systematic review conducted by CADTH. The VISION trial data were analyzed descriptively; no statistical hypotheses were tested. Per the clinical experts consulted by CADTH, the results suggested a potential beneficial effect of tepotinib on OS, PFS, ORR, and DOR, based on their clinical experience and expectations of the natural progression of the disease in patients with METex14 skipping alterations. The clinical experts indicated that there is significant unmet need for targeted treatment and improved outcomes in this patient population. However, due to the absence of a comparator arm and statistical testing, no definitive conclusions can be drawn regarding the efficacy of tepotinib based on the VISION trial. The HRQoL and PRO data from VISION suggested that quality of life may be maintained with tepotinib therapy per the clinical experts, but there is substantial uncertainty in these data due to decreased sample sizes in later treatment cycles, open-label administration of tepotinib, and absence of a comparator arm. As a result, the effect of tepotinib on HRQoL and PROs remains unknown. Almost all study patients reported treatment-emergent AEs, the most common of which was peripheral edema. The most frequently reported SAEs were pleural effusion, disease progression, and pneumonia. Few patients experienced interstitial lung disease or pneumonitis. The most common cause of death was disease progression. The clinical experts consulted by CADTH indicated that the safety of tepotinib was acceptable.

No direct evidence on the relative efficacy and safety of tepotinib versus standard of care therapies used to treat advanced NSCLC with METex14 skipping alterations in Canada (i.e., immunotherapy, chemotherapy, or immunotherapy with chemotherapy) was identified. Results from the indirect treatment analyses submitted by the sponsor suggested that tepotinib therapy may be associated with a benefit in PFS and OS compared to chemotherapy and immunotherapy. However, the ITCs are associated with substantial risk of bias and important limitations (i.e., methodological limitations, limited assessment of heterogeneity, reporting lacked important details, small sample sizes). In view of the substantial uncertainty in the ITC results, no conclusions can be drawn on the efficacy of tepotinib compared to chemotherapy or immunotherapy in patients with advanced NSCLC harbouring METex14 skipping alterations. Harms outcomes were not assessed in the ITC. The potential benefits and safety of tepotinib compared with other therapies remain unknown.

Introduction

Disease Background

Lung cancer is the most commonly diagnosed cancer and the leading cause of deaths from cancer in Canada.¹ Survival from lung cancer of all stages and histologic subtypes is poor, with an overall 5-year net survival of 19%.¹ In 2020, it was estimated that there would be 29,800 new cases of lung cancer diagnosed and 21,200 deaths from lung cancer that year.¹ It is estimated that 1 in 17 Canadians will die from lung cancer.¹⁷

Lung cancer is classified into small cell lung cancer or NSCLC, which accounts for approximately 88% of cases in Canada.¹ NSCLC is further classified into 3 main histologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The symptoms of metastatic NSCLC are often variable at presentation and 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.² In patients with advanced NSCLC and distant metastasis, signs and symptoms may include fatigue, loss of appetite, pain, bone pain, headache, neurologic or psychiatric abnormalities, paraplegia, hepatomegaly, and pathological fractures.³

The MET receptor tyrosine kinase and its ligand are oncogenic drivers of NSCLC. Mutations that result in loss of exon 14 in the MET gene, called METex14 skipping alterations, lead to dysregulation and inappropriate signalling.⁴ METex14 skipping alterations occur in approximately 3% of NSCLC cases and are associated with poor prognosis, according to retrospective studies and the clinical experts consulted by CADTH.^4-7 A retrospective study has also found that patients with NSCLC harbouring METex14 skipping mutations may be less responsive to immunotherapy.⁸ Patients with NSCLC harbouring METex14 skipping mutations are more likely to be older, and the mutation occurs more frequently in adenocarcinoma.^4,6 The clinical experts consulted by CADTH reported that METex14 skipping mutations can be seen in squamous cell and sarcomatoid lung cancer as well. There are several methods to detect METex14 skipping mutations in NSCLC using tumour tissue biopsy or liquid biopsy (e.g., NGS-based panel tests, immunohistochemistry, real-time polymerase chain reaction, Sanger sequencing).^4,5

Standards of Therapy

The clinical experts consulted by CADTH indicated that, in current practice, 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 according to guidelines for advanced NSCLC without oncogenic driver alterations. 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 maintain HRQoL.

First-line treatment for patients with locally advanced or metastatic NSCLC without driver mutations is immunotherapy, with or without chemotherapy.^9,10 According to the clinical experts consulted by CADTH, pembrolizumab, in combination with a platinum-doublet therapy, as well as nivolumab plus ipilimumab with 2 cycles of a platinum-doublet therapy, are treatment options, regardless of PD-L1 expression. For patients with PD-L1 tumour proportion score of 50% or more, single-agent pembrolizumab is an option.⁹ Patients ineligible for immunotherapy may receive chemotherapy in the first-line setting. A combination of 2 cytotoxic chemotherapies is recommended for these patients.¹⁰ Platinum-based doublet regimens are recommended over non-platinum therapy; non-platinum chemotherapy may be offered to patients who are ineligible for platinum therapy.¹⁰

In the second- or later-line setting, single-agent chemotherapy, single-agent immunotherapy, or platinum-based chemotherapy doublets may be used.¹⁰ According to the clinical experts consulted by CADTH, immunotherapy is generally used first-line for patients who are eligible; therefore, second-line immunotherapy is less common. In the post-chemotherapy setting, nivolumab, pembrolizumab, or atezolizumab may be used.¹⁰ In the third-line setting, docetaxel or pemetrexed may be recommended.¹⁰

In March 2021, the American Society of Clinical Oncology (ASCO) and the OH-CCO issued a joint guideline update, including guidance for patients with NSCLC with a METex14 skipping mutation.¹⁸ These guidelines recommend that, for patients with a METex14 skipping mutation, an ECOG PS of 0 to 2, and previously untreated NSCLC, clinicians may offer MET-targeted therapy with capmatinib or tepotinib, or standard first-line therapy based on nondriver mutation guidelines. For patients with a METex14 skipping mutation and an ECOG PS of 0 to 2, who have previously received or been ineligible for first-line chemotherapy with or without immunotherapy, clinicians may offer MET-targeted therapy with capmatinib or tepotinib. At the time of this review, capmatinib was being reviewed by Health Canada under the Notice of Compliance with Conditions (NOC/c) guidance (the Health Canada submission was accepted for review September 2021).¹⁹

Drug

Tepotinib is an oral, ATP-competitive, and highly selective MET receptor tyrosine kinase inhibitor.¹¹ The MET receptor and its ligand hepatocyte growth factor (HGF) are involved in carcinogenesis and tumour progression. Oncogenic activation of MET has been shown to promote cancer cell proliferation, survival, migration and invasion, and tumour angiogenesis, as well as to mediate resistance to cancer therapies.¹¹ Tepotinib targets MET receptor tyrosine kinase, including variants with exon 14 skipping alterations and inhibits HGF-dependent and -independent MET phosphorylation and MET-dependent downstream signalling pathways. Tepotinib is taken orally, and the recommended dosage is 450 mg as tepotinib hydrochloride once daily. Per the Health Canada product monograph, it is recommended that treatment be continued until disease progression or unacceptable toxicity.

Tepotinib underwent expedited review by Health Canada through Project ORBIS. On May 27, 2021, tepotinib was issued a Notice of Compliance with Conditions (NOC/c), pending the results of trials to verify its clinical benefit. Tepotinib is indicated for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14 skipping alterations. Documentation of METex14 skipping alteration status, based on a validated METex14 assay, is required before treatment with tepotinib. The sponsor’s reimbursement request is for the treatment of adult patients with advanced NSCLC harbouring METex14 skipping alterations. Tepotinib has not been previously reviewed by CADTH.

Table 3: Key Characteristics of Tepotinib

HGF = hepatocyte growth factor; MET = mesenchymal-epithelial transition; NSCLC = non–small cell lung cancer.

^aHealth Canada–approved indication.

Source: Product monograph.¹¹

Stakeholder Perspectives

Patient Group Input

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

CADTH received input from 2 patient advocacy groups: the LHF and LCC.

The LHF (formerly the Ontario Lung Association) is a registered charity that advocates for patients with lung diseases and their caregivers. They collected information from an online survey with 13 patients and 1 caregiver (on or before August 31, 2021), and phone interviews with 2 patients (in September 2021). In addition, the LHF received input from a registered nurse and a certified respiratory educator. Patients’ experiences with lung cancer varied from no symptoms to negative impact on their instrumental activities of daily living. The most frequently reported symptoms were shortness of breath (64%), fatigue (57%), and depression (25%). Other notable concerns expressed by patients were anxiety associated with a poor prognosis and stigma attached to their diagnosis, which prevent them from fully engaging with their families and participating in social activities. Patients reported experiencing varying degrees of side effects from chemotherapy, ranging from hair loss and mild fatigue that are well-tolerated, to nausea, vomiting, and anemia that significantly affected their quality of life, even leading to hospitalization. Moreover, some patients experienced deconditioning and chronic fatigue after surgery, as well as tissue scarring, skin changes, and lung injury–related chronic obstructive pulmonary disease from radiation. Patients indicated that they want treatments that stop or slow the progression of disease, prolong life, and have minimal side effects. Given the poor prognosis of lung cancer, which is usually discovered in later stages, patients want treatments that are effective in advanced disease. Last, patients reported that they struggled to navigate the health care system and want equal access to biomarker testing at the time of diagnosis or early in treatment.

LCC is a national, registered organization that is a resource for lung cancer education, patient support, research, and advocacy. It collected data from phone and video interviews with 4 patients with NSCLC (in the US and Canada) and 1 caregiver (in Canada) in September 2021. All patients, including a patient for whom the caregiver answered the questionnaire, had confirmed METex14 skipping mutations. According to the survey, some patients found the diagnosis difficult to accept because the lung cancer was found at an advanced stage and the patient was otherwise healthy, and some were never exposed to smoking. In addition, patients indicated they became increasingly dependent on caregivers due to fatigue and functional deterioration, which increased mental distress and financial burden. The patients expressed that it is important to maintain independence and functioning so they can live in a manner similar to pre-diagnosis. Additionally, patients expressed that improving symptoms of NSCLC and quality of life, reducing side effects, delaying disease progression or achieving long-term remission, and living longer were important outcomes. There were 4 patients who had been treated with tepotinib, and all reported that their quality of life improved within a few months of starting therapy (e.g., reduced pain, returned to active lifestyle). One patient with a brain metastasis, who had previously tried another targeted therapy, became free of brain cancer after 8 months of tepotinib treatment. Patients also reported experiencing side effects from tepotinib treatment. One patient became hospitalized due to pulmonary edema and had to interrupt tepotinib therapy for 2 months. Two patients experienced edema at the extremities, which was managed with compression stockings. Patients who had previously tried other MET inhibitors and encountered tolerability and/or resistance issues appreciated having another treatment option. In terms of health care navigation, 1 patient did not have access to biomarker testing for MET mutations in Canada and had testing done in the US, where she paid $4,000 out of pocket after 50% reimbursement. This patient indicated that every Canadian with lung cancer should be able to access and afford the biomarker testing as well as the treatment itself so that they can benefit from targeted therapy.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of NSCLC.

The clinical experts consulted by CADTH indicated that the goals of treatment in locally advanced (not amenable to curative treatment) or metastatic NSCLC are to improve survival, delay progression, and increase clinical response rate, as well as maintain or improve HRQoL. In addition, the clinical experts thought that new treatment options should minimize AEs compared to current standard of care therapies.

The clinical experts noted that retrospective studies have indicated that patients with METex14 mutations have a poor prognosis, and there appears to be less benefit with the use of immunotherapy, even in patients with high PD-L1 expression.^7,8 Moreover, the clinical experts noted that patients with METex14 skipping mutations tend to be an older population compared to other lung cancer patient populations with different targetable mutations. The clinical experts reported that elderly patients often experience increased side effects with chemotherapy; thus, treatments that are better tolerated are needed.

The clinical experts noted that there is currently no targeted treatment for NSCLC with METex14 mutations that is publicly funded in Canada. Patients with METex14 skipping alterations in Canada are currently treated per the funded treatment algorithm for locally advanced or metastatic NSCLC without an identified driver mutation.

Place in Therapy

The clinical experts indicated that tepotinib would preferentially be used in the first-line setting for patients with METex14 skipping alterations because targeted agents are usually preferred as initial therapy. If patients received tepotinib or another MET 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.

Patient Population

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 NSCLC with METex14 mutations would be identified by molecular biomarker testing using tumour tissue biopsy or liquid biopsy and NGS panel testing. Ideally, this testing would be done at the time of diagnosis of advanced NSCLC. The clinical experts noted that both tumour tissue biopsy and liquid biopsy were used in the VISION trial. The clinical experts would also consider using tepotinib in patients with an ECOG PS of 2 or more who otherwise met the VISION trial eligibility criteria.

Assessing Response to Treatment

The clinical experts indicated that response to treatment is assessed using CT or bone scans every 2 to 4 months, as clinically indicated. In addition, clinical assessments are conducted at regular intervals (e.g., every 3 months) to assess symptom control if patients present with disease-related symptoms before starting treatment. The clinical experts reported that a clinically meaningful response to treatment would be improved survival and maintenance or improvement in HRQoL.

Discontinuing Treatment

The clinical experts indicated that treatment with tepotinib would be discontinued if a patient experienced disease progression or intolerable treatment-related side effects.

Prescribing Conditions

The clinical experts indicated that tepotinib would be administered in the outpatient setting under the supervision of a medical oncologist.

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

CADTH received input from 3 clinician groups comprising a total of 21 clinicians: Northeast Cancer Centre – Thoracic Cancer Clinicians, OH-CCO’s Lung and Thoracic Cancers Drug Advisory Committee, and LCC’s Medical Advisory Committee.

Northeast Cancer Centre – Thoracic Cancer Clinicians is a group of oncologists based in Sudbury, Ontario, who treat and advocate for older, rural patients, mostly francophone and Indigenous, throughout 12 satellite systemic therapy sites. They stated that patients with METex14 skipping mutations tend to be older, female, and non-smokers, and they have poorer prognosis. The clinicians reported that patients are currently treated without precision care and/or patient-directed therapy (i.e., systemic chemotherapy and immunotherapy) and are treated according to guidelines for NSCLC without mutations. These patients become refractory to the current treatments and experience frequent side effects. The clinician group indicated that there is a need for molecularly targeted and better-tolerated therapy that can delay disease progression, prolong OS, and improve quality of life. The oncologist group suggested that tepotinib could be used as any line of therapy for patients with good ECOG PS and METex14 alterations confirmed by either liquid or tissue biopsy. The clinician groups indicated that patients should be monitored for symptoms, disease progression, and survival every 3 months or at any change in ECOG PS. The group indicated that tepotinib should be discontinued if the patient’s PS deteriorates, intolerable AEs (e.g., edema) occur, or the disease progresses.

The OH-CCO’s Lung and Thoracic Cancers Drug Advisory Committee provides timely, evidence-based clinical and health system guidance. According to the OH-CCO, current first-line therapies for patients with METex14 mutation positive, stage IV NSCLC include pembrolizumab (if PD-L1 > 50%), platinum-based chemotherapy doublet plus pembrolizumab (with pemetrexed if PD-L1 is 50% or less and histologic subtype is non-squamous; with paclitaxel if PD-L1 is 50% or less and histologic subtype is squamous), or 2 cycles of platinum-based chemotherapy plus nivolumab and ipilimumab. Docetaxel or clinical trials could be considered as subsequent therapies. In addition, nondrug treatments, palliative or supportive care, and radiation could be used for symptomatic lesions. They stated that NSCLC is incurable, with a median OS of less than 2 years. Thus, there is an unmet need for a new therapy that can prolong survival, delay disease progression, reduce/improve symptoms, and shrink tumours. The clinician group reported that, unlike other targetable mutations, METex14 alterations occur in patients with squamous and sarcomatoid cancers, as well as certain pulmonary risk factors, such as smoking. Therefore, these patients fall into the unmet need group as well. According to the OH-CCO, because of tepotinib’s unique mechanism of action, tepotinib monotherapy would complement, not displace, other treatment options currently available. Based on OH-CCO and ASCO joint guidelines for stage IV NSCLC with targetable mutations, tepotinib would be preferentially offered in the community setting as first-line therapy and as a subsequent therapy to those who have already received other treatments. The OH-CCO indicated that re-treatment could be considered in rare cases, such as recurrence after completion of tepotinib therapy or interruption of tepotinib therapy for reasons other than disease progression. The group indicated that METex14 mutations should be identified in eligible patients by NGS platform testing. If MET mutation status is unknown, the patient should not be treated with tepotinib, the group thought. The clinician group indicated that, once tepotinib is initiated, patients should be monitored for improvement in symptoms, quality of life, tumour shrinkage, and disease progression every 4 to 8 weeks with imaging (e.g., radiography, CT scans), if imaging is needed. In cases of disease progression or intolerable side effects, the OH-CCO thought that tepotinib should be discontinued.

