Capmatinib inMETExon 14–Mutated orMET-Amplified Non–Small-Cell Lung Cancer

Abstract

BACKGROUNDAmong patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET 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. METHODSWe conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET 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. RESULTSA total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET 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 MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET 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. CONCLUSIONSCapmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-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.

Activity and bioavailability of tepotinib for leptomeningeal metastasis of NSCLC with MET exon 14 skipping mutation

“…The response rate of patients with brain metastases was 55%. In cohorts 4 and 5b of the A2201 phase II trial, 13 patients with brain metastases received capmatinib, and the response rate was 54% [6]. However, the cerebrospinal fluid transferability of capmatinib has not been elucidated.…”

“…Recently, tepotinib, a mesenchymal‐epithelial transition receptor tyrosine kinase proto‐oncogene (MET) inhibitor, was found to have durable clinical activity in non‐small cell lung carcinoma (NSCLC) patients with MET exon 14 skipping [5]. Further, capmatinib, a highly‐selective inhibitor of MET, also demonstrated promising antitumor activity in NSCLC patients with MET exon 14 skipping mutation [6]. These two MET inhibitors for NSCLC patients with MET exon 14 skipping mutation at the same time was approved.…”

“…After stereotactic radiosurgery, he received the first-line chemotherapy from November 2019 to April 2020. He received tepotinib from May 2020 to October 2020 antitumor activity in NSCLC patients with MET exon 14 skipping mutation [6]. These two MET inhibitors for NSCLC patients with MET exon 14 skipping mutation at the same time was approved.…”

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

“…Capmatinib, a selective MET inhibitor, has been evaluated in the multi-center, multicohort phase II GEOMETRY mono-1 study [259]. GEOMETRY mono-1 enrolled patients with advanced NSCLC with a MET exon 14 mutation and/or a MET amplification.…”

Spectrum of Mesenchymal–Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis

“…For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B). MET X1010_splice alteration is known to be oncogenic, and LUAD patients harboring the MET X1010 splice can be treated with the NCCNcompendium listed drug crizotinib (32,33) and FDA approved capmatinib (34,35). Meanwhile, tepotinib, a MET inhibitor, was also approved in Japan in March 2020 for the treatment of LUAD patients harboring MET exon 14 skipping (36,37).…”