Tepotinib Shows Manageable Safety in MET Exon 14+ NSCLC
Tepotinib was associated with frequent but manageable adverse events in MET exon 14–positive NSCLC, with peripheral edema most common.
More than one-third of patients needed at least 1 dose reduction.
A pooled analysis of cohorts A and C from the phase 2 VISION trial (NCT02864992) showed that tepotinib (Tepmetko) was linked to a high frequency of adverse effects (AEs) in patients with non–small cell lung cancer (NSCLC) harboring MET exon 14 alterations; however, the agent’s safety profile was considered manageable.1
Notably, these findings were consistent with prior reports from the trial. In the pooled safety analysis of cohorts A and C (n = 313), any-grade AEs occurred in 99.0% of patients, and grade 3 or higher AEs were reported in 68.4% of patients. Treatment-related AEs (TRAEs) were observed in 91.7% of patients, including grade 3 or higher TRAEs in 36.1% of patients. Any-grade serious AEs and serious TRAEs occurred in 54.6% and 16.0% of patients, respectively. AEs led to dose reductions in 33.2%, treatment interruptions in 43.8%, and permanent discontinuation in 15.7% of patients. These rates of TRAEs were 33.2%, 43.8%, and 15.7%, respectively. Additionally, 13.7% of patients experienced an AE that led to death, 3 of which were treatment related.
The most common TRAEs included peripheral edema (any-grade, 67.7%; grade ≥ 3, 11.8%), hypoalbuminemia (25.2%; 3.8%), nausea (23.3%; 0.6%), diarrhea (22.7%; 0.3%), increased blood creatinine levels (22.0%; 1.3%), alanine aminotransferase (ALT) level elevation (14.1%; 2.2%), decreased appetite (11.5%; 0.3%), aspartate aminotransferase level elevation (11.2%; 1.9%), and amylase level increase (10.5%; 1.9%).
In total, 37.4% of patients required at least 1 dose reduction. The most common any-grade TRAE leading to dose reduction, treatment interruption, and treatment discontinuation was peripheral edema (15.3%, 18.8%, and 6.1% of patients, respectively). Other TRAEs leading to dose reductions were generalized edema (3.2%), edema (2.2%), pleural effusion (1.6%), increased blood creatinine levels (2.6%), hypoalbuminemia (1.3%), fatigue (1.0%), asthenia (1.0%), and localized edema (1.0%). Other TRAEs leading to treatment interruptions included increased increased blood creatinine levels (5.8%), generalized edema (4.8%), edema (3.5%), pleural effusion (3.2%), increased ALT levels (2.6%), localized edema (2.2%), and nausea (2.2%). Other TRAEs leading to treatment discontinuation included edema (1.3%), generalized edema (1.0%), pleural effusion (1.0%), interstitial lung disease (1.0%), and pneumonitis (1.0%).
Additionally, health-related quality of life (HRQOL) patient-reported outcome (PRO) scores remained stable with tepotinib use. Investigators observed no meaningful change in European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) or EuroQol 5-Dimension 5-Level (EQ-5D-5L) scores up to 228 weeks. At the end of treatment, among patients evaluated for HRQOL, the mean change from baseline for the EORTC QLQ-C30 global health status (GHS) was –7.1 (standard deviation [SD], 26.66; n = 174), and the mean change for the EuroQol visual analogue scales (EQ-VAS) was –10 (SD, 23.7; n = 172); positive values signified improvement. The mean changes from baseline in the EORTC QLQ-lung cancer (LC13) symptom scores for cough, dyspnea, and chest pain, respectively, were –6.1 (SD, 28.16; n = 175), 7.1 (SD, 21.05; n = 175), and –2.3 (SD, 28.13; n = 174); negative values signified improvement. Furthermore, the median time to deterioration of the EORTC QLQ-LC13 symptom scores for cough, chest pain, and dyspnea were 36.5 months, 30.4 months, and 5.5 months, respectively.
“Throughout the VISION trial, patients completed questionnaires evaluating their QOL before and while receiving tepotinib,” Enriqueta Felip, MD, PhD, lead study author and head of the Thoracic Cancer Unit at Hospital Universitari de la Vall d'Hebron in Barcelona, Spain, and coauthors explained in the conclusion of the poster presentation. “Overall, patients reported that health and QOL remained stable while receiving tepotinib. Specific scores relating to symptoms experienced by patients with lung cancer were improved during treatment for symptoms such as cough and chest pain, and remained stable for shortness of breath.”
What Was the Design of the VISION Trial of Tepotinib in Patients With MET-Altered NSCLC?
The VISION trial was a single-arm study evaluating tepotinib in patients with advanced NSCLC harboring MET exon 14 skipping alterations.2 The study evaluated tepotinib at a dose of 500 mg orally once daily and comprised 3 cohorts.
Eligible patients were at least 18 years of age, had histologically or cytologically confirmed NSCLC with MET exon 14 skipping alterations detected by liquid biopsy and/or tissue biopsy, measurable disease per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. Prior immunotherapy was permitted.
Patients were excluded if their tumors harbored EGFR mutations or ALK rearrangements, if they had received more than 2 prior lines of systemic therapy, or if they had prior exposure to MET or HGF inhibitors.
The primary end point of the study was objective response rate by independent review committee per RECIST 1.1 criteria. Key secondary end points included duration of response; progression-free survival; overall survival; safety; and PROs measured using the EORTC QLQ-C30 GHS and 5 functional scales, EQ-5D-5L questionnaire with EQ-VAS, and EORTC QLQ-LC13 symptom scores (focusing on cough, dyspnea, and chest pain as predefined items of interest). Scores ranged from 0 to 100, with at least 10-point changes from baseline considered clinically meaningful.1,2
The data cutoff date for this analysis was May 20, 2024.1 PRO data were collected at baseline, on day 1 of treatment, every 6 weeks for the first 9 months, and subsequently every 12 weeks during treatment. Time to deterioration was estimated via Kaplan-Meier methodology, defined as the time from baseline to the first clinically meaningful deterioration, with assessments repeated every 3 months. A mixed-model repeated measures analysis was used to evaluate longitudinal changes from baseline in EORTC QLQ-LC13 symptom scores.
What Were the Baseline Patient Demographics in the VISION NSCLC Trial?
The median age of patients with MET exon 14 skipping NSCLC was 72.0 years (range, 41-94). In total, 50.8% of patients were female, 73.8% of patients had an ECOG performance status of 1, and 47.6% of patients had received prior treatment.
The distribution of ECOG performance status score was skewed toward 1, observed in 73.8% of patients, whereas 25.9% of patients had a score of 0. At study entry, 47.6% of patients had received at least 1 prior systemic therapy. The median treatment duration was 7.5 months (range, 0.03-83.12 months), and 19 patients remained on tepotinib for at least 48 months.
References
- Felip E, Ferrara R, Veillon R, et al. Safety and patient-reported outcomes with tepotinib in patients with METex14 skipping NSCLC: ≥3 years follow-up of VISION. Presented at: 2025 IASLC World Conference on Lung Cancer; September 6-10, 2025; Barcelona, Spain. Poster P3.12.40.
- Tepotinib phase II in NSCLC harboring MET alterations (VISION). ClinicalTrials.gov. Updated August 14, 2025. Accessed September 9, 2025. https://www.clinicaltrials.gov/study/NCT02864992
