Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Modelling the Effectiveness of Tepotinib in Comparison to Standard-of-Care Treatments in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) Harbouring METex14 Skipping in the UK.

BACKGROUND: Patients with non-small cell lung cancer harbouring mesenchymal-epithelial transition exon 14 (METex14) skipping typically demonstrate poorer prognosis than overall non-small cell lung cancer. Until recently, no targeted treatments were available for patients with non-small cell lung cancer harbouring METex14 skipping in the UK, with limited treatments available. OBJECTIVE: This study estimates the long-term survival and quality-adjusted life-year benefit of MET inhibitor tepotinib versus current standard of care from a UK perspective. METHODS: A partitioned-survival model assessed the survival and quality-adjusted life-year benefits of tepotinib versus immunotherapy ± chemotherapy and chemotherapy for untreated and previously treated patients, respectively, using evidence from the single-arm VISION trial (NCT02864992). Two approaches were used to inform an indirect treatment comparison: (1) published clinical trials in overall non-small cell lung cancer and (2) real-world evidence in the METex14 skipping population. Results are presented as median and total quality-adjusted life-year gain and survival for progression-free survival and overall survival. Survival curves were validated against the external literature and uncertainty assessed using a probabilistic sensitivity analysis. RESULTS: Using the indirect treatment comparison against the published literature, tepotinib is estimated to have a median progression-free survival gain versus pembrolizumab ± chemotherapy (11.0 and 9.2 months) in untreated patients, and docetaxel ± nintedanib (5.1 and 6.4 months) in previously treated patients. Across the populations, tepotinib is estimated to have a median survival gain of 15.4 and 9.2 months versus pembrolizumab ± chemotherapy in untreated patients and 12.8 and 5.1 months versus docetaxel ± nintedanib in previously treated patients. The total quality-adjusted life-year gain ranges between 0.56 and 1.17 across the untreated and previously treated populations. Results from the real-world evidence of indirect treatment comparisons are consistent with these findings. CONCLUSIONS: Despite the limitations of the evidence base, the numerous analyses conducted have consistently indicated positive outcomes for tepotinib versus the current standard of care.

Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B.

High-level MET amplification (METamp) is a primary driver in ∼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).

MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology, Clinical Characteristics, and Outcomes.

INTRODUCTION: MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes. METHODS: On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC. RESULTS: We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy. CONCLUSIONS: Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.

Health Utility Analysis of Tepotinib in Patients With Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping.

OBJECTIVES: The VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION. METHODS: 5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). RESULTS: Utilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends. CONCLUSIONS: In this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment.

Cost-Effectiveness of Tepotinib Versus Capmatinib for the Treatment of Adult Patients With Metastatic Non-Small Cell Lung Cancer Harboring Mesenchymal-Epithelial Transition Exon 14 Skipping.

OBJECTIVES: From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non-small cell lung cancer with tumors harboring mesenchymal-epithelial transition factor gene exon 14 skipping. METHODS: A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. RESULTS: In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and -$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. CONCLUSIONS: Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs.

Matching-Adjusted Indirect Comparison (MAIC) of Tepotinib with Other MET Inhibitors for the Treatment of Advanced NSCLC with MET Exon 14 Skipping Mutations.

INTRODUCTION: MET exon 14 skipping in patients with advanced non-small cell lung cancer (aNSCLC), can be targeted with MET inhibitors including tepotinib, capmatinib, savolitinib, and crizotinib. Matching-adjusted indirect comparison (MAIC) methodology was used to compare outcomes data between agents and to address bias from differences in baseline characteristics. METHODS: Patient-level data from the VISION study (tepotinib) were weighted for comparison with aggregate data from the GEOMETRY mono-1 (capmatinib), NCT02897479 (savolitinib) and PROFILE 1001 (crizotinib) studies in patients with aNSCLC, using baseline characteristics prognostic for overall survival (OS) in VISION. Overall response rate (ORR), OS, progression-free survival (PFS), and duration of response (DOR) were compared. Patients were stratified by line of therapy: overall (all lines), previously treated, and treatment-naïve. RESULTS: Improvements in ORR and all time-to-event endpoints were predicted for tepotinib compared with crizotinib and savolitinib in the different populations, although comparisons with savolitinib were hindered by considerable differences in baseline patient populations. Tepotinib appeared to be associated with prolonged PFS and OS compared with capmatinib in previously treated patients (PFS HR 0.54; 95% CI 0.36-0.83; OS HR 0.66; 95% CI 0.42-1.06) and the overall populations (PFS HR 0.60; 95% CI 0.43-0.86; OS HR 0.72; 95% CI 0.49-1.05), with smaller improvements in DOR. The ORR comparisons between tepotinib and capmatinib identified a swing of up to ± 6 percentage points in the weighted tepotinib ORR depending on the population studied (treatment-naïve vs. previously treated patients). CONCLUSIONS: The MAIC identified potential differences in efficacy endpoints with the different MET inhibitors, and predicted prolonged PFS and OS with tepotinib compared with capmatinib and crizotinib. Although MAIC cannot balance for unobserved factors, it remains an informative method to contextualize single-arm studies, where head-to-head trials are unlikely to be feasible.

