The Lynx Group

Capmatinib Shows Substantial Antitumor Activity in Treatment-Naïve Patients with Metastatic NSCLC and MET Exon 14 Mutations

October 2020, Vol 11, No 5

Capmatinib (Tabrecta), a selective inhibitor of the mesenchymal-epithelial transition (MET) receptor, showed significant antitumor activity in patients with metastatic non–small-cell lung cancer (NSCLC) and gene mutations that lead to MET exon 14 skipping, according to the results of a recently published study (Wolf J, et al. N Engl J Med. 2020;383:944-957).

Capmatinib showed strong efficacy in patients with metastatic NSCLC and a mutation in the MET exon 14 skipping gene who had not received any previous treatment. In addition, capmatinib showed increased benefit in patients whose tumor was associated with a higher gene copy number than in those with a lower gene copy number.

“Although these efficacy results need confirmation in a larger population, the results are similar to those reported with effective, established targeted therapies for NSCLC,” Jürgen Wolf, MD, and colleagues wrote.

Mutations in the MET exon 14 skipping gene occur in 3% to 4% of patients with NSCLC, and MET amplifications occur in 1% to 6% of patients with NSCLC. The prognosis is poor in patients with NSCLC who harbor a MET exon 14 skipping mutation and receive standard treatments, including immunotherapies, according to the study’s investigators.

Based on this study’s results, in May 2020 capmatinib was approved by the FDA as the first targeted therapy indicated for the treatment of adults with metastatic NSCLC and gene mutations that lead to MET exon 14 skipping.

Study Details

The multicohort phase 2 GEOMETRY mono-1 clinical trial included 364 patients with MET-dysregulated advanced NSCLC who were assigned to a treatment cohort with capmatinib based on previous lines of therapy and their MET status, which consisted of MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue. All patients received oral capmatinib 400 mg twice daily. Cohorts 1 through 5 received capmatinib under fasting conditions, whereas cohorts 6 and 7 received it without fasting restrictions.

The study’s primary end point was overall response rate (ORR), including complete or partial response. The key secondary end point was duration of response; an independent review committee assessed the results.

Of the 69 patients with metastatic NSCLC and a MET exon 14 skipping mutation who had received 1 or 2 previous lines of therapy, the ORR was 41% (95% confidence interval [CI], 29-53). By comparison, among the 28 treatment-naïve patients, the ORR was 68% (95% CI, 48-84).

The median duration of response was 9.7 months (95% CI, 5.6-13.0) in patients who had previously received therapy for this indication compared with 12.6 months (95% CI, 5.6-not estimable) in treatment-naïve patients with metastatic NSCLC.

The benefit of capmatinib was limited among previously treated patients with advanced NSCLC and MET amplification. The ORR was 12% (95% CI, 4-26) in patients who had received previous treatment and whose tumor tissue showed a gene copy number of 6 to 9; 9% (95% CI, 3-20) in patients with a gene copy number of 4 or 5; and in 7% (95% CI, 1-22) of patients with a gene copy number <4. At the interim analysis, these cohorts were discontinued, because of insufficient response to treatment with capmatinib.

By contrast, the ORR was 29% (95% CI, 19-41) in the 69 patients with MET amplification and a gene copy number ≥10. Moreover, the ORR was 40% (95% CI, 16-68) among the 15 treatment-naïve patients.

Adverse Events

The most common adverse events reported were peripheral edema (51%) and nausea (45%); the majority of these events, however, were grade 1 or 2 in severity.

“Our results and those from previous trials confirm that MET exon 14 skipping mutations constitute a valid biomarker for the selection of patients for MET-directed treatment,” the investigators wrote.

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