GEOMETRY Mono-1 Study: Capmatinib in MET Exon 14–Mutated or MET-Amplified NSCLC

Researchers report higher overall response rate, median duration of response, and median progression-free survival in treatment-naïve patients with a MET exon 14 skipping mutation compared with previously treated patients.

MET exon 14 skipping mutations are present in approximately 3% to 4% of patients with non–small-cell lung cancer (NSCLC), and are predictive of poor prognosis. Capmatinib is an oral kinase inhibitor that inhibits MET and has shown promising efficacy in patients with MET-dysregulated NSCLC. The phase 2 GEOMETRY mono-1 trial evaluated the efficacy and safety of capmatinib in patients with advanced NSCLC with a MET exon 14 skipping mutation or MET amplification.

A total of 364 patients with MET-dysregulated advanced disease were assigned to cohorts based on previous lines of therapy and MET exon 14 skipping mutation (N = 97) or MET amplification (N = 210) according to gene copy number in tumor tissue. Patients received capmatinib 400 mg twice daily. Those who were previously treated had received ≤2 lines of prior therapy. The primary end point was overall response rate (ORR; complete or partial response) based on Response Evaluation Criteria in Solid Tumours version 1.1, as assessed by an independent review committee blinded to cohort assignments. Secondary end points included investigator-assessed response and duration of response (DOR), time to response, disease control (defined as best overall response [complete response, partial response, or stable disease]), progression-free survival (PFS), safety, and pharmacokinetics.

In patients with a MET exon 14 skipping mutation, the ORR was 41% (95% confidence interval [CI], 29%-53%) in those who were previously treated (N = 69) and 68% (95% CI, 48%-84%) in those who were treatment-naïve (N = 28); the median DOR was 9.7 months (95% CI, 5.6-13.0 months) and 12.6 months (95% CI, 5.6 months-not estimable), respectively. The tumor response rate at first evaluation after the start of treatment was 82% in previously treated patients and 68% in treatment-naïve patients. The median PFS was 5.4 months (95% CI, 4.2-7.0 months) in pretreated patients and 12.4 months (95% CI, 8.2 months-not estimable) in treatment-naïve patients.

In patients with MET amplification, the ORR was 12% (95% CI, 4%-26%) in those who had tumor tissue with a gene copy number of 6 to 9, 9% (95% CI, 3%-20%) in those who had tumor tissue with a gene copy number of 4 or 5, and 7% (95% CI, 1%-22%) in those who had tumor tissue with a gene copy number <4; the ORR was 29% (95% CI, 19%-41%) in those who were previously treated (N = 69) and 40% (95% CI, 16%-68%) in those who were treatment-naïve (N = 15). The median DOR was 8.3 months in previously treated patients and 7.5 months in treatment-naïve patients. The median PFS was 4.1 months (95% CI, 2.9-4.8) in pretreated patients and 4.2 months (95% CI, 1.4-6.9) in treatment-naïve patients.

The most common adverse events (AEs) of any grade across all cohorts were peripheral edema (51%), nausea (45%), vomiting (28%), and increased creatinine (24%). Most AEs were grade 1/2, and 67% of patients had grade 3/4 AEs. A total of 83 (23%) patients had ≥1 AEs leading to dose reduction, and 39 (11%) had AEs leading to treatment discontinuation.

The researchers concluded that capmatinib showed efficacy, with a good safety profile, and may offer benefit in patients with MET exon 14–mutated or MET-amplified NSCLC.

Reference
Wolf J, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383:944-957.