Brief Report: Combination Capmatinib and Trametinib in Metastatic MET-Driven NSCLC

MET tyrosine kinase inhibitor (TKI) therapy has improved outcomes in patients with NSCLC harboring MET alterations. Nevertheless, primary and acquired resistance ultimately limit the durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor.

A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced-stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A three-plus-three dose-escalation design was used to assess the safety and tolerability of the combination.

Three patients (N = 3) were enrolled in the study and completed a median of three cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and the initiation of therapy in the third patient at a lower dose level. Ultimately, all patients discontinued therapy because of treatment-related adverse events (TRAEs). The study was terminated early because of poor accrual and TRAEs. No radiographic objective responses were observed.

In this phase I trial, capmatinib plus trametinib was associated with marked TRAEs, and treatment was discontinued in all participants. On the basis of these findings, further investigation of this combination of MET and MEK inhibitors at the tested dose levels is not recommended. Future studies, if pursued, should consider modified dosing strategies, alternative MET and MEK inhibitor combinations, and MET-altered tumors with evidence of MAPK-mediated resistance.

NCT05435846.