The LCC’s Medical Advisory Committee shared their recommendations on the management of NSCLC with MET mutations, which is in press at the journal Current Oncology as of this writing. The current therapies for treatment-naive patients are platinum-doublet, platinum-doublet with pembrolizumab (mostly for patients with PD-L1 of less than 50%; or patients with PD-L1 of 50% or more who are non-smokers, women, with a high burden of disease or symptoms), and pembrolizumab alone (if PD-L1 is 50% or more), unless this immunotherapy is contraindicated (e.g., due to auto-immune disease or active immunosuppressant therapy). For patients with metastatic NSCLC who had disease progression on prior systemic therapy, treatment options are platinum-doublet (if pembrolizumab was prior therapy); anti–PD-(L)1 therapies such as pembrolizumab, nivolumab, or atezolizumab (if platinum or pemetrexed, or platinum-doublet and pembrolizumab were previous therapy); and docetaxel (if disease progressed on platinum-doublet and pembrolizumab). The group reported that, since NSCLC with METex14 skipping mutations is aggressive, often resistant to anticancer therapies, and metastatic, the response rates to non-targeted therapies tend to be low, leading to poor prognosis. The group indicated that selective inhibition of MET, with few off-target effects, would be beneficial. The group reported that there is an unmet need for therapy that can improve OS, can rapidly improve symptoms, can delay disease progression, has intracranial activity for brain metastasis, has tolerable side effects, and minimizes health care resource utilization. Because METex14 skipping mutations often occur in older patients, smokers, those with sarcomatoid carcinoma, and a small percentage of those with squamous cell carcinoma, tepotinib could address unmet need in this population. The group suggested that tepotinib be offered as a single agent as early as possible, in the community setting, and in a line-agnostic manner to treatment-naive and pre-treated patients who have ECOG PS score 0 to 2 (and potentially 3) and a METex14 skipping mutation confirmed by NGS testing of either tumour or liquid biopsy. The group felt that NGS testing is unlikely to pose an obstacle to access to tepotinib because it is provincially funded in some circumstances and available through philanthropic or research settings in other cases. Furthermore, the group advocates that liquid biopsy testing should be considered across Canada to reduce the need for biopsy or repeat biopsy of tumour tissue. Last, the clinician group indicated that patients should have follow-up visits every 2 to 3 months to monitor for symptoms, with or without radiological evidence (e.g., CT imaging) of tumour shrinkage. The group stated that, if the patient wishes, safety issues arise, or the disease progresses, tepotinib should be discontinued.

Drug Program Input

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

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

ECOG PS = Eastern Cooperative Oncology Group performance status; METex14 = MET exon 14; NSCLC = non–small cell lung cancer; PD-L1 = programmed death-ligand 1; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; ROS = reactive oxygen species; TPS = tumour proportion score.

Clinical Evidence

The clinical evidence included in the review of tepotinib is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. No additional relevant studies were submitted by the sponsor or identified in the literature.

After CADTH issued a draft pERC recommendation for tepotinib in March 2022, the following additional information was provided to CADTH. The sponsor provided additional unpublished data from the pivotal VISION study with a data cut-off date of February 2021. The sponsor provided an additional unanchored MAIC comparing tepotinib to the combination of chemotherapy and immunotherapy. These data were not included in the submission to CADTH (the sponsor reported that the data became available only after the 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. The information has been summarized and critically appraised as an addendum to the CADTH report in Appendix 5.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of tepotinib (450 mg, as tepotinib hydrochloride) for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring METex14 skipping mutations.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CNS = central nervous system; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; HRQoL = health-related quality of life; METex14 = MET exon 14; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PRO = patient-reported outcome; RCT = randomized controlled trial; SAE = serious adverse events; vs. = versus; WDAE = withdrawal due to adverse events.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁰

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Tepmetko/tepotinib. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

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

The initial search was completed on September 23, 2021. Regular alerts updated the search until the meeting of the CADTH pERC on February 9, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature reference.²¹ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

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

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

AE = adverse event; CR = complete response; DCO = data cut-off; DOR = duration of response; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EORTC = European Organization for the Research and Treatment of Cancer; EQ-5D-5L = 5-Level EQ-5D; HGF = hepatocyte growth factor; IRC = independent review committee; METex14 = MET exon 14; NA = not applicable; NSCLC = non–small cell lung cancer; OL = open-label; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic; PR = partial response; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer 13; RECIST = Response Evaluation Criteria in Solid Tumours; TEAE = treatment-emergent adverse event.

Note: 4 additional reports were included from the sponsor’s submission to CADTH.^12,14,23

^aPatients with brain metastases whose condition was neurologically stable and whose glucocorticoid dose was being tapered were eligible to participate, as were patients with untreated asymptomatic brain metastases measuring 1 cm or less in diameter.

Source: VISION Clinical Study Reports,^12,14 Paik et al. (2020).¹³

Description of Studies

One ongoing, phase II, single-arm, open-label, multi-centre study (VISION) was included in this systematic review.^12-14 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 CR or PR), determined according to RECIST v1.1 criteria, based on independent review in patients that tested positive for METex14 skipping alterations or MET amplification. A total of 130 sites in 11 countries in Europe, Asia, and the US participated. 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 ctDNA derived from plasma. Patients with METex14 skipping alterations were enrolled in cohort A and cohort C under the same eligibility criteria and underwent the same study procedures. Cohort A was the pivotal cohort for the METex14 skipping alterations population; 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 skipping alteration 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 included patients who tested positive for MET amplification only and were negative for METex14 skipping alterations. Cohort B does not align with the Health Canada indication or reimbursement request; therefore, data for cohort B will not be presented in this review.

The VISION study design is depicted in Figure 2. Determination of patients’ METex14 skipping alteration status or MET amplification was conducted during the pre-screening period (which could be more than 28 days before the first dose of study treatment) after patients had signed a pre-screening informed consent form. Tumour tissue for testing was obtained from archived samples or from freshly obtained biopsy tissue. ctDNA was isolated from freshly collected plasma samples (i.e., liquid biopsy). Parallel testing for METex14 skipping alterations in both tumour tissue and plasma was highly recommended, although not required. If, for any reasons, either tumour tissue biopsy or liquid biopsy material was not available, a positive test result from either specimen type was sufficient to enrol a patient. After confirmation of METex14 skipping alteration status or MET amplification, patients entered the 28-day screening period to confirm that they met the study’s eligibility criteria. During the treatment period, patients in all cohorts received tepotinib monotherapy as tepotinib hydrochloride hydrate at a dosage of 500 mg once daily in 21-day cycles. The 500 mg tepotinib hydrochloride hydrate contained 450 mg tepotinib (active moiety). Patients continued treatment until disease progression according to RECIST v1.1 criteria, death, an AE leading to discontinuation, or withdrawal of consent. An end-of-treatment visit was conducted within 14 days of the last dose of study treatment. A 30-day follow-up visit was performed at 30 days after the last dose of study treatment for all patients who discontinued study treatment permanently, including patients who completed an end-of-treatment visit.

The primary analysis for the US FDA was an interim analysis with a data cut-off date of January 1, 2020.^12,13 The primary analysis population for this interim analysis was patients enrolled in cohort A who received their first dose of tepotinib before April 2, 2019 (N = 99).^12,13 An updated interim analysis was conducted with a data cut-off date of July 1, 2020.¹⁴ At both interim analyses, enrolment in cohort A was complete and enrolment in cohort C was ongoing at the time of data cut-off.

Populations

Inclusion and Exclusion Criteria

Patients were included in cohort A or cohort C of the VISION trial if they were adults 18 years of age or older (20 years of age or older in Japan) with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with METex14 skipping mutations. Prospective testing of METex14 skipping mutations was performed centrally on ctDNA obtained from plasma (liquid biopsy) or by evaluating RNA obtained from tumour tissue biopsy. Dual testing by the 2 biopsy methods was not a requirement for enrolment, although it was recommended. All patients had measurable disease according to RECIST v1.1 and an ECOG PS of 0 or 1. In addition, all patients had negative results on local testing for the presence of EGFR mutations or ALK rearrangements. Patients could have received up to 2 previous treatments for advanced or metastatic NSCLC. Patients with brain metastases whose condition was neurologically stable and whose glucocorticoid dose was being tapered were eligible to participate, as were patients with untreated asymptomatic brain metastases measuring 1 cm or less in diameter.

Figure 2: VISION Study Design

METex14 = MET exon 14; qd = once daily.

Source: VISION Clinical Study Report.¹²

Baseline Characteristics

Baseline characteristics of patients enrolled in cohort A and pooled cohort A plus C of the VISION study are summarized in Table 7. The mean age of study patients was 73 years. Most patients were White (70.9% in cohort A, 67.1% in cohort A plus C), had an ECOG PS of 1 (73.5% in cohort A, 72.2% in cohort A plus C), adenocarcinoma histology type (86.8% in cohort A, 81.2% in cohort A plus C), and stage IV disease at study entry (74.8% in cohort A, 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, 44.3% in cohort A plus C) and immunotherapy (25.8% in cohort A, 25.9% in cohort A plus C). The most frequently administered prior drug therapies were carboplatin, pemetrexed, cisplatin, and pembrolizumab. Most patients had not had prior anticancer surgery (68.9% in cohort A, 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.

Table 7: Summary of Baseline Characteristics — VISION Cohort A and Cohort A + C as of July 1, 2020, Data Cut-Off Date

ECOG PS = Eastern Cooperative Oncology Group performance status; IRC = independent review committee; mITT = modified intention-to-treat; NR = not reported; NSCLC = non–small cell lung cancer; SAS = safety analysis set; SD = standard deviation.

^aAll prior therapy lines are considered, so patients may be included in more than 1 category.

^bFrequency 5% or higher.

Source: VISION Clinical Study Report.¹⁴

Interventions

In the VISION study, patients received 500 mg tepotinib hydrochloride hydrate, which is equivalent to 450 mg tepotinib (the active moiety). Patients took tepotinib orally once daily, at approximately the same time each morning (± 2 hours), immediately after breakfast with a full glass of water (approximately 200 mL), during each 21-day cycle until disease progression per RECIST v1.1 criteria, withdrawal of consent, or an AE leading to discontinuation.

Any concomitant medications that were considered necessary for the patients’ welfare and would not interfere with tepotinib were permitted at the investigator’s discretion. Supportive treatment (e.g., bisphosphonates, agents for improving appetite), initiated before study entry, was allowed to continue. Changes in dose or schedule on study were discouraged. Initiation of prophylactic bisphosphonates during study treatment was avoided. Symptomatic treatment of brain metastasis with anticonvulsants known to have a reduced risk for drug interactions (e.g., lamotrigine, levetiracetam, pregabalin, or valproic acid) was allowed. Localized radiation therapy to alleviate symptoms such as bone pain was allowed, provided that the total dose delivered was in a palliative range and did not involve a target lesion used to determine response.

The following treatments were prohibited during the study: any other anticancer therapy, including chemotherapy, biologic therapy, hormonal therapy for anticancer purposes, targeted therapy, or investigational product other than tepotinib; drugs for which the product labelling included a contraindication for permeability glycoprotein, breast cancer resistance protein, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion protein 1, and multidrug and toxin extrusion protein 2 inhibiting drugs; and drugs that were known to induce permeability glycoprotein and thereby may decrease efficacy of tepotinib (e.g., avasimibe, carbamazepine, phenytoin, rifampin, Saint John’s Wort). Patients were withdrawn from the VISION study if they were using prohibited medicines for any reason.

Dose Reductions and Interruptions

If a patient experienced an AE in the VISION study, the investigator could either temporarily interrupt tepotinib treatment or continue tepotinib treatment at a lower dosage until the AE recovered to Grade 2 or less or to baseline values. Before Protocol Amendment 8 (January 17, 2020; see Table 9 for a summary of protocol amendments), the dosage was initially reduced to 300 mg tepotinib hydrochloride hydrate once daily. Further dosage reductions were made on a case-by-case basis in agreement with the sponsor. If the permitted lowest dosage was not tolerable, the patient was withdrawn from the study. After the implementation of Protocol Amendment 8, the standard dose reduction was changed to 250 mg tepotinib hydrochloride hydrate once daily. If the patient did not tolerate the 250 mg once daily dosage, or the AE did not resolve following treatment interruption, permanent treatment discontinuation was discussed with the sponsor. Following the dosage reductions, the daily dosage of tepotinib hydrochloride hydrate could be increased to 500 mg at the discretion of the investigator.

The maximum permitted period of continuous treatment interruption was 21 days. Before Protocol Amendment 8 (January 17, 2020), patients could be rechallenged at the initial dosage level of 500 mg tepotinib hydrochloride hydrate daily following a treatment interruption, or at a lower dosage level on a case-by-case basis, in agreement with the sponsor. Following the implementation of Protocol Amendment 8, re-exposure at the 250 mg tepotinib hydrochloride hydrate daily dosage level following a treatment interruption was permitted on a case-by-case basis.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the VISION trial and included in this review is provided in Table 8. These end points are further summarized in this section.

Efficacy Measurement for Primary and Secondary Outcomes

In VISION, a baseline tumour assessment was completed during the screening period. CT or MRI (MRI) with contrast enhancement was recommended for tumour assessment. Imaging studies, including CT or MRI of the chest, abdomen, and pelvis were performed at baseline to survey metastasis. Images from all patients at screening were independently reviewed by a single radiologist who checked the presence of measurable disease (measured in at least 1 dimension [longest diameter]) according to RECIST v1.1 before study treatment was started. Following the implementation of Protocol Amendment 8 (January 17, 2020; see Table 9 for a summary of protocol amendments), brain imaging by MRI with IV (IV) contrast enhancement was performed at baseline. MRI could be performed without contrast enhancement, if contrast was contraindicated. If MRI was not clinically feasible, CT of the brain with IV contrast enhancement could be used. For patients with brain metastases detected at baseline, subsequent brain imaging by MRI with IV contrast enhancement was performed for tumour assessment.

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

CNS = central nervous system; DOR = duration of response; EORTC = European Organization for the Research and Treatment of Cancer; EQ-5D-5L = 5-Level EQ-5D; HRQoL = health-related quality of life; IRC = independent review committee; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PRO = patient-reported outcome; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer 13; TTD = time to deterioration; VAS = visual analogue scale.

Source: VISION Clinical Study Reports,^12,14 sponsor’s submission to CADTH.²³

Table 9: Summary of Key Protocol Amendments in VISION

AE = adverse event; CSP = clinical study protocol; ctDNA = circulating tumour DNA; ILD = interstitial lung disease; METex14 = MET exon 14; mITT = modified intention-to-treat; NSCLC = non–small cell lung cancer; PD = progressive disease; PRO = patient-reported outcome.

Source: VISION Clinical Study Report,¹⁴ Paik et al. (2020).¹³

During the treatment period, patients had tumour assessments according to RECIST v1.1 every 6 weeks until 9 months and every 12 weeks thereafter, until disease progression, death, or withdrawal of consent. Patients who withdrew from treatment for reasons other than disease progression had tumour assessments performed every 6 weeks until 9 months and every 12 weeks thereafter, until radiologically documented disease progression, death, the end of study, or start of a new anticancer therapy, whichever occurred first. All tumour responses (PR and/or CR) were assessed every time with the same methods (CT or MRI) used at the first evaluation of the response.

For the determination of objective response and other RECIST-related outcomes, tumour evaluations were performed by the investigator and study centre radiologist as well as by independent review by the IRC. The decision to stop study treatment was primarily based on the investigator’s assessment.

Patients were followed-up every 3 months to collect information about survival and anticancer treatments.

Outcomes

In the VISION study, OS was a secondary outcome. OS time was measured as the time in months from first trial treatment administration to the date of death due to any cause. OS time was censored at the last date the patient was known to be alive, for patients not known to be deceased at time of analysis.

PFS by IRC and PFS by investigator assessment were secondary outcomes. PFS time was defined as the time in months from the first administration of trial treatment to the date of the first documentation of PD or death due to any cause within 84 days of the last evaluable tumour assessment, whichever occurred first. The PFS data were censored on the date of the last evaluable tumour assessment for patients who did not have an event (PD or death) or for patients with an event more than 84 days after the last evaluable tumour assessment. Patients who did not have an evaluable post-baseline tumour assessment were censored at the date of the start of trial treatment unless death occurred within 84 days of the first dose of trial treatment, in which case the death was considered an event.

The ORR confirmed by IRC was the primary outcome of the VISION study. Patients were identified as having an objective response if they achieved either a confirmed CR or PR from first administration of trial treatment to first observation of PD. Confirmation needed to take place by a tumour assessment at least 4 weeks (28 days) after the tumour assessments initially indicating CR or PR.

The ORR by investigator assessment was a secondary outcome. Objective response based on investigator assessment was derived and analyzed identically to the primary end point, apart from the use of the investigator’s evaluation instead of the IRC.

The DOR by IRC and DOR by investigator assessment were secondary outcomes. The DOR was evaluated only in patients who had an objective response. The DOR was defined as the time from when the CR or PR (whichever occurred first) criteria were first met until PD or death due to any cause within 84 days of the last evaluable tumour assessment, whichever occurred first. The DOR data were censored on the date of the last evaluable tumour assessment for patients who did not have an event (PD or death) or for patients with an event more than 84 days after the last evaluable tumour assessment.

