Current Trial Report: A Multicenter Phase I/Ib study of Capmatinib Plus Trametinib in Patients With Metastatic Nonsmall Cell Lung Center Harboring MET Exon 14 Skipping Mutations and Other MET-Alterations.

Autor: Lara MS; University of California Davis Comprehensive Cancer Center, Sacramento CA, USA., Riess JW; University of California Davis Comprehensive Cancer Center, Sacramento CA, USA., Goldman JW; University of California Los Angeles, Los Angeles, CA, USA., Jiang F; University of California San Francisco Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA., Bivona TG; University of California San Francisco Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA., Blakely CM; University of California San Francisco Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address: Collin.Blakely@ucsf.edu.
Jazyk: angličtina
Zdroj: Clinical lung cancer [Clin Lung Cancer] 2024 Jul 05. Date of Electronic Publication: 2024 Jul 05.
DOI: 10.1016/j.cllc.2024.07.002
Abstrakt: Introduction: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC.
Methods: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination.
Conclusion: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.
Competing Interests: Disclosure C.M.B. receives institutional research funding from Novartis, AstraZeneca, Mirati, Verastem, and Puma. J.W.R. received institutional research funding from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Revolution Medicines, Arrivent and Spectrum; consulting fees from Blueprint, Boehringer Ingelheim, EMD Serono, and Novartis; participation on an Advisory Board for Bayer, Beigene, Biodesix, Regeneron, Turning Point, Bristol Myers Squibb, Daiichi Sankyo, Roche/Genentech, Janssen, Jazz Pharmaceuticals, Mervus, Seattle Genetics, Summit and Sanofi.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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