As reported in The New England Journal of Medicine by Wolf et al, the phase II GEOMETRY mono-1 trial has shown durable responses with the selective MET inhibitor capmatinib in patients with advanced non–small cell lung cancer (NSCLC) and MET exon 14–skipping mutations.

The trial supported the May 2020 accelerated U.S. Food and Drug Administration approval of capmatinib for treatment of adult patients with metastatic NSCLC with tumors that have a mutation that leads to MET exon 14 skipping.

Study Details

The study enrolled a total of 364 patients with MET-dysregulated advanced disease, with assignment to cohorts based on previous lines of therapy and MET status of MET exon 14–skipping mutation or MET amplification according to gene copy number in tumor tissue. Patients received oral capmatinib at 400 mg twice daily. All previously treated patients had received one or two lines of prior therapy. The primary endpoint was objective response on Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by an independent review committee blinded to cohort assignments.

Responses

Across cohorts, a total of 97 patients had a MET exon 14–skipping mutation and 210 had MET amplification.

Among 97 patients with a MET exon 14–skipping mutation, objective response was observed in 41% of 69 patients who had received one or two lines of prior therapy and in 68% of 28 patients who had received no prior treatment. Median durations of response were 9.7 months (95% confidence interval [CI] = 5.6–13.0 months) and 12.6 months (95% CI = 5.6 months–not estimable), respectively.

Among patients with MET amplification, all patients with a gene copy number of 10 or lower had received previous treatment. Objective response was observed in 12% of 42 patients with a gene copy number of six to nine, in 9% of 54 with a gene copy number of four or five, and in 7% of 30 with a gene copy number of less than four. Median progression-free survival was 2.7 months, 2.7 months, and 3.6 months, respectively, in these cohorts. These cohorts were closed for futility at the interim analysis.

Among patients with a gene copy number of 10 or higher, objective response was observed in 29% of 69 with previous treatment and in 40% of 15 with no previous treatment. The overall response rate among these patients did not meet the prespecified threshold for clinically relevant activity. Median durations of response were 8.3 months and 7.5 months in the two groups. Median progression-free survival was 4.1 months and 4.2 months, respectively.

Adverse Events

Among all 364 patients enrolled in the trial, the most common adverse events of any grade irrespective of causality attribution were peripheral edema (51%) and nausea (45%). Grade 3 or 4 adverse events regardless of causality were reported in 67% of patients.

Treatment-related serious adverse events occurred in 13%. Treatment-related adverse events led to discontinuation of treatment in 11%, with causes including peripheral edema (2%). Overall, 23% of patients had an adverse event regardless of causality that led to dose reduction. One death—due to pneumonitis—was considered related to treatment.

The investigators concluded, “Capmatinib 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.”

Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.