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This phase I trial investigated the combination of capmatinib (a MET inhibitor) and trametinib (a MEK inhibitor) in three patients with metastatic MET-driven non-small cell lung cancer who had previously progressed on MET inhibitor therapy. All three patients experienced dose-limiting toxicities including rash, edema, and nausea, ultimately requiring treatment discontinuation in every case. No objective radiographic responses were observed, and the study was terminated early due to poor patient accrual and treatment-related adverse events.
Why it matters
Resistance to MET inhibitors remains a critical clinical challenge in NSCLC, and this study provides useful negative evidence suggesting that combining MET and MEK inhibition through capmatinib and trametinib is not a viable therapeutic strategy due to an unacceptable toxicity profile. These findings help narrow the search for effective combination approaches in this patient population, redirecting research efforts toward alternative strategies.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Abstract Introduction: MET tyrosine kinase (TKI) therapy has improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring MET alterations. However, primary and acquired resistance ultimately limits 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. Methods: 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 3+3 dose-escalation design was employed to assess safety and tolerability of the combination. Results: Three patients (n = 3) were enrolled in the study and completed a median of 3 cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and initiation of the third patient at a lower dose level. Ultimately, all patients discontinued therapy due to treatment-related adverse events. The study was terminated early due to poor accrual and TRAEs. No radiographic objective responses were observed. Conclusions: In this phase I trial, capmatinib plus trametinib was associated with significant treatment-related adverse events and treatment was discontinued in all participants. Based on these findings, further investigation of this combination of MET and MEK inhibitors is not recommended.