In VISION, HRQoL and PROs were measured by 3 instruments: EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13. The questionnaires were completed every 6 weeks from cycle 1, day 1 until 9 months and every 12 weeks thereafter until disease progression, death, or withdrawal of consent. Change from baseline and TTD in EQ-5D-5L VAS score, EORTC QLQ-C30 global health status and quality of life score, and 3 EORTC QLQ-LC13 symptom scales (coughing, dyspnea, and chest pain) were assessed as secondary outcomes. A detailed discussion and critical appraisal of these outcomes is available in Appendix 4. In VISION, TTD was defined as the time between first dose and the first occurrence of a 10-point deterioration compared to the baseline score.²³ For the TTD analysis, the PROs were censored at the date of last PRO assessment or date of start of treatment, whichever was later.

The EQ-5D-5L is a generic quality of life instrument that may be applied to a wide range of health conditions and treatments. The EQ-5D-5L consists of the EQ-5D Likert-type scale (index score) and the EQ VAS. The EQ-5D-5L VAS records the patient’s self-rated health on a vertical VAS on which the end points are labelled 0 (“the worst health you can imagine”) and 100 (“the best health you can imagine”). CADTH identified a minimal important difference (MID) of 7 to 11.5 points in patients with lung cancer.²⁴ In VISION, the sponsor defined a clinically meaningful deterioration as a decrease of 10 points or more from baseline.²³

The EORTC QLQ-C30 is a standardized questionnaire for evaluating the quality of life of patients with cancer participating in clinical trials. This questionnaire is complemented by the lung cancer–specific questionnaire, the QLQ-LC13. The EORTC QLQ-C30 consists of 5 functional scales, 3 symptom scales, 6 single items, and a global health status and quality of life scale. A higher score on a functional scale and on global health status and quality of life corresponds to higher function and better quality of life, while a higher score on a symptom scale corresponds to higher symptom burden. For the global health status and quality of life score, CADTH identified an MID of 4 to 9 points for improvement and 4 points for deterioration in patients with NSCLC.²⁵ In VISION, the sponsor defined a clinically meaningful deterioration in global health status and quality of life score as a decrease of 10 points or more from baseline.²³

The EORTC QLQ-LC13, which supplements the QLQ-C30, consists of lung cancer–related symptoms and treatment side effects. Higher scores represent increased symptom burden. No MID was identified in the literature for the EORTC-LC13 symptom scales. In VISION, the sponsor defined a clinically meaningful deterioration as an increase of 10 points or more from baseline.²³

Intracranial central nervous system (CNS) outcomes were assessed in a post hoc exploratory analysis, which was reported in a poster and conference abstract included in the sponsor’s submission to CADTH.²³ A retrospective analysis of brain lesions determined by CT or MRI was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Responses were determined in patients with 1 or more evaluable post-baseline tumour assessment. Confirmation was not required. For patients with non-measurable lesions per RANO-BM, disease control in the brain was defined as no CR or PD.

To assess safety, the VISION study collected data on the number of patients with treatment-emergent AEs and deaths, laboratory parameters (hematology and coagulation, biochemistry, and urinalysis), vital signs, electrocardiograms, and physical examinations. Abnormal laboratory findings (Grade 1 to 3) and other abnormal investigational findings (e.g., on an electrocardiogram trace) were not reported as AEs unless they were associated with clinical signs and symptoms, led to treatment discontinuation or were considered otherwise medically important by the investigator. If a laboratory abnormality fulfilled these criteria, the identified medical condition (e.g., anemia, increased ALT) was reported as the AE rather than the abnormal value itself.

Statistical Analysis

In the VISION trial, no formal statistical hypotheses were tested. Data were analyzed descriptively. Analyses were performed by cohorts, and cohort A and cohort C (i.e., entire METex14 skipping alteration population) results were pooled and presented.

Determination of Sample Size

For all cohorts, the VISION study aimed to show an ORR assessed by IRC in the range of 40% to 50% and to demonstrate that the lower limit of the corresponding exact 2-sided 95% CI (according to Clopper-Pearson) for ORR exceeded 20% across lines of therapy. With a sample size of 60 patients per analysis set, a maximum width for the 95% CI of 26.4% would be achieved in the range for ORR of 40% to 60%.

The study planned to enrol patients in cohort A until at least 60 patients who had positive results of a liquid biopsy and at least 60 patients who had positive results of a tumour biopsy for METex14 skipping alterations were enrolled. Due to an anticipated overlap of patients who tested positive for METex14 skipping alterations in tumour tissue and in ctDNA derived from plasma, it was estimated that a total of approximately 100 patients would be enrolled in cohort A. Furthermore, the study planned to enrol at least 25 second- or later-line patients in cohort A.

Enrolment in cohort C was ongoing as of the most recent data cut-off date and was planned to continue until at least 60 patients who has positive results of a liquid biopsy and at least 60 patients who had positive results of a tumour biopsy for METex14 skipping alterations were enrolled. An overlap of patients who tested positive for METex14 skipping alterations in tumour tissue and in ctDNA derived from plasma was anticipated. Regardless of material used for inclusion in the study (i.e., liquid biopsy or tumour biopsy), the study planned to include at least 50 first-line, 30 second-line, and 20 third-line patients in cohort C.

Planned Analyses

Multiple analyses were planned in the VISION trial. Per the protocol, the primary efficacy analysis was conducted when the target enrolment population of at least 60 patients in both the subgroups of patients with positive results of a liquid biopsy and with positive results of a tissue biopsy had undergone at least 9 months of follow-up. For cohort A, the follow analyses were planned:

• Interim futility analysis: Conducted when 12 patients who had positive results of a tumour tissue biopsy had completed 4 cycles of trial treatment (84 ± 3 days) or prematurely discontinued trial treatment for any reason. If 3 or fewer confirmed responders were observed, enrolment in cohort A of patients who tested positive for METex14 skipping alterations on tumour biopsy, but not on plasma ctDNA, would be discontinued. No stopping criteria were defined for any other interim analysis.

• Interim analysis: Conducted when 12 patients who had positive results of a liquid biopsy had completed 4 cycles or prematurely discontinued trial treatment for any reason.

• 6-month follow-up analysis: Conducted when at least 60 patients who has positive results of a liquid biopsy and at least 60 patients who had positive results of a tumour biopsy had either been treated with tepotinib for 6 months or more, died or prematurely discontinued trial treatment for any reason.

• 9-month follow-up analysis: Conducted when at least 60 patients who had positive results of a liquid biopsy and at least 60 patients who had positive results of a tumour biopsy had either been treated with tepotinib for 9 months or more, died or prematurely discontinued trial treatment for any reason. This analysis was used as the primary analysis for the FDA. This analysis had a data cut-off date of January 1, 2020, and included 99 patients who received their first dose of tepotinib before April 2, 2019.^12,13 Results for this analysis and the population of patients in cohort A who received their first dose of tepotinib before April 2, 2019, are provided in Appendix 3.

• 15-month follow-up analysis: Conducted once at least 60 patients who had positive results of a liquid biopsy and at least 60 patients who had positive results of a tumour biopsy had either been treated with tepotinib for at least 15 months, died or prematurely discontinued trial treatment for any reason, whichever came first. This analysis was introduced in accordance with feedback from the FDA. This corresponds to the analysis conducted with a data cut-off date of July 1, 2020.¹⁴

• Periodic safety reviews

• Final analysis: To be conducted when all patients in cohort A have discontinued trial drug and two-thirds of the patients have died.

• The confirmatory cohort C was added to the VISION study as part of Protocol Amendment 6 (March 26, 2019; see Table 9 for a summary of protocol amendments). In addition to a separate analysis of cohort C, a pooled analysis of all subjects with METex14 skipping alterations was conducted (i.e., combining data from cohort A and cohort C). The following analyses were planned for the confirmatory part of the VISION study:

  • Primary (9-month follow-up) analysis: To be conducted once all patients have either been treated with tepotinib for at least 9 months, died, or prematurely discontinued trial treatment for any reason.

  • 21-month follow-up analysis: To be conducted once all patients have either been treated with tepotinib for at least 21 months, died, or prematurely discontinued trial treatment for any reason.

  • Final analysis: To be conducted at the end of the confirmatory cohort C of the VISION study, defined as the time point at which all patients have discontinued trial drug and two-thirds of the patients have died.

  • Primary outcome analysis

The primary end point of VISION was ORR (CR or PR), determined according to RECIST v1.1 based on IRC assessment. The primary analysis of the primary end point was based on the mITT population. As the study is ongoing, analysis of ORR was conducted based on all patients enrolled, as well as all patients who had at least 2 post-baseline assessments or who discontinued treatment for any reason. No formal statistical hypotheses were tested. The number of patients achieving objective response and the ORR by IRC with the corresponding 2-sided exact Clopper-Pearson 95% CI were presented.

Sensitivity Analyses

Sensitivity analyses were performed using mITT populations of patients who had positive results of a tumour biopsy or liquid biopsy for METex14 skipping alterations. A further sensitivity analysis was conducted on the mITT analysis set, in which the start of any other anticancer treatment or procedure before study discontinuation was considered as PD, and any subsequent tumour assessments were not considered in the objective response assessment. If only partial dates were known for the start of other anticancer treatment or procedures, then the earliest possible date (based on partial date entered) up to the date of last dose of trial treatment was used.

Subgroup Analyses

Subgroup analyses were specified a priori. Subgroups of interest outlined in the protocol included ECOG PS (0 or 1), line of therapy (first-line, second-line, second- or later-line, third- or later-line), baseline brain metastases per IRC assessment (present or absent), and histological classification (adenocarcinoma, squamous, or other). Best objective response details and ORRs (based on IRC and investigator assessment) and corresponding 2-sided exact Clopper-Pearson 95% CIs were presented for each of the identified subgroups. If there were fewer than 10 patients in any subgroup, then the results were presented in listings rather than calculating ORRs and 95% CIs.

Secondary Outcome Analysis

Secondary end point analyses were performed on the mITT population. The ORR based on investigator assessment was derived and analyzed identically to the primary end point, apart from the use of the investigator’s evaluation rather than that of the IRC. For DOR and PFS, the end points were assessed using both the IRC results and the investigator assessment.

For OS, PFS, and DOR, Kaplan-Meier estimates were presented with a summary of associated statistics (median and 3-, 6-, 9-, 12-, 15-, 18-month rate estimates and estimates for every 3 months thereafter, as applicable) including the corresponding 2-sided 95% CIs. The CIs for the median were calculated according to Brookmeyer and Crowley (1982) and CIs for the survival function estimates at the defined time points were derived using the log-log transformation according to Kalbfleisch and Prentice (1980). The estimate of the standard error was computed using Greenwood’s formula. Kaplan-Meier plots were also presented.

For the HRQoL and PROs, data were presented for the EQ-5D-5L VAS, EORTC QLQ-C30 global health status and quality of life score, and 3 symptom scales of the EORTC QLQ-LC13 (coughing, dyspnea, and chest pain). A TTD analysis was planned for these outcomes. Kaplan-Meier estimates were presented, including the corresponding 2-sided 95% CIs. The CIs for the median were calculated according to Brookmeyer and Crowley (1982). Kaplan-Meier plots were also presented.

For the EORTC QLQ-LC13 symptom scales, a mixed-effect model repeated measures (MMRM) analysis was performed to evaluate longitudinal change from baseline. The MMRM including change from baseline as the dependent variable; patient, analysis visit, and baseline score as a covariate; and baseline score by analysis visit interaction to account for nonconstant baseline effect across visits.

For all secondary end points except for HRQoL and PROs, subgroup analyses were performed for the same subgroups as the primary end point, depending on whether there was a sufficient number of patients (at least 5) in each subgroup. No subgroup analyses were performed on the HRQoL and PROs.

Handling of Missing Data

To impute missing tumour assessment dates, a missing day was imputed as the 15th of the month, if month and year were documented. If the imputation was earlier than the date of start of treatment, the day of start of treatment was taken. In all other cases, missing or incomplete dates were not imputed. To impute missing death dates, if month and year were available, the day was imputed as the 15th of the month, unless this resulted in a date earlier than the last date the patient was known to be alive. In that case, the date of death was imputed as the day after the last date the patient was known to be alive. No imputation was done for missing HRQoL and PRO data.

Analysis Populations

In the VISION trial, the mITT population included all patients who were administered at least 1 dose of tepotinib and had METex14 skipping alterations confirmed by a validated central laboratory assay.

The safety analysis set included all patients enrolled in the VISION trial who were administered at least 1 dose of tepotinib.

Protocol Amendments and Deviations

A total of 8 protocol amendments were implemented during the VISION trial, and the key changes made with these amendments are summarized in Table 9. In Protocol Amendment 4, the eligible study population was expanded to include all subtypes of NSCLC and patients who were treatment-naive and would receive tepotinib as first-line treatment. Before this amendment, only patients with adenocarcinoma were eligible, and patients were required to have failed 1 to 2 lines of systemic therapy, including a platinum-doublet-containing regimen. Cohort B and cohort C were added as part of Protocol Amendments 5 and 6, respectively. Following Protocol Amendment 6, the VISION trial consisted of 2 parts: part 1 included pivotal cohort A (METex14 skipping alterations) and cohort B (MET amplification); part 2 included cohort C (confirmatory part for METex14 skipping alterations).

In cohort A, 104 (68.4%) patients had at least 1 important protocol deviation. Important protocol deviations reported in 10% or more of patients were related to laboratory assessment criteria (40.1%), SAE criteria (14.5%), informed consent (13.2%), study procedures criteria (13.2%), and efficacy criteria (11.8%). Nine (5.9%) of patients had at least 1 clinically important protocol deviation: 3 patients had missed tumour imaging scans due to the COVID-19 pandemic, 5 patients deviated from key entry criteria, and 1 patient did not have METex14 skipping alterations confirmed by a validated central laboratory assay.

In cohort A plus C, 149 (58.4%) patients had at least 1 important protocol deviation. Protocol deviations reported in 10% or more of patients were related to laboratory assessment criteria (25.9%), study procedures criteria (15.3%), informed consent (11.8%), and SAE criteria (10.2%). Twelve (4.7%) patients in cohort A plus C had at least 1 clinically important protocol deviation. In addition to the deviations described earlier for cohort A, a tumour evaluation or staging imaging scan (CT or MRI) was not performed at a required time point for 3 patients.

Results

Patient Disposition

The disposition of patients in cohort A and cohort A plus C of the VISION study as of July 1, 2020, data cut-off date is summarized in Table 10. A total of 7,658 patients were pre-screened to determine MET alteration status in tissue and blood samples. Following identification of a METex14 skipping alteration in the pre-screening period, 168 patients were screened for enrolment in the pivotal cohort A. In total, 15 patients failed screening and were discontinued from the study because they did not meet the eligibility criteria (n = 9), they withdrew consent (n = 1), they died (n = 4), or “other” reasons (n = 1). A total of 152 patients were enrolled in cohort A and treated with at least 1 dose of tepotinib. One patient enrolled and treated in cohort A was excluded from the mITT population because the patient tested negative for METex14 skipping alterations in the liquid biopsy and had tumour biopsy data that were not evaluable.

To maintain recruitment for the confirmatory cohort C, cohort A recruitment was not interrupted in the study, and enrolment at sites was gradually shifted from cohort A to cohort C. As of the July 1, 2020, data cut-off, 282 patients were screened for enrolment in the pooled cohort A plus C. In total, 21 patients failed screening and discontinued the study because they did not meet the eligibility criteria (n = 13), they withdrew consent (n = 1), they had AEs (n = 1), they died (n = 5), or “other” reasons (n = 1). Following screening, 255 patients were enrolled in the study in the pooled cohort A plus C and treated with at least a single dose of tepotinib.

Exposure to Study Treatments

Patient exposure to tepotinib in the VISION study is summarized in Table 11. In cohort A, the mean duration of exposure to tepotinib was 9.38 (standard deviation [SD] = 7.63) months. Most patients (64.5%) were exposed to a relative dose intensity of 90% to 100%. Overall, 37.5% of patients had at least 1 dose reduction. Most patients (59.9%) experienced a therapy delay, which was defined as at least 2 days between 2 administrations of tepotinib. Therapy delays were attributed to AEs (48.0%), missed doses (29.6%), and other reasons (19.1%).

In cohort A plus C, the mean duration of exposure to tepotinib was 7.05 (SD = 6.71) months. Most patients (69.4%) were exposed to a relative dose intensity of 90% to 100%. Overall, 29.8% of patients had at least 1 dose reduction, and 50.2% of patients experienced therapy delays. Therapy delays were attributed to AEs (42.0%), missed doses (22.4%), and other reasons (15.7%). Data were missing for 7.5% of patients.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in this section. Data from the updated interim analysis (data cut-off date of July 1, 2020) for the overall pivotal cohort A (N = 151) and pooled cohort A plus C (i.e., entire METex14 skipping population; N = 254) are reported here.¹⁴

See Appendix 3 for detailed efficacy data, including results from the primary analysis for the FDA (data cut-off date of January 1, 2020; N = 151 in cohort A and N = 180 in cohort A plus C) and the primary analysis population for the FDA submission, which consisted of patients in cohort A who received the first dose of tepotinib before April 2, 2019 (N = 99).^12,13

Overall Survival

In the VISION trial, OS was a secondary end point. Results for OS in cohort A and cohort A plus C as of the July 1, 2020, data cut-off are summarized in Table 12. The Kaplan-Meier curve for cohort A is depicted in Figure 3; the Kaplan-Meier curve for cohort A plus C is depicted in Figure 4. In cohort A, the median duration of follow-up for OS was 16.4 (95% CI, 13.6 to 18.5) months, and the median OS was 17.6 (95% CI, 15.0 to 21.0) months. In cohort A plus C, the median duration of follow-up for OS was 9.9 (95% CI, 8.1 to 12.0) months, and the median OS was 19.1 (95% CI, 15.3 to 22.1) months.