Diagnostic and economic value of biomarker testing for targetable mutations in non-small-cell lung cancer: a literature review.

We aimed to assess the diagnostic and economic value of next-generation sequencing (NGS) versus single-gene testing, and of liquid biopsy (LBx) versus tissue biopsy (TBx) in non-small-cell lung cancer biomarker testing through literature review. Embase and MEDLINE were searched to identify relevant studies (n = 43) from 2015 to 2020 in adults with advanced non-small-cell lung cancer. For NGS versus single-gene testing, concordance was 70-99% and sensitivity was 86-100%. For LBx versus TBx, specificity was 43-100% and sensitivity was ≥60%. Turnaround times were longer for NGS versus single-gene testing (but not vs sequential testing) and faster for LBx versus TBx. NGS was cost-effective, and LBx reduced US per-patient costs. NGS versus single-gene testing and LBx versus TBx were concordant. NGS and LBx may be cost-effective for initial screening.

Plain language summary Patients with lung cancer with specific genetic mutations can benefit from medications that are specific to those mutations, known as targetable mutations. There are many methods to test for specific genetic mutations in patients with lung cancer. To detect genetic mutations, doctors can test the blood or urine, or they can test biopsy tissue; a small piece of the tumor removed from the lung. These tests can either look for mutations in one specific gene at a time, or they can use technology that reads the entire DNA sequence to observe multiple genes at once. In this review, we examined scientific reports to answer important questions about using genetic testing to find targetable mutations in patients with lung cancer. How accurate are different genetic tests? How fast can doctors get results from different genetic tests? How much do different genetic tests cost? We found that reading the entire DNA sequence was as accurate as testing one specific gene. Reading the entire DNA sequence takes more time than testing one specific gene, but it might reduce overall costs. Testing blood or urine was not as accurate as testing tissue, but it took less time for doctors to receive genetic test results and reduced costs.

Budget impact of tepotinib in the treatment of adult patients with metastatic non-small cell lung cancer harboring METex14 skipping alterations in the United States.

AIMS: To estimate the budget impact of adding tepotinib to United States (US) health plans for treating adult patients with metastatic non-small cell lung cancer (mNSCLC) harboring mesenchymal-epithelial transition exon 14 (METex14) skipping alterations. METHODS: The base-case analysis was conducted from the perspective of a hypothetical Medicare plan of 1 million members. Scenarios were analysed for other US health plans. Treatments included tepotinib, capmatinib, crizotinib, and standard of care (SoC). Patients eligible for tepotinib were estimated from published epidemiological data and literature, and real-world evidence. Clinical inputs were derived from the phase II VISION trial, US prescribing information, and published literature. Tepotinib uptake and projected testing rates for METex14 skipping alterations were based on market research. Unit costs (2020 US dollars (USD)) and resource utilization associated with drug acquisition and administration, treatment monitoring, disease and adverse event (AE) management, and subsequent treatment were derived primarily from public sources. RESULTS: In the base-case, 38-65 patients were eligible for tepotinib each year over the three-year time horizon. The cumulative net budgetary impact of tepotinib was -$692,541 (-2.6%); $26,531,670 in the scenario without tepotinib and $25,839,129 in the scenario with tepotinib. A negligible net budget impact was observed per member per month (PMPM) at $0.2457 and $0.2393, respectively, before and after tepotinib's introduction. Results were most sensitive to variability in unit costs of capmatinib and tepotinib and their corresponding median treatment durations. Sensitivity and scenario analyses support the conclusion that introducing tepotinib will have minimal budgetary impact for Medicare health plans. Similar results were obtained for other US health plans. LIMITATIONS: Assumptions and expert opinion were applied to address data gaps in key model inputs. CONCLUSIONS: The estimated budgetary impact of tepotinib for the treatment of adult patients with mNSCLC harboring METex14 skipping alterations is minimal from the perspective of US health plans.