Tepmetko (tepotinib)

Combining targeted therapies with immune checkpoint inhibitors showed promising results in two patients with advanced BTC driven by specific genetic mutations. Significant tumor reduction and successful surgeries suggest this approach may improve resectability and outcomes. These cases highlight the potential of personalized treatment guided by genetic profiling. Further research is needed to confirm these findings and explore broader applications for this strategy.

P2, N=140, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Oct 2025 --> May 2026

Utilising a robust next-generation sequencing platform, we have identified this mutation in 5.3% of cases in our cohort. In the absence of information on MET exon 14 skipping from India, this case series will throw some light on this variation in our subcontinent and highlights the fact that the real-world effectiveness of MET inhibitors like Tepotinib and Capmantinib might be lower than expected.

P3, N=133, Recruiting, Intergroupe Francophone de Cancerologie Thoracique | Not yet recruiting --> Recruiting | Initiation date: Jul 2025 --> Nov 2025

Splice site mutations around or within exon 14 of MET (METex14+) are rare, but are one of the common actionable driver mutations in elderly patients with non-small cell lung cancer (NSCLC). On June 30, 2025, vebreltinib has been approved for NSCLC with MET amplification while combination of savoltinib and osimertinib has been approved for EGFR+ post EGFR TKINSCLC with MET amplification post EGFR TKI based on the SACHI trial (NCT05015608). We discuss the current unmet clinical need (need to develop Type II MET TKI to overcome acquired resistance MET mutations at D1228 and Y1230) and future optimal treatment approaches.

The patient continued tepotinib treatment for approximately two years after the first administration. Therefore, the treatment sequence should be considered based on comprehensive multigene testing results to achieve better therapeutic benefits.

Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.

This case supports the potential role of systemic therapy intensification in METex14-driven NSCLC, highlighting the therapeutic value of continued MET inhibition beyond disease progression, particularly when local treatment and advanced molecular monitoring such as ctDNA are unavailable. Trial Registration: ClinicalTrials.gov identifier: NCT05439993.

MDRVV exhibited antitumor effects not only in the inoculated tumors but also in distant tumors, with the most pronounced effect observed when combined with tepotinib. These findings suggest that combining a MET inhibitor with oncolytic vaccinia virus represents a promising and effective strategy for improving lung cancer treatment by targeting both tumor cells and the tumor microenvironment.

P1, N=19, Recruiting, Institute of Cancer Research, United Kingdom | Trial completion date: Feb 2028 --> Jan 2029

P1, N=19, Recruiting, Institute of Cancer Research, United Kingdom | N=38 --> 19

Furthermore, capmatinib and tepotinib demonstrate extraordinary efficacy for patients with NSCLC and MET exon 14 (METex14) skipping mutation, and the combination of capmatinib and gefitinib in particular can achieve remarkable therapeutic effects in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC. The administration of capmatinib can help mitigate potential food-intake and drug-drug interactions in clinical settings. This facilitates the optimization of long-term medication schedules, enhancing the clinical efficacy of the treatment.