Results of the subgroup analyses of OS conducted in cohort A and cohort A plus C are summarized in Table 13. The median OS was broadly consistent across subgroups. In the pivotal cohort A, the median OS was 17.6 (95% CI, 9.7 to 29.7) months in the first-line therapy subgroup and 19.7 (95% CI, 15.0 to 21.0) months in the second- or later-line therapy subgroup.

Table 10: Patient Disposition — VISION as of the July 1, 2020, Data Cut-Off Date

AE = adverse event; mITT = modified intention-to-treat; PD = progressive disease.

Source: VISION Clinical Study Report.¹⁴

Table 11: Exposure to Tepotinib in VISION Cohort A and Cohort A + C (Safety Analysis Set) as of July 1, 2020, Data Cut-Off Date

SD = standard deviation.

Source: VISION Clinical Study Report.¹⁴

Table 12: OS Results in VISION, Cohort A and Cohort A + C (mITT Population) as of the July 1, 2020, Data Cut-Off Date

CI = confidence interval; mITT = modified intention-to-treat; OS = overall survival.

^aCalculated using the Brookmeyer and Crowley method.

^bEstimated using the Kaplan-Meier method.

Source: VISION Clinical Study Report.¹⁴

Table 13: Subgroup Analyses of OS in Cohort A and Cohort A + C (mITT Population) as of the July 1, 2020, Data Cut-Off Date

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IRC = independent review committee; mITT = modified intention-to-treat; NE = not estimable; OS = overall survival.

^aEstimated using the Kaplan-Meier method.

^bCalculated using the Brookmeyer and Crowley method.

Source: VISION Clinical Study Report.¹⁴

Table 14: PFS Results in VISION, Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; IRC = independent review committee; mITT = modified intention-to-treat; PD = progressive disease; PFS = progression-free survival.

^aCalculated using the Brookmeyer and Crowley method.

^bEstimated using the Kaplan-Meier method.

Source: VISION Clinical Study Report.¹⁴

Figure 3: Kaplan-Meier Curve Showing OS in Cohort A (mITT Population, N = 151) as of the July 1, 2020, Data Cut-Off Date

CI = confidence interval; mITT = modified intention-to-treat; OS = overall survival.

Source: VISION Clinical Study Report.¹⁴

Figure 4: Kaplan-Meier Curve Showing OS in Cohort A + C (mITT Population, N = 254) as of the July 1, 2020, Data Cut-Off Date

CI = confidence interval; mITT = modified intention-to-treat; OS = overall survival.

Source: VISION Clinical Study Report.¹⁴

Progression-Free Survival

In the VISION trial, PFS by IRC and PFS by investigator assessment were secondary end points. Results for PFS in the cohort A and cohort A plus C as of the July 1, 2020, data cut-off are summarized in Table 14. The Kaplan-Meier curve of PFS by IRC in cohort A is depicted in Figure 5; the Kaplan-Meier curve of PFS by IRC in cohort A plus C is depicted in Figure 6. In cohort A, 57.6% of patients had an event (i.e., progressive disease or death) by IRC assessment, whereas 64.9% of patients had an event per investigator assessment. Median PFS by IRC was 8.9 (95% CI, 8.2 to 11.0) months, and median PFS by investigator was 8.5 (95% CI, 6.9 to 11.0) months in cohort A. In cohort A plus C, 41.3% of patients had an event per IRC assessment, whereas 47.6% had an event per investigator assessment. Median PFS by IRC was 9.5 (95% CI, 8.2 to 11.2) months, and median PFS by investigator was 8.3 (95% CI, 6.9 to 10.6) months in cohort A plus C.

Results of the subgroup analyses of PFS by IRC conducted in cohort A and cohort A plus C are summarized in Table 15. The median PFS by IRC was broadly consistent across all subgroups. In the pivotal cohort A, median PFS was 8.5 (95% CI, 6.8 to 11.3) months in the first-line therapy subgroup and 10.9 (95% CI, 8.2 to 12.7) months in the second- or later-line therapy subgroup.

Results of the subgroup analyses of ORR by IRC for cohort A are summarized in Table 17. The ORRs based on IRC assessment were similar across subgroups and consistent with the ORR in overall cohort A.

Figure 5: Kaplan-Meier Curve Showing PFS by IRC in Cohort A mITT Population (N = 151), as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; IRC = independent review committee; mITT = modified intention-to-treat; PFS = progression-free survival.

Source: VISION Clinical Study Report.¹⁴

Figure 6: Kaplan-Meier Curve Showing PFS by IRC in Cohort A + C mITT Population (N = 254), as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; IRC = independent review committee; mITT = modified intention-to-treat; PFS = progression-free survival.

Source: VISION Clinical Study Report.¹⁴

Table 15: Subgroup Analyses of PFS by IRC in Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IRC = independent review committee; mITT = modified intention-to-treat; NE = not estimable; PFS = progression-free survival.

^aEstimated using the Kaplan-Meier method.

^bCalculated using the Brookmeyer and Crowley method.

Source: VISION Clinical Study Report.¹⁴

Objective Response Rate

Results for the ORR by IRC and ORR by investigator are summarized in Table 16. 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 PR. The ORR by investigator assessment was a secondary end point. For cohort A, the ORR by investigator assessment was 53.0% (95% CI, 44.7 to 61.1). For cohort A plus C, the ORR by investigator was 43.7% (95% CI, 37.5 to 50.0). Most observed responses by investigator assessment were PR.

Table 16: ORR Results in VISION, Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; CR = complete response; IRC = independent review committee; mITT = modified intention-to-treat; ORR = objective response rate; PD = progressive disease; PR = partial response; SD = stable disease.

^aOnly patients with 2 ore more post-baseline assessments or who discontinued study treatment for any reason are included in the analysis.

^b95% CI calculated using the Clopper-Pearson method.

^cCR and PR had to be confirmed. SD had to last at least 12 weeks.

Source: VISION Clinical Study Report.¹⁴

Table 17: Subgroup Analyses of ORR by IRC in Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IRC = independent review committee; mITT = modified intention-to-treat; ORR = objective response rate.

^a95% CI calculated using the Clopper-Pearson method.

Source: VISION Clinical Study Report.¹⁴

Duration of Response

The DOR by IRC assessment and DOR by investigator assessment were secondary end points in the VISION trial. Results for DOR in cohort A and cohort A plus C as of the July 1, 2020, data cut-off date are summarized in Table 18.

In cohort A, a total of 68 patients had an objective response (confirmed CR or PR) by IRC assessment, and 31 (45.6%) of those patients experienced PD or death as of the July 1, 2020, data cut-off date. Median DOR by IRC was 11.1 (95% CI, 8.4 to 18.5) months. A total of 80 patients had an objective response by investigator assessment, and 39 (48.8%) of those patients experienced PD or death. Median DOR by investigator assessment was 12.7 (95% CI, 9.7 to 18.3) months.

In cohort A plus C, a total of 104 patients had an objective response by IRC assessment, and 33 (31.7%) of those patients experienced PD or death as of the July 1, 2020, data cut-off date. Median DOR by IRC was 11.1 (95% CI, 9.5 to 18.5) months. A total of 111 patients had an objective response by investigator assessment, and 43 (38.7%) of those patients experienced PD or death. Median DOR by investigator assessment was 12.5 (95% CI, 9.7 to 18.3) months.

Results of the subgroup analyses of DOR by IRC are summarized in Table 19. The median DOR by IRC assessment across subgroups was broadly consistent with the main analysis.

Health-Related Quality of Life and Patient-Reported Outcomes

The VISION trial assessed change from baseline and TTD by 10 points in the EQ-5D-5L VAS score; EORTC QLQ-C30 global health status and quality of life score; and EORTC QLQ-LC13 cough, chest pain, and dyspnea symptom scale scores as secondary end points. Results of the TTD analysis of each HRQoL and PRO outcome are summarized in Table 20. No subgroup analyses were performed on the HRQoL and PROs.

Table 18: DOR Results in VISION, Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; CR = complete response; DOR = duration of response; IRC = independent review committee; mITT = modified intention-to-treat; PD = progressive disease; PR = partial response.

^aCalculated using the Brookmeyer and Crowley method.

^bEstimated using the Kaplan-Meier method.

Source: VISION Clinical Study Report.¹⁴

Table 19: Subgroup Analyses of DOR by IRC in Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; CR = complete response; DOR = duration of response; IRC = independent review committee; mITT = modified intention-to-treat; NE = not estimable; PD = progressive disease; PR = partial response.

^aEstimated using the Kaplan-Meier method.

^bCalculated using the Brookmeyer and Crowley method.

Source: VISION Clinical Study Report.¹⁴

Table 20: TTD by 10 Points in HRQoL and PROs in VISION, Cohort A and Cohort A + C (mITT Population) as of July 1, 2020, Data Cut-Off Date

CI = confidence interval; EORTC = European Organization for the Research and Treatment of Cancer; EQ-5D-5L = 5-Level EQ-5D; HRQoL = health-related quality of life; NE = not estimable; mITT = modified intention-to-treat; PRO = patient-reported outcome; QLQ-C30 = Quality of Life Questionnaire; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer 13; TTD = time to deterioration; VAS = visual analogue scale.

^aEstimated using the Kaplan-Meier method.

^bCalculated using the Brookmeyer and Crowley method.

Source: VISION Clinical Study Report.¹⁴

EQ-5D-5L VAS

At baseline, 89.4% (135/151) of patients in cohort A completed the EQ-5D-5L questionnaire and had a resulting VAS score. The mean baseline VAS score was 62 (SD = 20.4). A boxplot of change from baseline in EQ-5D-5L VAS score in cohort A is depicted in Figure 7. Mean values were generally stable over time. The mean change from baseline from cycle 3 up to cycle 21 ranged from 0 to 7 across cycles in cohort A. The number of patients contributing to the analysis deceased at later cycles: 115 at cycle 3, 108 at cycle 5, 98 at cycle 7, 82 at cycle 9, 66 at cycle 11, 59 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, and 75 at end-of-treatment or 30-day safety follow-up.

A boxplot of change from baseline in VAS score in cohort A plus C is depicted in Figure 8. Trends observed in cohort A plus C are similar to those observed in cohort A. At baseline, 84.6% (215 of 254) of patients in cohort A plus C completed the EQ-5D-5L questionnaire and had a resulting VAS score. The number of patients contributing to the analysis deceased at later cycles: 180 at cycle 3, 157 at cycle 5, 133 at cycle 7, 99 at cycle 9, 73 at cycle 11, 62 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, and 91 at end-of-treatment or 30-day safety follow-up.

Figure 7: Boxplot of Change From Baseline in EQ-5D-5L VAS by Time Point, Cohort A mITT Population (N = 151); July 1, 2020, Data Cut-Off Date

C = cycle; D = day; EOT/FU = end-of-treatment/30-day safety follow-up; EQ-5D-5L = 5-Level EQ-5D; EQ VAS = EQ-5D visual analogue scale; mITT = modified intention-to-treat; VAS = visual analogue scale.

Note: Visits with 10 patients or fewer are not summarized and presented. ||

Source: VISION Clinical Study Report.¹⁴

Figure 8: Boxplot of Change From Baseline in EQ-5D-5L VAS by Time Point, Cohort A + C mITT Population (N = 254); July 1, 2020, Data Cut-Off Date

C = cycle; D = day; EOT/FU = end-of-treatment or 30-day safety follow-up; EQ-5D-5L = 5-Level EQ-5D; EQ VAS = EQ-5D visual analogue scale; mITT = modified intention-to-treat; VAS = visual analogue scale.

Note: Visits with 10 patients or fewer are not summarized and presented.

Source: VISION Clinical Study Report.¹⁴

In cohort A, 40.4% (n = 61) of patients experienced a deterioration in EQ-5D-5L VAS score by 10 points as of the July 1, 2020, data cut-off date. Median TTD in EQ-5D-5L VAS score was 8.3 (95% CI, 5.8 to 17.7) months. In cohort A plus C, 31.9% (n = 81) of patients experienced a deterioration in EQ-5D-5L VAS score by 10 points, and median TTD was 8.3 (95% CI, 5.9 to 17.7) months.

EORTC QLQ-C30 Global Health Status and Quality of Life Score

In cohort A, 89.4% (135 of 152) of patients completed the EORTC QLQ-C30 questionnaire at baseline. The mean global health status and quality of life score at baseline was 54.3 (SD = 24.20). A boxplot of change from baseline in global health status and quality of life score by time point for cohort A is depicted in Figure 9. Mean values were generally stable over time, with mean changes from baseline from cycle 3 up to cycle 21 ranging from −0.3 to 10.2 across cycles. The number of patients contributing to the analysis deceased at later cycles: 115 at cycle 3, 108 at cycle 5, 99 at cycle 7, 82 at cycle 9, 66 at cycle 11, 59 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, and 76 at end-of-treatment or 30-day safety follow-up.

In cohort A plus C, 84.6% (215 of 254) of patients completed the EORTC QLQ-C30 questionnaire at baseline. A boxplot of change from baseline in global health status and quality of life score in cohort A plus C is depicted in Figure 10. The number of patients contributing to the analysis deceased at later cycles: 180 at cycle 3, 157 at cycle 5, 134 at cycle 7, 99 at cycle 9, 73 at cycle 11, 62 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, and 92 at end-of-treatment or 30-day safety follow-up.

Figure 9: Boxplot of Change From Baseline in EORTC QLQ-C30 Global Health Status or Quality of Life Score by Time Point, Cohort A mITT Population (N = 151); July 1, 2020, Data Cut-Off Date

C = cycle; D = day; EORTC = European Organisation for Research and Treatment of Cancer; EOT/FU = end-of-treatment or 30-day safety follow-up; mITT = modified intention-to-treat; QLQ-C30 = Quality of Life Questionnaire Core 30; QoL = quality of life.

Note: Visits with 10 patients or fewer are not summarized and presented.

Source: VISION Clinical Study Report.¹⁴

Figure 10: Boxplot of Change From Baseline in EORTC QLQ-C30 Global Health Status or Quality of Life Score by Time Point, Cohort A + C mITT Population (N = 254); July 1, 2020, Data Cut-Off Date

C = cycle; D = day; EORTC = European Organisation for Research and Treatment of Cancer; EOT/FU = end-of-treatment or 30-day safety follow-up; mITT = modified intention-to-treat; QLQ-C30 = Quality of Life Questionnaire Core 30; QoL = quality of life.

Note: Visits with 10 patients or fewer are not summarized and presented.

Source: VISION Clinical Study Report.¹⁴

As of the July 1, 2020, data cut-off date, 35.8% (n = 54) of patients in cohort A experienced a deterioration in QLQ-C30 global health status and quality of life score by 10 points, and median TTD was 15.2 (95% CI, 6.0 to 33.2) months. In cohort A plus C, 29.1% (n = 74) of patients experienced a deterioration in global health status and quality of life score by 10 points, and median TTD was 15.2 (95% CI, 6.2 to 33.2) months.

EORTC QLQ-L13 Symptom Scales (Coughing, Dyspnea, and Chest Pain)

In cohort A, 89.4% (135 of 152) of patients completed the EORTC QLQ-LC13 questionnaire at baseline. The number of patients with an evaluable questionnaire decreased over time: 108 at cycle 5, 82 at cycle 9, 59 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, 8 at cycle 33, 6 at cycle 37, 3 at cycle 41, and 2 at cycle 45 as of the July 1, 2020, data cut-off date.

In cohort A plus C, 84.6% (215 of 254) of patients completed the EORTC QLQ-LC13 questionnaire at baseline. Similarly, the number of patients an evaluable questionnaire decreased over time: 180 at cycle 3, 157 at cycle 5, 99 at cycle 9, 62 at cycle 13, 43 at cycle 17, 28 at cycle 21, 14 at cycle 25, 13 at cycle 29, 8 at cycle 33, 6 at cycle 37, 3 at cycle 41, and 2 at cycle 45.

An MMRM was performed on the QLQ-LC13 symptom scales assessed in the VISION trial (coughing, dyspnea, and chest pain). The best variance-covariance pattern was chosen based on model fit using Akaike information criterion among unstructured, Toeplitz, first-order autoregressive, and variance components. The QLQ-LC13 symptom scales range in score from 0 to 100, and a decrease in score represents an improvement in symptoms. The least squares mean changes from baseline in the EORTC QLQ-LC13 symptom scales of coughing, dyspnea, and chest pain are depicted in Figure 11, Figure 12, and Figure 13, respectively. A decrease in QLQ-LC13 symptom scale score represents an improvement; an increase in QLQ-LC13 symptom scale score represents increased symptom burden.

