Intracranial response to capmatinib after progression on crizotinib in a patient with MET exon 14 skipping non-small cell lung cancer-a case report.

Background: Capmatinib, a potent and selective MET tyrosine kinase inhibitor (TKI), holds promise as a therapeutic agent due to its potentially elevated intracranial efficacy in metastatic non-small cell lung cancer (NSCLC) patients harboring exon 14 skipping alterations in MET (MET Proto-Oncogene). This study aims to evaluate a targeted therapeutic approach to an MET exon 14 skipping (METex14) advanced NSCLC patient that progressed on Crizotinib and developed off target resistance alteration in PIK3CA.
Case Discription: We present a case of advanced METex14 NSCLC patient wherein central nervous system (CNS) relapse occurred post complete surgical resection and remission of the lung tumor under first-line crizotinib treatment. Subsequent disease monitoring demonstrated a profound intracranial response to capmatinib in a crizotinib-resistant brain lesion. Molecular analysis unveiled the original METex14 D1028N driver mutation and a newly arisen PIK3CA bypass mutation, potentially contributing to off-target resistance.
Conclusions: Before capmatinib was approved as a first line treatment option for metastatic NSCLC harboring somatic METex14 mutations, crizotinib conferred a potential option for targeted treatment. Switching to a selective MET -TKI like capmatinib with a better CNS penetration, it appears to be a promising approach for CNS metastasized NSCLC patients with METex14 mutations that failed on crizotinib. Further research is needed to more effectively understand and monitor resistance mechanisms using advanced diagnostic techniques such as DNA-based hybrid-capture (HC) next generation sequencing (NGS) to guide molecularly stratified therapy beyond the first line setting.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-769/coif). M.F. reports receiving consulting and lecture fees from Roche, AstraZeneca, Novartis, Boehringer Ingelheim, and Pfizer. M.T. reports receiving honoraria for lectures and presentation for Novartis. F.G. has received consulting fees, payment or honoraria for lectures, presentations, speakers’ bureaus and manuscript writing from Roche, Pfizer, MSD, Takeda, BMS, Abbvie, Sanofi, AMGEN and Novartis. He has also been supported by Pierre Fabre, Roche, Abbvie, Daiichi Sankyo, AstraZeneca and Takeda for attending meetings or travelling. He is a member of data safety monitoring board and advisory board in AstraZeneca, Roche, Pfizer, Merck and Takeda. His institution received payment for expert testimony by Merck, MSD, Roche, Lilly, Janssen, CSL, Behring, BEigene, AOP, Jazz, Pfizer, Takeda, Novartis, AstraZeneca, BMS, Abbvie, AMGEN, Incyte, Sobi and GSK for expert meetings in NSCLC, Oncology and Hematology Wrap ups. The other authors have no conflicts of interest to declare.
(2024 Translational Lung Cancer Research. All rights reserved.)