Capmatinib in <i>MET</i> Exon 14-Mutated or <i>MET</i>-Amplified Non-Small-Cell Lung Cancer.

Abstract

Among patients with non-small-cell lung cancer (NSCLC), <i>MET</i> exon 14 skipping mutations occur in 3 to 4% and <i>MET</i> amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with <i>MET</i>-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and <i>MET</i> status (<i>MET</i> exon 14 skipping mutation or <i>MET</i> amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a <i>MET</i> exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with <i>MET</i> amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with <i>MET</i> amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a <i>MET</i> exon 14 skipping mutation, particularly in those not treated previously. The efficacy in <i>MET</i>-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).