Figure 11: Line Plot of LS Mean Change From Baseline by Visit in EORTC QLQ-LC13 Coughing Symptom Score, Cohort A (N = 151; Left) and Cohort A + C (N = 254; Right) mITT Population as of July 1, 2020, Data Cut-Off Date

BSL = baseline; C = cycle; D = day; EORTC = European Organisation for Research and Treatment of Cancer; LS = least squares; mITT = modified intention-to-treat; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer-13; SEM = standard error of mean.

Source: VISION Clinical Study Report.¹⁴

Figure 12: Line Plot of LS Mean Change From Baseline by Visit in EORTC QLQ-LC13 Dyspnea Symptom Score, Cohort A (N = 151; Left) and Cohort A + C (N = 254; Right) mITT Population as of July 1, 2020, Data Cut-Off Date

BSL = baseline; C = cycle; D = day; EORTC = European Organisation for Research and Treatment of Cancer; LS = least squares; mITT = modified intention-to-treat; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer-13; SEM = standard error of mean.

Source: VISION Clinical Study Report.¹⁴

Figure 13: Line Plot of LS Mean Change From Baseline by Visit in EORTC QLQ-LC13 Chest Pain Symptom Score, Cohort A (N = 151; Left) and Cohort A + C (N = 254; Right) mITT Population as of July 1, 2020, Data Cut-Off Date

BSL = baseline; C = cycle; D = day; EORTC = European Organisation for Research and Treatment of Cancer; LS = least squares; mITT = modified intention-to-treat; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer-13; SEM = standard error of mean.

Source: VISION Clinical Study Report.¹⁴

In cohort A, 29.8% (n = 45) of patients experienced a deterioration by 10 points in coughing symptom score, and median TTD was 11.1 (95% CI, 11.1 to NE) months. For chest pain, 29.8% (n = 45) of patients experienced a deterioration event, and median TTD was 17.7 (95% CI, 11.1 to NE) months. For dyspnea, 50.3% (n = 76) of patients experienced a deterioration event, and median TTD was 5.5 (95% CI, 4.1 to 6.9) months.

In cohort A plus C, 20.5% (n = 52) of patients experienced a deterioration by 10 points in coughing symptom score, and median TTD was 13.8 (95% CI, 11.1 to NE) months. For chest pain, 22.0% (n = 56) of patients experienced a deterioration event, and median TTD was 17.7 (95% CI, 11.8 to NE) months. For dyspnea, 40.9% (n = 104) of patients experienced a deterioration event, and median TTD was 5.6 (95% CI, 4.1 to 6.9) months.

Intracranial CNS Outcomes

Intracranial CNS outcomes in cohort A were reported in an abstract and poster included in the sponsor’s submission to CADTH.²³ According to these reports, 23 (15%) of the 152 patients enrolled in cohort A had brain metastases by RECIST v1.1 criteria at baseline, determined by IRC or investigator. New lesions in the brain were identified by the investigator in 6 of 152 patients. Four of the patients who developed new brain lesions also had brain metastases at baseline. A post hoc retrospective analysis of brain lesions determined by CT or MRI was conducted by an IRC using RANO-BM criteria, with a data cut-off date of July 1, 2020. A total of 15 patients had brain metastases at baseline that were evaluable according to RANO-BM criteria. Of 7 patients with measurable CNS disease per RANO-BM, all of whom had received prior radiotherapy, intracranial best-observed responses were PR (n = 5), SD (n = 1), and PD (n = 1). Of 8 patients with non-measurable brain lesions only, 7 achieved intracranial disease control and 1 had PD. Of the 7 patients with disease control, 3 had CR. No data on intracranial CNS outcomes were reported for cohort A plus C.

Harms

Only those harms identified in the review protocol are reported in this section. See Table 21 for detailed harms data on cohort A and cohort A plus C (safety analysis set) as of the July 1, 2020, data cut-off date.

Table 21: Summary of Harms in VISION, Cohort A and Cohort A + C (Safety Analysis Set) as of July 1, 2020, Data Cut-Off Date

AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; SAE = serious adverse event.

^aFrequency > 10% in cohort A or cohort A + C.

^bFrequency > 4% in cohort A or cohort A + C.

^cFrequency > 2% in cohort A or cohort A + C.

Source: VISION Clinical Study Report.¹⁴

Adverse Events

In cohort A, 99.3% of patients experienced at least 1 treatment-emergent AE as of the July 1, 2020, data cut-off date. The most frequently reported AE was peripheral edema (75.0%). Grade 3 or higher peripheral edema was reported in 18 (11.8%) patients. Other frequently reported AEs 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 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 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%).

Withdrawals Due to Adverse Events

In cohort A, 27.6% of 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%).

Mortality

In cohort A, 50.0% 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 patient had died. Causes of death were reported to be disease progression in 25.9% of patients and an AE in 5.9% of patients.

Notable Harms

The most frequently reported hepatotoxicity-related AEs in cohort A and cohort A plus C were increased ALT (11.8% and 11.4%, respectively), increased AST (8.6% and 7.5%, respectively), increased blood ALP (7.2% and 7.8%, respectively), and increased GGT (5.9% and 5.5%, respectively). The most frequently reported renal toxicity-related AE in cohort A and cohort A plus C was increased blood creatinine (28.9% and 25.1%, respectively). A total of 2 patients experienced interstitial lung disease and 6 patients experienced pneumonitis, all 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 had experienced peripheral edema.

Critical Appraisal

Internal Validity

For the primary end point and most secondary end points, an IRC was appropriately used. However, in some secondary assessments, only investigator judgment was used to assess occurrence of the end point, which could lead to observer bias due to the open-label nature of the study. In general, the investigator assessments were in line with the IRC when both were completed on the same end point, although, for ORR, there were marginally fewer patients with a CR (noted by the IRC) during follow-up.

VISION is an open-label, single-arm study. There is no direct evidence comparing tepotinib to a control arm. Furthermore, no statistical testing was performed; data were analyzed descriptively. Due to these limitations of the study design, no definitive conclusions can be drawn from the VISION study regarding the efficacy of tepotinib relative to a comparator, which increases the risk of bias in the estimation of treatment effects due to the potential for confounding related to fluctuations in health status and other unidentified prognostic factors that could affect subjectively assessed outcomes. The open-label, single-arm design can increase the risk of bias in reporting outcomes that are subjective in measurement and interpretation (e.g., response, HRQoL, and AEs) and likely results in overestimating the treatment effect. Outcomes such as OS time and mortality are less likely to be affected. The risk of bias due to the open-label design may be unavoidable, given the unmet need in this population. The potential for this bias was also reduced by using IRC assessment for key study outcomes, such as ORR, DOR, and PFS.

In the original VISION study protocol, only patients with adenocarcinoma were eligible, and patients were required to have failed at 1 or 2 lines of systemic therapy, including a platinum-doublet-containing regimen. In a protocol amendment that was implemented after enrolment in the study had begun, the eligible study population was expanded to include all subtypes of NSCLC and patients who were treatment-naive (i.e., would receive tepotinib as first-line treatment). Significant changes to the study eligibility criteria after participant enrolment had begun may have introduced bias. The direction of this potential bias is unknown. However, the sponsor did conduct subgroup analyses of treatment-naive patients versus patients that were previously treated, and the results were broadly consistent with the overall analyses.

Most patients enrolled in VISION had at least 1 important protocol deviation. This adds to the uncertainty of the results observed.

The analysis populations used in the VISION trial were appropriate. The efficacy outcomes were analyzed descriptively in a mITT population, which excluded 1 patient who was enrolled and treated in cohort A, because the patient tested negative for METex14 skipping alterations in the liquid biopsy and had tumour biopsy data that were not evaluable. Exclusion of 1 patient is unlikely to affect outcomes. Safety outcomes were assessed in all patients who were treated with tepotinib. The clinical experts indicated that exposure to tepotinib in VISION was adequate to assess the efficacy and safety outcomes.

The time-to-event analyses were appropriate, but the data are difficult to interpret in a single-arm trial without a comparator. The median duration of follow-up at the time of the analysis was sufficient. Survival times (median OS and median PFS) were estimated from the Kaplan-Meier models, and patients that did not have an event were censored, which is appropriate.

Subgroup analyses were performed on the outcomes OS, PFS, ORR, and DOR. These subgroup analyses were specified a priori. However, many of the subgroups had limited sample size, resulting in imprecise results for many of the subgroups and uncertainty in the data. There were no tests for statistical differences between subgroups, as the sponsor was only interested in evaluating the overall robustness and consistency of treatment effects.

Intracranial CNS outcomes were analyzed post hoc as an exploratory analysis, which was reported in a conference abstract and poster included in the sponsor’s submission to CADTH only. Furthermore, intracranial CNS outcomes were assessed in patients in cohort A that presented with brain metastases at baseline, as opposed to the overall cohort A patient population. This limits interpretation of the intracranial CNS outcome data because data were not reported for all enrolled study patients (e.g., the proportion of all study patients who experienced disease progression in the CNS).

The VISION study assessed HRQoL and PROs using the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires. However, data were not reported in the Clinical Study Reports for the overall cohort A or cohort A plus C for all components of these instruments. Analyses of the PROs were focused on the EQ-5D-5L VAS, global health status and quality of life from the QLQ-C30, and 3 symptoms scales from the QLQ-LC13. The TTD analysis for this subset of scores was pre-specified in the study protocol. Exclusion of the other components of the instruments may have created bias. The sponsor defined a clinically significant deterioration as a change in 10 points for each of the PROs assessed in the VISION trial. CADTH identified an MID of 7 to 11.5 points for the EQ-5D-5L VAS and 4 points for deterioration in EORTC QLQ-C30 global health status and quality of life score. No MID was identified in the literature for the EORTC QLQ-LC13 symptom scales.

HRQoL outcomes had significant missing data at later time points, affecting the interpretability of trends over time and creating potential for bias in those that remain; the outcomes may therefore not reflect the overall population (i.e., patients who did not continue to complete assessments or who died may have had poorer HRQoL). Therefore, it cannot be concluded that HRQoL is maintained or improves over time. Regarding the EORTC QLQ-LC13 data, the sponsor noted in the Clinical Study Report that data late in the study (i.e., after cycle 25) may not be valid or reliable, due to small sample sizes. The number of patients contributing to the analysis of the EORTC QLQ-C30 global health status and quality of life score and EQ-5D-5L VAS similarly decreased to relatively small sample sizes at later cycles as well. The decreased number of patients contributing to the analysis of the HRQoL and PROs over time creates uncertainty in the data. All HRQoL and PRO data are likely biased in favour of tepotinib and overestimate effects due to the missing data at baseline and follow-up because patients who respond to treatment or have no AEs are more likely to continue in the study and complete the questionnaires. Regarding the MMRM analysis of the EORTC QLQ-LC13 data, the assumption of data missing at random is unlikely to hold true. As a result, the MMRM is unlikely to be a valid method to evaluate the changes in QLQ-LC13 over the follow-up period. The investigators have assumed missing data were missing at random, which is not supported by the losses to follow-up and reasons for discontinuations noted. Moreover, the MMRM approach further assumes that patients missing data would continue to behave or change in a fashion similar to those with ongoing data points. This assumption is strong and unverifiable, and may increase the bias in the observed results, particularly when patients discontinue therapy due to AEs or lack of efficacy, as observed in this study. Last, no index scores for the EQ-5D-5L were provided, and, as a result, the net treatment effect across domains could not be captured.

External Validity

The VISION trial was an international, multi-centre study that included sites in Europe, the US, and Asia. There were no study sites in Canada. The treatment regimen used in the VISION trial aligns with Health Canada’s recommended dose, which is 450 mg tepotinib as tepotinib hydrochloride.

The clinical experts consulted by CADTH indicated that the eligibility criteria used in the VISION trial were appropriate and commonly used in NSCLC trials. It was noted that the VISION study included patients with intracranial CNS metastases at baseline who were neurologically stable and whose glucocorticoid dose was being tapered and patients with untreated CNS metastases who were asymptomatic and had lesions 1 cm or less in diameter. The clinical experts indicated that this reflects the advanced NSCLC patient population in Canada, as a proportion of patients present with brain metastases at baseline and/or develop brain metastases as their disease progresses. However, the clinical experts also noted that the VISION trial restricted enrolment to patients with an ECOG PS of 0 or 1, and patients with NSCLC in Canada often have an ECOG PS of 2 or more.

The clinical experts noted that the study patient population was older than patients typically seen in NSCLC trials, which reflects the population of NSCLC patients with METex14 skipping mutations in Canada. Most patients enrolled in the VISION trial were also White, which the clinical experts indicated was expected because METex14 skipping mutations are typically found in elderly White patients. Although there were some differences in the baseline characteristics of the patients in the study versus the Canadian patient population, the clinical experts indicated that these differences were minor and unlikely to affect generalizability of the study results.

The clinical experts noted that METex14 skipping alterations are rare, which was reflected in the number of patients pre-screened for MET alteration status in the VISION trial. Furthermore, the clinical experts noted that the VISION trial used liquid and/or tumour tissue biopsy to determine the patients’ METex14 skipping alteration status. The clinical experts indicated that both methods could be used in Canada to identify patients with METex14 skipping alterations.

The clinical experts consulted by CADTH indicated that they would preferentially use tepotinib in the first-line setting. In VISION, approximately half of the study patients had received prior anticancer drug therapy and therefore received tepotinib as second- or later-line therapy. The clinical experts indicated that a greater proportion of patients received tepotinib as second- or later-line therapy than they would expect to observe in Canadian practice, and they thought that this is likely due to the eligibility criteria in the original trial protocol (i.e., patients were required to have failed at 1 or 2 lines of systemic therapy), which was later amended to include patients who would receive tepotinib as first-line treatment. The clinical experts noted some differences in previous anticancer drug treatments received by the study patients from what they would expect with standard practice in Canada. More patients appeared to be treated with single-agent platinum therapy than the clinical experts expected, and the most frequently used therapies (≥ 5%) did not include a triplet combination with pembrolizumab. The clinical experts noted that this may have been due to the elderly population, as well as the timing of the trial and approval or availability of other treatments in the countries that trial was conducted in.

The patient groups that provided input on this review indicated that they want treatments that improve symptoms, improve or maintain HRQoL, increase survival, delay disease progression, and help patients achieve long-term remission. This aligns with the following outcomes assessed in the VISION trial: HRQoL and PROs (EORTC QLQ-C30 global health status and quality of life; QLQ-LC13 coughing, dyspnea, chest pain; and EQ-5D-5L VAS), OS, PFS, ORR, and DOR. Similarly, OS was identified as the most important outcome by the clinical experts consulted by CADTH and was assessed as a secondary outcome in VISION. The clinical experts also identified PFS, response rate (i.e., ORR), and maintenance of quality of life as important outcomes.

Patients in the VISION trial had access to study physicians more frequently than patients would in standard practice. In the VISION trial, imaging for tumour assessment was conducted every 6 weeks until 9 months and every 12 weeks thereafter, until disease progression, death, or withdrawal of consent. The clinical experts indicated that, in standard practice, imaging is done every 2 to 4 months. In standard practice, the follow-up visits are done every 4 to 8 weeks in Canada, per the clinical experts. The difference in access to imaging and follow-up visits could affect generalizability of results. A higher level of care may have biased outcomes and resulted in an overestimation of the treatment effect.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

As there was no direct evidence comparing tepotinib to other therapies for the treatment of advanced NSCLC harbouring METex14 skipping alterations, CADTH reviewed the indirect evidence. In addition to reviewing the sponsor’s submission, CADTH conducted a literature search to identify potentially relevant ITCs in patients with advanced NSCLC. A focused literature search for ITCs dealing with non–small cell lung cancer was run in MEDLINE All (1946–) on September 23, 2021. No language or date limits were applied to the search. No potentially relevant ITCs were identified in the literature search. One sponsor-submitted ITC¹⁵ is included in this review. The objective of this section of the Clinical Review Report is to summarize and critically appraise the indirect evidence.

Description of Indirect Comparisons

The sponsor-submitted ITCs¹⁵ consisted of 2 parts: indirect comparisons of individual patient data from the VISION trial to pooled RWD using propensity scoring, and indirect comparisons of individual patient data from the VISION trial to retrospective observational studies using unanchored MAIC methods.¹⁵ In the indirect comparison using propensity scoring, tepotinib data from cohort A of the VISION trial was compared to chemotherapy (without immunotherapy), immunotherapy alone, and crizotinib using a pooled dataset derived from 4 RWE data sources. Crizotinib was not identified as a relevant comparator in the CADTH systematic review protocol outlined in Table 5. Thus, results for the indirect comparison of tepotinib to crizotinib are not included in CADTH’s summary of the ITC results. For the indirect comparisons using unanchored MAICs, cohort A of the VISION trial was compared to 3 retrospective observational studies of patients with NSCLC harbouring METex14 skipping alterations who were treated with chemotherapy or immunotherapy.

Methods of the Sponsor-Submitted ITC

Objectives

The objective of the sponsor-submitted ITC was to estimate the comparative effectiveness of tepotinib relative to commonly used therapies (i.e., chemotherapy and immunotherapy).

