A Phase II Study of Capmatinib in Patients with MET-Altered Lung Cancer Previously Treated with a MET Inhibitor.

ABSTRACT Purpose Capmatinib is approved for MET exon 14-altered NSCLC based on activity in targeted therapy-naive patients. We conducted a phase II study to assess efficacy of capmatinib in patients previously treated with a MET inhibitor. Methods Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping received capmatinib 400 mg twice daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), intracranial response rate, and overall survival (OS). Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms. Results Twenty patients were enrolled between 5/2016 and 11/2019, including 15 patients with MET skipping alterations and 5 patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range 4-374). Two (10%) patients achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among 5 patients who discontinued crizotinib for intolerance, DCR was 83%, including two patients with best tumor shrinkage of -25% and -28%. Intracranial DCR among 4 patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median PFS and OS were 5.5 (95% CI 1.3-11.0) and 11.3 (95% CI 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in post-crizotinib, pre-capmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib. Conclusion Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially due to overlapping resistance mechanisms.