Study Selection Methods

The sponsor-submitted ITC analyses included studies and RWE that provided information on patients with NSCLC harbouring METex14 skipping alterations. The methods used to select studies for inclusion were not clearly described in the technical report¹⁵ or in CADTH’s requests for additional information.^15,26,27 No a priori protocol for selecting studies for inclusion in the indirect comparisons was reported. The eligibility criteria for study inclusion and exclusion (i.e., population, intervention, comparators, outcomes) were not clearly described in the technical report beyond studies that provided information on patients with NSCLC harbouring METex14 skipping alterations.

The sponsor provided a systematic literature review on METex14 skipping alterations in NSCLC.¹⁶ For their review, the following databases were searched: PubMed, Embase, and conference proceedings from the ASCO, the World Conference on Lung Cancer, the Society for Health Economics and Outcomes Research (ISPOR), and the European Society of Medical Oncology. The electronic database searches were performed on January 20, 2020, and updated on August 3, 2020; the conference website searches were conducted on September 4, 2020. Publications included in the sponsor’s systematic literature review were required to meeting the following eligibility criteria:

• indication: NSCLC with METex14 mutation skipping

• interventions: any pharmacologic treatment

• types of publication: any study design

• patient population: adult patients with NSCLC who harbour METex14 mutation skipping

• outcomes:

  • clinical outcomes

  • humanistic outcomes

  • economic outcomes

  • prognostic outcomes

  • epidemiological outcomes

• publications published in English until January 22, 2020, for the first report and publications published until September 24, 2020, for the updated literature review.

Overall, the sponsor’s systematic literature review identified 17 unique studies assessing clinical burden in patients with NSCLC harbouring METex14 skipping alterations. All identified studies were non-randomized interventional studies or observational studies. This list of studies identified 2 of the 3 studies included in the unanchored MAIC only. It is unclear how the third study in the MAIC was identified and selected for inclusion. In addition, the sponsor’s systematic literature review did not identify the 4 real-world cohort studies included in the indirect comparison using propensity scoring. The sponsor’s systematic literature review concluded that, given the lack of head-to-head comparison, unanchored ITCs may be needed with updated data on novel MET tyrosine kinase inhibitors to determine relative effectiveness. The feasibility of conducting unanchored comparisons was not further discussed in the sponsor’s systematic literature review report.

For the indirect comparison using propensity scoring, the authors of the ITC reported that they gained access to patient-level data from 4 noninterventional, real-world cohort studies. Data from the studies were imported into a Common Data Model (CDM). For the unanchored MAIC, the authors included studies published in the literature that reported outcomes in patients with NSCLC harbouring METex14 skipping alterations. The ITC technical report indicated that a MAIC was conducted to compare the retrospective studies to VISION because patient-level data were not available to the sponsor. The methods used to extract data from the 3 studies included in the unanchored MAIC were not reported. Study quality was not assessed by the authors of the ITC. A limited assessment of heterogeneity was provided as a narrative.^15,27

The sponsor-submitted ITC assessed 2 efficacy outcomes: OS and PFS. It is unclear whether these outcomes were pre-specified. No safety outcomes were included in the ITC.

ITC Analysis Methods

Indirect Comparison to VISION Study Using Propensity Scoring

Data from 4 real-world cohort studies were imported into a CDM. The patient-level data were aligned to the VISION study using inclusion and exclusion criteria, which were implemented in the following order:

• include age 18 years or older

• exclude stages I-IIIA

• exclude missing both disease stage and advanced or metastatic disease status

• exclude ECOG 2 or more

• exclude missing both PFS or time to next treatment or death and OS

• include METex14 skipping population

• exclude ALK positive

• exclude EGFR positive.

Before the eligibility criteria were applied, there were 360 patients in the overall dataset. After the eligibility criteria were applied, 140 patients with data for 273 treatment lines remained in the CDM.

Two mutually exclusive analysis groups were derived based on therapy type: patients who received chemotherapy (potentially in combination with other medicines, but not immunotherapy or MET inhibitors), and patients who received immunotherapy alone. As there were more treatment lines than patients, a maximum of 1 treatment line was included per patient in each analysis. When there was more than 1 line available for a given analysis, a random line was selected. For example, for a patient with first-line immunotherapy and then 2 lines of chemotherapy, the immunotherapy line would be included in the immunotherapy comparison, with 1 of the 2 chemotherapy lines selected randomly for the chemotherapy comparison. Similarly, a patient who received a MET inhibitor and then chemotherapy would be included as a previously treated chemotherapy patient.

Propensity scoring was then conducted on the immunotherapy and chemotherapy groups, with propensity scores calculated on variables selected by clinical input. A standardized mortality ratio weighting approach was used to reweight the RWD to match the tepotinib data from the VISION study. The authors indicated that reweighting was used instead of matching to use all available data. The authors of the ITC chose variables included in the calculation of the propensity score based on input from 2 clinical experts (lung cancer oncologists) they consulted. These clinicians reviewed a list of possible covariates and deemed the following variables to be relevant:

• prior treatment experience

• mean age

• metastatic or stage 4 disease (versus non-metastatic)

• sex

• adenocarcinoma histology

• smoking history.

The authors of the ITC noted that, per their clinical experts, ECOG PS would ideally have been included in the models, but this was not possible due to the amount of missing data.

The authors presented baseline demographic characteristics for the chemotherapy and immunotherapy analysis sets before and after weighting. ESS measures were reported.

The ITC reported data for the outcomes OS and PFS. In the ITC technical report, the authors indicate that they considered response rate but did not evaluate this outcome due to a large volume of data that were missing or not reported. Kaplan-Meier curves were presented for OS and PFS for visual comparison. It was unclear whether PFS by investigator assessment or IRC assessment from the VISION trial was used. In addition, the authors reported Cox proportional HRs and restricted mean survival time (RMST) for the propensity score results. Statistical tests were performed on unweighted and weighted data, for both PFS and OS, in all comparisons.

When PFS data were unavailable, time to next treatment or death, or time on treatment, was used as a proxy. Data-cleaning rules were used so that censoring was consistent across end points. When patients continued treatment without an OS event, they were assumed to be censored for OS at their last contact point for treatment. When a patient’s death was confirmed, any data after the death were discarded because the authors thought they were likely either estimated or predicted data. If a patient’s treatment times added up to more than their survival time, the final line of treatment time was shortened so that the treatment time data matched the OS time.

Subgroup analyses were conducted by line of treatment (previously untreated versus previously treated). It is unclear whether the subgroup analyses were pre-specified. The same approach to propensity score weighting was taken as with the overall groups, with standardized mortality ratio weights used to reweight the comparator group to match the characteristics of the VISION study patients from the same line of treatment. Kaplan-Meier curves were presented for visual comparison.

A sensitivity analysis was conducted, using only patients with ECOG PS data available. It is unclear whether this sensitivity analysis was pre-specified.

Indirect Comparison to VISION Study Using MAIC

The authors selected 3 retrospective studies for inclusion in the unanchored MAIC. The technical report did not include a justification for selection of the model or choice of the comparator studies. The methods used to extract data from the studies were not reported. An unanchored MAIC was performed because the index trial (VISION) is a single-arm study.

Patient characteristics available from each of the studies were presented to clinical experts to select variables for matching. The following characteristics were selected and adjusted for:

• prior treatment experience

• mean age

• sex

• smoking status

• adenocarcinoma histology

• metastatic disease.

As noted earlier, the authors of the ITC reported that that ECOG PS ideally would have been included in the models, but this was not possible due to missing data.

The MAIC package in R was used to reweight the patient-level tepotinib data from the VISION study to match the 3 selected retrospective studies. ESS measures were reported, and the authors presented demographic data before and after weighting. A limited assessment of heterogeneity was provided as a narrative. The authors did not report any steps taken to address potential heterogeneity.

OS and PFS were analyzed. It was unclear whether PFS by investigator assessment or IRC assessment from the VISION trial was used. Kaplan-Meier curves were presented for visual comparison only. No subgroup or sensitivity analyses were performed.

Results of Indirect Comparison to VISION Using Propensity Scoring

Summary of Included Studies

The authors provided a limited description of the RWE studies and database that were pooled for the indirect comparison using propensity scoring, which are summarized in this section and in Table 22.

Table 22: Summary of Studies — Indirect Comparison Using Propensity Scoring

OS = overall survival; PFS = progression-free survival; RWE = real-world evidence; TTNTD = time to next treatment or death.

Source: Sponsor’s technical report.¹⁵

The noninterventional 0015 study consisted of data collected from the Concerto HealthAI US real-world database taken from electronic medical records (EMRs) used in a real-world retrospective cohort study. Most sites were community oncology practices in the US. The study period used was January 1, 2004, until September 30, 2019. The dataset included 39 patients with MET alterations, with 76 treatment lines. Outcomes captured included PFS, OS, and response rate. As the data were taken from clinical practice, all assessments were done by an investigator.

The noninterventional 0035 study consisted of EMR data collected via chart abstraction at 6 sites in 4 countries (Israel, the Netherlands, Taiwan, the US). The inclusion period was January 1, 2010, to September 30, 2018. Patients were followed from an index treatment exposure date (first recorded exposure to systemic therapy) until death, loss-to follow-up, or the end of available data. The dataset included 86 patients harbouring a MET alteration, with details of 165 treatment lines. The data captured did not include response. PFS was not directly captured and was estimated from time to next treatment or death.

The COTA RWE database is a de-identified data source drawn from EMRs of mainly academic, for-profit, and community oncologist provider sites and hospital systems in the US. In total, 202 patient records were available for a total of 680 lines of therapy. These data were collected from August 15, 2008, to February 10, 2020.

The Wong et al. (2021) study was a retrospective review of treatments and outcomes for patients with metastatic NSCLC harbouring METex14 skipping alterations in British Colombia, Canada, from January 2016 to September 2019. The objective of the study was to identify patients treated in British Columbia with METex14 skipping to understand prevalence, biology, and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy in the setting of advanced disease. Data were available for 41 patients with METex14 skipping alterations, although not all received treatment. Treatments used are not identified beyond class for platinum-doublet chemotherapy and immunotherapy.

Baseline Patient Characteristics

Baseline characteristics of patients in the immunotherapy and chemotherapy analysis sets from the CDM compared to patients treated with tepotinib in the VISION study are summarized in Table 23.

Table 23: Baseline Patient Characteristics of the Analysis Sets Used in the Indirect Comparison With Propensity Scoring

CDM = common data model; NA = not applicable; SD = standard deviation.

Source: Sponsor’s technical report.¹⁵

In cohort A (N = 151) of the VISION study, the mean age was 73.0 years. Most patients were White (70.9%), had an ECOG PS of 1 (73.5%), adenocarcinoma histology type (86.8%), and stage IV disease at study entry (74.8%). Overall, 54.3% of patients had received prior anticancer drug therapy for advanced or metastatic disease, and 51.7% had a smoking history. The most frequently administered prior drug therapies were carboplatin, pemetrexed, cisplatin, and pembrolizumab.

The chemotherapy analysis set (N = 66) had a mean age of 69.9 years. Most patients were treatment-experienced (56.1%), had a history of smoking (56.1%), had metastatic disease (97.0%), and had adenocarcinoma on histology (74.2%). The proportion of patients in the chemotherapy analysis set that had adenocarcinoma histology was lower than VISION, as was the mean age. Data on ECOG PS were not reported in the ITC technical report. Most chemotherapy regimens contained pemetrexed (37 of 66) or platinum-based chemotherapy (51 of 66). The most frequently reported treatment regimen was carboplatin and pemetrexed (30.3%).

The immunotherapy analysis set (N = 51) had a mean age of 71.7 years. The majority of patients were previously untreated (60.8%), had a history of smoking (60.8%), and had adenocarcinoma on histology (78.4%). The proportion of patients who were previously untreated was higher, and the proportion of patients who had adenocarcinoma on histology was lower in the immunotherapy analysis set compared to VISION. All patients (100%) had metastatic disease. Data on ECOG PS were not reported in the ITC technical report. Of the immunotherapies that were specified, the most frequently received were pembrolizumab (43.1%) and nivolumab (21.6%).

Results

The unweighted and weighted baseline patient characteristics for the chemotherapy and immunotherapy analysis sets compared to patients treated with tepotinib in VISION are summarized in Table 24. The authors of the ITC reported that the matching worked as intended in the chemotherapy dataset. However, the authors noted that there remained some imbalances in the immunotherapy dataset, likely due to low patient numbers. Metastatic disease remained more than a standardized mean difference of 0.1, which is an often-used metric in the literature to indicate imbalance in the covariate.

Table 24: Baseline Patient Characteristics of the Chemotherapy and Immunotherapy Analysis Sets in the CDM Before and After Standardized Mortality Ratio Weighting, Compared to VISION

CDM = common data model; ESS = effective sample size; NA = not applicable; SD = standard deviation.

Source: Sponsor’s technical report.¹⁵

The Kaplan-Meier curves of OS and PFS for the chemotherapy analysis set compared to tepotinib in VISION are depicted in Figure 14 and Figure 15, respectively. The Kaplan-Meier curves of OS and PFS for the immunotherapy analysis set compared to tepotinib in VISION are depicted in Figure 16 and Figure 17, respectively.

Figure 14: Kaplan-Meier Plot of OS for the Unweighted and Weighted Chemotherapy Analysis Set From RWD Compared to VISION

RWD = real-world data.

Source: Sponsor’s technical report.¹⁵

Figure 15: Kaplan-Meier Plot of PFS for the Unweighted and Weighted Chemotherapy Analysis Set From RWD Compared to VISION

RWD = real-world data.

Source: Sponsor’s technical report.¹⁵

Figure 16: Kaplan-Meier Plot of OS for the Unweighted and Weighted Immunotherapy Analysis Set From RWD Compared to VISION

RWD = real-world data.

Source: Sponsor’s technical report.¹⁵

Figure 17: Kaplan-Meier Plot of PFS for the Unweighted and Weighted Immunotherapy Analysis Set From RWD Compared to VISION

RWD = real-world data.

Source: Sponsor’s technical report.¹⁵

Propensity score results for OS and PFS for the immunotherapy and chemotherapy analysis sets compared to tepotinib in the VISION study are summarized in Table 25. An HR of less than 1 favoured tepotinib. For OS, the Cox proportional HR was 0.91 (95% CI, 0.62 to 1.35) for chemotherapy and 0.91 (95% CI, 0.59 to 1.42) for immunotherapy. The RMST for OS was 18.30 months and 18.60 months in the chemotherapy and immunotherapy groups, respectively, compared to 19.25 months in the tepotinib group. For PFS, the Cox proportional HR was 0.49 (95% CI, 0.35 to 0.69) for chemotherapy and 0.59 (95% CI, 0.39 to 0.90) for immunotherapy. The RMST for PFS was 7.52 months and 8.15 months in the chemotherapy and immunotherapy groups, respectively, compared to 12.71 months in the tepotinib group. The authors of the ITC indicated that the Cox proportional hazards assumption may not have been met.

Table 25: Summary of Propensity Score Results of Immunotherapy and Chemotherapy vs. Tepotinib

CI = confidence interval; Cox = Cox proportional hazards; ESS = effective sample size; HR = hazard ratio; NA = not applicable; NE = not estimable; OS = overall survival; PFS = progression-free survival; RMST = restricted mean survival time; vs. = versus.

^aHR less than 1.0 favours tepotinib.

Source: Sponsor’s technical report.¹⁵

Based on visual comparison of the Kaplan-Meier curves and the data presented in Table 25, the authors of the ITC concluded that, when the patient populations were balanced, patients treated with tepotinib had a greater PFS compared to patients treated with chemotherapy or immunotherapy. The authors also concluded that tepotinib conferred a benefit of smaller magnitude in OS compared to chemotherapy and immunotherapy.

Subgroup analyses were performed by line of treatment (untreated or treatment-naive versus previously treated). Results of the subgroup analyses are summarized in Appendix 3 (Table 44). The Kaplan-Meier plots for visual comparison are also presented in Appendix 3 (Figure 28 to Figure 35). In general, the subgroup analyses of PFS were consistent with the overall cohort analysis. The subgroup analysis results for OS varied by comparison and subgroup.

The results of the sensitivity analysis using only patients with an ECOG PS available were generally consistent with the overall analysis of PFS and OS.

Critical Appraisal of Indirect Comparison Using Propensity Scoring

The methods used in the sponsor-submitted ITC lacked important details, which creates uncertainty in the data. The methods used to identify and select the RWE cohort studies that contributed RWD to the CDM were not reported. The sponsor’s systematic literature review¹⁶ did not identify any of the 4 RWE cohort studies. The criteria used to select these studies were unclear. No a priori protocol was reported for selecting the studies used in the ITC specifically. Furthermore, it is unclear why other studies that were identified in the sponsor’s systematic literature review were not included in this ITC. As a result, there is significant risk of bias in study selection, and there is a lack of certainty that all relevant studies were identified. The authors of the ITC did not assess the quality of the RWE cohort studies and therefore did not consider their quality in the ITC analysis. Any potential risks of bias of the included data sources (i.e., methodological limitations) were not assessed or reported. A limited assessment of heterogeneity was reported. In addition to reporting issues, a number of methodological limitations were noted.

First, the authors of the ITC used propensity scoring to indirectly compare an interventional, prospective trial (VISION) to RWD from retrospective, noninterventional cohort studies and databases. Differences in the study designs could not be accounted for in the indirect comparison. This may be problematic, as there are notable differences in treatments and procedures received by patients, data collection methods, and assessments. 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.

The authors of the ITC applied inclusion and exclusion criteria to the patient-level data imported into the CDM based on the eligibility criteria used in VISION trial. Although the data were restricted to better align with VISION, the authors of the ITC noted that the remaining patients in the immunotherapy and chemotherapy analysis sets of RWD cannot be confirmed as eligible for the VISION study (i.e., they may have been excluded for other reasons if they had been prospectively screened). In addition, details regarding key baseline characteristics (e.g., ECOG PS, presence of brain metastases at baseline) of the patients included in the RWD were not provided. As a consequence, there may be clinical differences between the RWD groups and the VISION study patients that could bias the results of the indirect comparison.

The comparison with immunotherapy may have been biased by the fact that this therapy is restricted to tumours with high PD-L1 expression in the first-line setting, which was not accounted for in the VISION trial.

A key assumption of propensity score analyses to ensure unbiased estimates is that all confounders that predict either receipt of therapy or the outcome itself are included in the development of the propensity score. However, the variables included for matching in the indirect comparison do not reflect all confounders. Per the author’s clinical experts consulted on the sponsor-submitted ITC, ECOG PS would ideally have been included in the models but was not included due to the large number of patients missing these data. The clinical experts consulted by CADTH also agreed that ECOG PS is an important confounder. The clinical experts indicated that, in clinical practice, many patients with an ECOG PS of 2 or higher are treated, whereas they were excluded from the VISION trial. Therefore, ECOG PS is likely unbalanced between the groups. In terms of histology, patient numbers allowed only the proportion of adenocarcinoma to be matched. Last, the clinical experts consulted by CADTH noted that the presence of brain metastases at baseline is an important confounder that was not accounted for in this analysis. Since not all confounders were included, there is a substantial risk of bias in the results. Moreover, to ensure unbiased estimates with the use of propensity scores, balance among all major confounders must be achieved, both those included in the propensity score development itself and other potential confounders. Balance among the limited list of confounders included in the propensity score development was achieved in the chemotherapy analysis set. However, there remained some imbalances in the immunotherapy dataset despite weighting, likely due to low patient numbers. The imbalances further contribute to the risk of bias and uncertainty in the results.

In addition, in propensity score analyses, after estimating the propensity score, the overlap (region of common support) of the distributions of the estimated propensity score for the treatment and comparison groups should be examined graphically or through formal goodness-of-fit tests before moving on to the propensity score application step. However, no information on the overlap or presence of extreme propensity score values between the groups was presented.

Clinically relevant outcomes, OS and PFS, were assessed in the sponsor-submitted ITC. However, the definitions of OS and PFS used in the RWD were not clear. The methods of assessing OS and PFS used in the studies that the RWD was extracted from were not reported. When PFS data were unavailable, the authors used time to next treatment or death or time on treatment as a proxy. The clinical experts consulted by CADTH indicated that this was a reasonable approach, and data-cleaning rules were used to try to ensure censoring was consistent across end points for patients in the immunotherapy and chemotherapy analysis sets. However, differences in how these outcomes were captured in VISION compared to the RWD sources (e.g., when assessments occurred, whether they were investigator-assessed versus IRC-assessed, use of other end points as proxy for PFS) contributed to uncertainty in the data.

In addition, the authors of the ITC noted limitations in their analysis of OS and PFS. First, the authors of the ITC indicated that the Cox proportional hazards assumption may not have been met, which is expected to introduce bias in the Cox proportional HRs, although the direction of bias is unclear. Second, the authors reported that there is a substantial amount of post-progression treatment in the immunotherapy and chemotherapy groups in the CDM, which is likely to confound the OS results. These limitations further contribute to the uncertainty in the PFS and OS results. The ITC did not provide data on other important efficacy outcomes (e.g., ORR, HRQoL). Safety outcomes (e.g., overall AEs, SAEs, discontinuation rates) were also not reported.

Overall, results of the indirect comparison of RWD to VISION using propensity scoring are expected to be biased, given the inherent limitations of the study design and conduct, and the reporting of the methods and results lacked important details. As a result, no conclusions can be made from the data. A number of key limitations related to the selection and assessment of patients, as well as the propensity score methods, were identified that could potentially bias the results. First, fundamental differences between the VISION trials and retrospective RWE databases and cohort studies for inclusion in the CDM were noted, as were concerns over differences in the assessment and timing of the clinical end points. Second, and most important, clinically important heterogeneity was incompletely assessed and reported, and the statistical analyses completed are unlikely to have accounted for all major differences. The generation of propensity scores did not include all important potential confounders and may have been biased by the differential distribution of invalid or missing data between the VISION clinical trial and retrospective datasets. Propensity score methods can control only for measured confounders, and systematic differences may remain between the VISION patients and those selected from the RWD sources.

With regard to external validity, 1 of the 4 sources of RWD included sites from Canada (British Columbia only). The majority of patient data were from sites in the US. A number of important differences likely exist between the US and Canada with regard to the management of these patients, differences in treatments available, health insurance coverage, and overall health care system structures, which would be expected to affect outcomes. In addition, the databases used included patients enrolled early in the studies, more than a decade ago, and these patients are unlikely to be representative of contemporary patients, because better therapies and supportive care are now available, which would be expected to bias the study results in favour of tepotinib. Immunotherapy with or without chemotherapy is the standard of care for first-line treatment of NSCLC in Canada. The indirect comparison using propensity scoring included chemotherapy without immunotherapy and immunotherapy alone as comparators, which were appropriate. Tepotinib was not compared to chemotherapy in combination with immunotherapy, which represents a significant gap in the evidence.

Results of the Unanchored MAIC

Summary of Included Studies

The authors of the sponsor-submitted ITC¹⁵ provided a limited description of the 3 retrospective studies included in the unanchored MAIC, and additional information was provided by the sponsor.²⁷ Details of the included studies and their designs are summarized in Table 26. Baseline characteristics of the patient populations in the retrospective studies and VISION are summarized in Table 27. Some sources of heterogeneity were identified by the authors of the ITC and the sponsor, which are summarized in this section.

The Awad et al. (2019) study²⁸ was a multi-centre retrospective study of 148 patients with METex14 mutations from 12 institutions. Most patients were from the US. Patients were included in the OS analysis if they were diagnosed on or after January 2010 and data were available until December 2016.²⁸ The study describes the patient characteristics and outcomes seen in a real-world METex14 population treated with different classes of therapy, focusing primarily on whether a MET inhibitor improves outcomes. The MET population in the Awad et al. (2019) study consisted of patients treated with crizotinib, glesatinib, capmatinib, savolitinib, tepotinib, cabozantinib, or merestinib. The authors noted that this patient population likely included patients who were enrolled in the VISION trial. The authors used the group of patients who did not receive a MET inhibitor in the MAIC only. This non-MET population consisted of 34 patients with a median age of 70, and median OS of 8.1 months. Ten (37%) patients had brain metastases at diagnosis. In the non-MET population, most patients received platinum- or pemetrexed-based regimens. The authors of the ITC noted that the lines of therapy differed from those in the VISION study, with a smaller proportion of patients receiving tepotinib first-line. In addition, the authors of the ITC highlighted that there were differences from the VISION study in cancer histology (76% adenocarcinoma), and MET alteration type, as a variety of MET alterations were included (i.e., not limited to METex14 skipping mutations). According to the author’s assessment, the Awad et al. (2019) study can provide historical control data, primarily for previously treated patients, although there are limitations to its interpretation, given the lack of reporting subsequent treatments. The Awad et al. (2019) study assessed OS and PFS, but it did not report PFS data for the group of patients that were not treated with a MET inhibitor in the study publication. OS was defined as the date of diagnosis of stage IV disease until death due to any cause.²⁸

The Sabari et al. (2018) study⁸ was a multi-centre retrospective study of 147 patients investigating the efficacy of immunotherapy in patients with METex14 skipping alterations. Patients identified between January 2014 and May 2017 were eligible.⁸ The authors of the ITC indicated that this study had authors and centres similar to those in the Awad et al. (2019) study. OS and PFS were assessed, but definitions of these outcomes were not reported.⁸ Immunotherapies received by the patients included pembrolizumab, nivolumab, atezolizumab, durvalumab, and ipilimumab plus nivolumab.¹⁵ The authors of the ITC indicated that the patient population was older than a typical NSCLC population (median age 73 years), which was similar to the VISION study population. The authors also reported that the study population was broader than VISION, with 46 patients not having metastatic disease and fewer having adenocarcinoma. The Sabari et al. (2018) study reported PFS and OS data for 24 patients treated with immunotherapy. The line of treatment that immunotherapy was received in was not reported. The authors of the ITC noted that other limitations of the study were a small sample size and heterogeneity of the immunotherapy received.

The Guisier et al. (2020) study²⁹ investigated the effectiveness of immunotherapy in NSCLC harbouring multiple alterations (BRAF, MET, HER2, and RET). The time period of the patient data collected was not reported. Of the 107 patients enrolled in the study, 30 had MET mutations and were the population of interest for the sponsor’s unanchored MAIC. The sponsor-submitted technical report indicated that these patients had METex14 skipping alterations. However, the Guisier et al. (2020) study publication²⁹ did not specify the types of MET mutations that were eligible. It is unclear whether the population with MET mutations from this study included only patients with METex14 skipping alterations. The authors of the ITC indicated that the baseline characteristics were similar to those in the VISION study population, based on metastatic sites and adenocarcinoma histology (93%). However, the authors of the ITC also indicated that the patient population did not align with the VISION study because 23% of patients had an ECOG PS of 2 and most patients were second- or later-line (4 of 30 patients were first-line). OS and PFS were assessed in the Guisier et al. (2020) study. OS was defined as the time from the introduction of immunotherapy to death.²⁹ PFS was defined as the time from initiation of immunotherapy to progression on immunotherapy (radiological progression per RECIST v1.1 criteria or clinical progression) or death.²⁹

A quality assessment of the Awad et al. (2019) and Sabari et al. (2018) studies was provided in the sponsor’s systematic literature review.¹⁶ Quality of the studies was assessed by the percentage of positive responses to the questions in the Downs and Black Checklist. The quality score was 57% for the Awad et al. (2019) study and 43% for the Sabari et al. (2018) study. The Guisier et al. (2020) study was not included in the sponsor’s systematic literature review, and a quality assessment of this study was not provided in the ITC technical report.

Table 26: Summary of Studies — Unanchored MAIC

DCR = disease control rate; DOR = duration of response; ICI = immune-checkpoint inhibitors; MAIC = matching-adjusted indirect comparison; METex14 = MET exon 14; NR = not reported; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; TKI = tyrosine kinase inhibitor.

Source: Sponsor’s technical report,¹⁵ Awad et al. (2019),²⁸ Sabari et al. (2018),⁸ Guisier et al. (2020),²⁹ and sponsor’s response to CADTH’s request for information.²⁷

Table 27: Baseline Characteristics for the VISION Study and Comparator Groups Used in the MAIC

MAIC = matching-adjusted indirect comparison; NR = not reported; SD = standard deviation.

Source: Sponsor’s technical report,¹⁵ Awad et al. (2019),²⁸ Sabari et al. (2018),⁸ Guisier et al. (2020),²⁹ and VISION Clinical Study Report.¹⁴

The tepotinib data from the VISION study was reweighted to match the 3 retrospective studies. A visual comparison of Kaplan-Meier curves was conducted for each comparison. No HRs or other statistics were reported.

Results of the reweighting of the VISION data to match the Awad et al. (2019) study are provided in Table 28. Patients were not matched using the characteristic of metastatic disease because these data were not reported in the Awad et al. (2019) study. After weighting, the sample size of the tepotinib group decreased from |||||| patients to an ESS of |||||| patients. The Kaplan-Meier plot of OS for the Awad et al. (2019) study data compared to the unweighted and MAIC-weighted VISION data is depicted in Figure 18. Since the Awad et al. (2019) study did not report PFS data for the group of patients that were not treated with MET inhibitors, no comparison was made for PFS.

Results of the reweighting of the VISION data to match the Sabari et al. (2018) study are provided in Table 29. After weighting, the sample size of the tepotinib group decreased from 151 patients to an ESS of 51.1 patients. The authors indicated that the large reduction in sample size was due to the lower proportion of patients with metastatic disease in the Sabari et al. (2018) study. The Kaplan-Meier plots of OS and PFS for the Sabari et al. (2018) study data compared to the unweighted and weighted VISION data are depicted in Figure 19 and Figure 20, respectively.

Results of the reweighting of the VISION data to match the Guisier et al. (2020) study are reported in Table 30. After weighting, the sample size of the tepotinib group decreased from 151 patients to an ESS of 79.5. The authors of the ITC reported that this notable loss in sample size was largely due to the Guisier et al. (2020) study population containing mostly treatment-experienced patients. The Kaplan-Meier plots of OS and PFS for the Guisier et al. (2020) study data compared to the unweighted and weighted VISION data are depicted in Figure 21 and Figure 22 respectively.

Table 28: VISION Patient Characteristics, Before and After Application of MAIC to Match Awad et al. (2019)

ESS = effective sample size; MAIC = matching-adjusted indirect comparison; NR = not reported; SD = standard deviation.

Source: Sponsor’s technical report.¹⁵

Figure 18: Kaplan-Meier Plot of OS of Awad et al. (2019) Compared to the Unweighted and Weighted VISION Data

Source: Sponsor’s technical report.¹⁵

Table 29: VISION Patient Characteristics, Before and After Application of MAIC to Match Sabari et al. (2018)

ESS = effective sample size; MAIC = matching-adjusted indirect comparison; NR = not reported; SD = standard deviation.

Source: Sponsor’s technical report.¹⁵

Figure 19: Kaplan-Meier Plot of OS of Sabari et al. (2018) Compared to the Unweighted and Weighted VISION Data

Source: Sponsor’s technical report.¹⁵

Figure 20: Kaplan-Meier Plot of PFS of Sabari et al. (2018) Compared to the Unweighted and Weighted VISION Data

Source: Sponsor’s technical report.¹⁵

Table 30: VISION Patient Characteristics, Before and After Application of MAIC to Match Guisier et al. (2020)

ESS = effective sample size; MAIC = matching-adjusted indirect comparison; NR = not reported; SD = standard deviation.

Source: Sponsor’s technical report.¹⁵

Figure 21: Kaplan-Meier Plot of OS of Guisier et al. (2020) Compared to the Unweighted and Weighted VISION Data

Source: Sponsor’s technical report.¹⁵

Figure 22: Kaplan-Meier Plot of PFS of Guisier et al. (2020) Compared to the Unweighted and MAIC-Weighted VISION Data

Source: Sponsor’s technical report.¹⁵

Critical Appraisal of the Unanchored MAIC

There were substantial methodological limitations of the unanchored MAIC. First, a MAIC can adjust only for heterogeneity that is directly related to differences in baseline patient characteristics. Other sources of heterogeneity, such as those related to differences in study design, definitions of study outcomes, or changes in the management of support of patients over time, cannot be adjusted for. The prospective, interventional VISION trial was compared to retrospective observational studies. This may be problematic, as there are notable differences in treatments and procedures received by patients, data collection methods, and assessments, and these differences in study design could not be accounted for in the MAIC. In addition, differences (or potential differences) in the studies’ outcome definitions could not be assessed due to lack of reporting. In the VISION study, OS was defined as the time from first trial treatment administration to the date of death, and a similar definition was used in the Guisier et al. (2020) study. However, the Awad et al. (2019) study defined OS as the date of diagnosis of stage IV disease until death due to any cause. The Sabari et al. (2018) study publication did not report definitions of PFS and OS; thus, it is unknown whether the study’s definition of outcomes differed from that in VISION. The definition of PFS used in the Guisier et al. (2020) study was similar to the definition used in the VISION study. Differences in study outcome definitions could not be accounted for in the MAIC; thus, these differences create uncertainty in the results.

Furthermore, an unanchored indirect comparison using MAIC methods provides an unbiased comparison only if all prognostic and effect-modifying factors are included in the weighting process. The variables included in the unanchored MAIC do not reflect all important effect modifiers and prognostic factors. The technical report for the sponsor-submitted ITC indicated that ECOG PS would ideally have been included in the model, but it was not possible due to the amount of missing data. Patients included in the retrospective studies were likely sicker (i.e., included patients with ECOG PS of 2 or more) than patients in VISION, which restricted enrolment to ECOG 0 or 1. The clinical experts consulted by CADTH indicated that ECOG PS and the presence of brain metastases at baseline are important factors and thus should have been included the model to provide an unbiased comparison. In addition, patient numbers allowed the proportion of adenocarcinoma to be matched only in terms of histology, and metastatic disease was not matched in the comparisons to the Awad et al. (2019) and Guisier et al. (2020) studies because data for this characteristic were not reported. Exclusion of important confounders in the matching introduces bias and creates substantial uncertainty in the results. Unanchored forms of population-adjusted indirect comparisons make the much stronger assumption of “conditional constancy of absolute effects.” This means that the absolute treatment effects are assumed to be constant at any given level of the effect modifiers and prognostic variables, and all effect modifiers and prognostic variables must be known. This assumption is unlikely to have been met in this unanchored MAIC; therefore, no conclusions can be made from the data.

In the comparisons, a large reduction in ESS was observed, which suggests there was likely significant heterogeneity between the VISION study and comparator studies. The results for indirect comparisons with major reductions of ESS indicate that the weights are highly variable due to a lack of population overlap and that the resulting estimate may not be reliable.

In addition, the methods and findings of the MAIC lacked important details, which creates further uncertainty in the results. The sponsor submitted a systematic literature review, which identified the Sabari et al. (2018) and Awad et al. (2019) studies included in the unanchored MAIC. However, the third study (Guisier et al. [2020]) was not identified in the sponsor’s systematic literature review, so it is unclear how this study was identified and selected for inclusion in the MAIC. Furthermore, it is unclear why other studies identified in the sponsor’s systematic literature review were not included in the ITC. The methods used to identify studies specifically for the submitted unanchored MAIC and the selection criteria were unclear. As a result, there is significant risk of bias in study selection and a lack of certainty that all relevant studies were identified. The data extraction methods were not reported. The quality of the Awad et al. (2019) and Sabari et al. (2018) studies was low; the quality of the Guisier et al. (2020) study was not assessed by the authors of the ITC and therefore not considered in the ITC analysis. Potential risks of bias in the included studies were not assessed and not reported. A limited assessment of heterogeneity was reported. Kaplan-Meier curves were presented for visual comparison only.

The MAIC assessed OS and PFS, which were identified as important outcomes by the clinical experts, clinician groups, and patient groups that provided input on this review. The OS results were likely confounded by subsequent therapies (i.e., post-progression treatments), which were not accounted for in the MAIC. In addition, the differences in definitions of OS time between studies may have also introduced bias in the results. The ITC did not include data on ORR, DOR, or HRQoL, which were also identified as important outcomes. In addition, safety outcomes were not reported in the ITC, which represents an important gap in the evidence.

Some of the patients included in the retrospective studies were from earlier time periods, and they would not be representative of current patients receiving contemporary treatments and would be expected to have worse outcomes. This may cause overestimation of the effects of tepotinib. Since the Awad et al. (2019) and Sabari et al. (2018) studies were from similar authors and centres, patients may have been included more than once. This would be expected to bias the study results because the same patients may have been included more than once in the estimates.

With regard to external validity, none of the studies included sites from Canada. Most patients in the retrospective studies (2 of 3 studies) were from sites in the US. A number of important differences likely exist between the US and Canada with regard to the management of these patients, most notably insurance coverage, which would be expected to affect outcomes.

In Canada, the standard of care for patients with advanced NSCLC is chemotherapy with or with immunotherapy, or immunotherapy alone. In the population from the Awad et al. (2019) study used for comparison, most patients were treated with chemotherapy. In the Sabari et al. (2018) and Guisier et al. (2020) studies, patients were treated with immunotherapy. Tepotinib was not compared to a combination of chemotherapy and immunotherapy in the MAIC, which represents a gap in the evidence.

Other Relevant Evidence

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

Discussion

Summary of Available Evidence

One ongoing, phase II, single-arm, open-label trial (VISION) was included in the systematic review. The 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 CR or PR) determined according to RECIST v1.1, based on independent review in patients who tested positive for METex14 skipping alterations or MET amplification. Patients with METex14 skipping alterations were enrolled in cohort A and cohort C under the same eligibility criteria and underwent the same study procedures. cohort A was the pivotal cohort (N = 151); cohort C was a confirmatory cohort added as a protocol amendment, and enrolment at sites was shifted from cohort A to cohort C once accrual for cohort A was completed (cohort A plus C: N = 254). 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 per RECIST v1.1 criteria, death, an AE leading to discontinuation, or withdrawal of consent. The primary outcome was ORR by 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 TTD in EQ-5D-5L VAS, EORTC QLQ-C30 (global health status and quality of life score), EORTC QLQ-LC13 (coughing, dyspnea, and chest pain symptom scales); and safety. Intracranial CNS outcomes were assessed in a post hoc exploratory analysis. Data were analyzed descriptively; no statistical testing was performed.

In VISION, the mean age of study patients was 73 years in cohort A and cohort A plus C. Most patients were White, had an ECOG PS of 1, adenocarcinoma histology type, and stage IV disease at study entry. Approximately half of the study patients had received prior anticancer drug therapy for advanced or metastatic disease. The most common types of prior anticancer therapies were cytotoxic therapy and immunotherapy. The most frequently administered prior drug therapies were carboplatin, pemetrexed, cisplatin, and pembrolizumab. Most patients had not had prior anticancer surgery. 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.

Since the primary clinical review of tepotinib consisted of a single-arm trial, a review of the available indirect evidence was conducted. The ITCs submitted by the sponsor were summarized and critically appraised. The objective of the ITC analyses was to estimate the comparative effectiveness of tepotinib relative to commonly used therapies (i.e., chemotherapy and immunotherapy). The ITCs consisted of an indirect comparison of VISION to pooled RWD using propensity scoring and unanchored MAICs comparing VISION to 3 retrospective observational studies. The authors reported results for clinical efficacy in terms of OS and PFS, comparing tepotinib to chemotherapy without immunotherapy and immunotherapy alone. Harms outcomes were not assessed.

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

Interpretation of Results

Efficacy

The clinical experts consulted by CADTH indicated that the goals of treatment in locally advanced (not amenable to curative treatment) or metastatic NSCLC are to improve survival, delay progression, and improve response rate, as well as improve or maintain HRQoL. They noted that METex14 skipping alterations are a rare mutation, and no targeted treatments are publicly funded in Canada. Patients with advanced NSCLC and METex14 mutations are currently treated per guidelines for advanced NSCLC without driver mutations, and therapy under these guidelines is immunotherapy with or without chemotherapy. The clinical experts reported that retrospective studies^7,8 have indicated that patients with NSCLC harbouring METex14 skipping mutations have a poor prognosis and there may be less benefit from the use of immunotherapy. The clinical experts indicated that there is unmet need in this patient population. Similar views were expressed by the clinician groups that provided input on this review.

The patient groups indicated that they want treatments that improve symptoms, improve or maintain HRQoL, increase survival, delay disease progression, and help patients achieve long-term remission. The patients also expressed that it is important to maintain independence and functioning. This aligns with the following outcomes assessed in the VISION trial: HRQoL and PROs, OS, PFS, ORR, and DOR.

OS, PFS, ORR, DOR, and HRQoL and PROs were identified as important outcomes in the CADTH review protocol, and these outcomes were assessed as secondary end points in the VISION study. Intracranial CNS outcomes were also identified as important in the CADTH review protocol.

For the primary end point, the VISION study aimed to show an ORR assessed by IRC of 40% to 50%, and to demonstrate that the lower limit of the corresponding exact 2-sided 95% CI exceeded 20%. The VISION trial achieved its primary end point. As of the July 1, 2020, data cut-off, ORR by IRC assessment was 45.0% (95% CI, 36.9% to 53.3%) in the pivotal cohort A. All responses were PR. The clinical experts consulted by CADTH indicated that these results were clinically meaningful. Results were similar in the pooled confirmatory cohort A plus C (i.e., entire METex14 skipping population). Furthermore, pre-specified subgroup analyses by line of treatment, presence of brain metastases at baseline, histological subtype, and ECOG PS were broadly numerically consistent with the overall analysis. No statistical testing was done on the differences between subgroups.

Time-to-event outcomes such as PFS and OS are difficult to interpret in single-arm trials. The clinical experts consulted by CADTH indicated that the Kaplan-Meier curves and median OS and PFS in the pivotal cohort A were clinically meaningful and suggested a benefit with tepotinib, although there is uncertainty due to the absence of a comparator arm. Similarly, the clinical experts indicated that the ORR and DOR results suggested a clinically meaningful benefit and that response to tepotinib was durable, although these data are difficult to interpret without a comparator arm as well. PFS, ORR, and DOR were assessed by both the IRC and the investigator, and results by investigator assessment were generally consistent with the results by IRC assessment. Pre-specified subgroup analyses of each secondary end point were broadly consistent with the overall analysis, although median OS and median PFS were numerically greater in the second- or later-line of therapy group compared to the first-line group. The reason for this numerical difference between subgroups in uncertain.

The HRQoL and PROs were assessed by change from baseline and TTD by 10 points for each PRO score. CADTH identified an MID of 7 to 11.5 points for the EQ-5D-5L VAS and 4 points for deterioration in EORTC QLQ-C30 global health status and quality of life score.^24,25 No MID was identified in the literature for the EORTC QLQ-LC13 symptom scales. Regarding change from baseline, the EQ-5D-5L and EORTC QLQ-C30 global health status and quality of life scores remained generally stable over time in cohort A and cohort A plus C, although there is uncertainty in the data due to the relatively small number of patients contributing to the analysis at later cycles. The missing data would be expected to overestimate the true effect of tepotinib on HRQoL outcomes. The sponsor indicated that results of the MMRM analysis of the QLQ-LC13 symptom scales were uncertain after cycle 25, due to small sample sizes. For the earlier cycles, the MMRM analysis of the QLQ-LC13 symptom scales indicated that there may have been some improvement in coughing, whereas dyspnea and chest pain remained relatively stable. However, the MRMM analysis would be expected to overestimate the treatment effects, as it is unlikely the assumptions of the MRMM have been met in this study. Overall, the clinical experts consulted by CADTH indicated that the HRQoL and PRO results suggested that HRQoL may be maintained with tepotinib therapy. However, there is substantial uncertainty in the data due to the decreasing number of patients that completed the questionnaires over time, which is likely to lead to an overestimation of treatment effects, and due to the absence of a control group. Furthermore, the VISION trial was open-label, which may have introduced bias in the reporting of subjective outcomes such as HRQoL and PROs.

In the original VISION study protocol, only patients with adenocarcinoma were eligible, and patients were required to have failed 1 to 2 lines of systemic therapy, including a platinum-doublet-containing regimen. In a protocol amendment that was implemented after enrolment in the study had begun, the eligible study population was expanded to include all subtypes of NSCLC and patients that were treatment-naive (i.e., would receive tepotinib as first-line treatment). These significant changes to the eligibility criteria implemented after participant enrolment had begun may have introduced bias. The direction of this bias is unknown. However, the sponsor did conduct subgroup analyses of treatment-naive patients versus patients who had been previously treated, and the results of these subgroup analyses were broadly consistent with the overall analyses.

The primary limitations of the VISION trial that impact the interpretation of results were the absence of a comparator group and statistical testing. Due to these limitations of the study design, no definitive conclusions can be drawn concerning the comparative effectiveness of tepotinib based on the VISION trial data alone.

There was no direct evidence available to assess the relative efficacy of tepotinib versus current standard of care therapies for patients with advanced NSCLC with METex14 skipping alterations. The sponsor submitted an ITC that included an indirect comparison of VISION to pooled RWD using propensity scoring and an unanchored MAIC comparing VISION to 3 retrospective observational studies. Relative efficacy was assessed in terms of PFS and OS. The comparators were chemotherapy without immunotherapy and immunotherapy alone. Key gaps in the evidence provided by the ITC were that no safety outcomes were assessed and that chemotherapy in combination with immunotherapy was not included as a comparator. Although the ITC reported a benefit in PFS and OS with tepotinib treatment compared to chemotherapy and immunotherapy, there is potential for significant bias in the ITC results. The methods and findings of the ITC were not adequately detailed, and several methodological limitations were noted. Differences in the study designs could not be accounted for in the indirect comparisons. This may be problematic, as there are notable differences in treatments and procedures received by patients, data collection methods, and assessments. There are concerns that not all effect modifiers and prognostic factors have been identified and adjusted for in the analyses, and that there are limitations regarding availability of data to allow for, including key variables in the weighting process. Most important, the authors of the ITC conducted a limited assessment of heterogeneity, and there is likely considerable heterogeneity among the patient populations of the pooled RWD, retrospective observational studies, and VISION trial. The small ESS in the studies used in the MAICs suggests that substantial differences exist between the patient population in the VISION trial and in the retrospective observational studies. These differences were not fully accounted for with the statistical analyses employed. Due to the methodological limitations, limited reporting of methods and results, and small sample sizes in the indirect comparisons, there is substantial risk of bias and uncertainty in the results. As a result, no conclusion can be made based on the ITC results.

Harms

The patient groups that provided input for this review indicated that they want treatments with minimal side effects. Similarly, the clinical experts consulted by CADTH indicated that new treatments would ideally minimize AEs compared to current standard of care therapies. Moreover, the clinical experts noted that patients with NSCLC harbouring METex14 skipping mutations tend to be an elderly population, and elderly patients often experience increased side effects with chemotherapy. Thus, treatments that are better tolerated are needed.

The evidence regarding the safety of tepotinib was derived from the VISION trial. Almost all study patients experienced at least 1 treatment-emergent AE. The most frequently reported AE was peripheral edema, which was a notable harm identified in the CADTH systematic review protocol. The clinical experts noted that peripheral edema is relatively manageable in most patients. Other common AEs included nausea, diarrhea, hypoalbuminemia, increased blood creatinine, and dyspnea. The clinical experts consulted by CADTH indicated that the toxicity profile of tepotinib may be preferable to that of standard of care therapies for some patients. The VISION trial was open-label, which may have affected the reporting of AEs. The direction of potential bias due to open-label administration of tepotinib is unknown.

As of the July 1, 2020, data cut-off date, 27.6% of patients in cohort A and 20.4% in cohort A plus C permanently discontinued study treatment due to an AE. The most common AEs leading to treatment discontinuation were peripheral edema, pleural effusion, and general physical health deterioration. The incidence of SAEs was 55.9% in cohort A and 45.1% in cohort A plus C. The most frequently reported SAEs were pleural effusion, disease progression, and pneumonia. Overall, 50% of patients in cohort A and 33.7% in cohort A plus C had died. The most common cause of death was disease progression.

Tepotinib has serious warnings and precautions in the Health Canada product monograph¹¹ for hepatotoxicity and interstitial lung disease or pneumonitis, which were included as notable harms in the CADTH systematic review protocol. The most frequently reported hepatotoxicity-related AEs were increased ALT, AST, blood ALP, and GGT. A total of 2 patients experienced interstitial lung disease, and 6 patients experienced pneumonitis. Another notable harm specified in the review protocol was renal toxicity, and the most common treatment-emergent AE related to renal toxicity was increased blood creatinine.

Harms outcomes were not assessed in the sponsor-submitted ITC; therefore, the relative safety of tepotinib compared to standard of care therapies remains unknown.

Conclusions

One ongoing phase II, single-arm trial (VISION) of tepotinib in patients with advanced (locally advanced or metastatic) NSCLC harbouring METex14 skipping alterations was identified in the systematic review conducted by CADTH. The VISION trial data were analyzed descriptively; no statistical hypotheses were tested. According to the clinical experts consulted by CADTH, the results suggested there may be a potential beneficial effect of tepotinib on OS, PFS, ORR, and DOR based on their clinical experience and expectations of the natural progression of the disease in patients with METex14 skipping alterations. The clinical experts indicated that there is significant unmet need for targeted treatment and improved outcomes in this patient population. However, due to the absence of a comparator arm and statistical testing, no definitive conclusions can be drawn regarding the efficacy of tepotinib based on the VISION trial. The HRQoL and PRO data from VISION suggested that quality of life may be maintained with tepotinib therapy per the clinical experts, but there is substantial uncertainty in these data due to 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 and PROs remains unknown. Almost all study patients reported treatment-emergent AEs, the most common of which was peripheral edema. The most frequently reported SAEs were pleural effusion, disease progression, and pneumonia. Few patients experienced interstitial lung disease or pneumonitis. The most common cause of death was disease progression. The clinical experts consulted by CADTH indicated that the safety of tepotinib was acceptable.

No direct evidence was identified concerning the relative efficacy and safety of tepotinib versus standard of care therapies used to treat advanced NSCLC with METex14 skipping alterations in Canada (i.e., immunotherapy, chemotherapy, or immunotherapy with chemotherapy). Results from the indirect treatment analyses submitted by the sponsor suggested that tepotinib therapy may be associated with a benefit in PFS and OS compared to chemotherapy and immunotherapy. However, the ITCs are associated with substantial risk of bias and important limitations were identified (i.e., methodological limitations, limited assessment of heterogeneity, reporting lacked important details, small sample sizes). In view of the substantial uncertainty in the ITC results, no conclusions can be drawn concerning the efficacy of tepotinib compared to chemotherapy or immunotherapy in patients with advanced NSCLC harbouring METex14 skipping alterations. Harms outcomes were not assessed in the ITC. The potential benefits and safety of tepotinib compared with other therapies remain unknown.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: September 23, 2021

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit retrieval by study type.

Limits:

• Publication date limit: none

• Humans

• Language limit: none

• Conference abstracts: excluded

Table 31: Syntax Guide