Capmatinib Shows Antitumor Activity in Advanced NSCLC with a MET exon 14 Skipping Mutation

According to a multiple-cohort, phase 2 study, published in The New England Journal of Medicine, capmatinib (Tabrecta) demonstrated substantial antitumor activity in patients with advanced non-small cell lung cancer (NSCLC) with a MET exon 14 skipping mutation, especially in those not treated previously.¹

Additionally, researchers found that the efficacy of capmatinib in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number.

“These results and the safety profile, involving mainly low-grade and reversible adverse events, suggest that capmatinib may be a new therapeutic option in patients with advanced NSCLC with a MET exon 14 skipping mutation,” the authors wrote.

In this study, patients were assigned to cohorts based on previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Participants received a 400 mg tablet of capmatinib twice daily. Overall, 364 patients were assigned to the cohorts.

The primary end point of the study was overall response (complete or partial response), and the key secondary end point was response duration. Notably, both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.

Of those with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% CI, 29 to 53) of 69 patients who had received 1 or 2 lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously. Moreover, 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.

“Among the patients with NSCLC with a MET exon 14 skipping mutation in our study, the difference in response between previously treated patients and patients who had not received treatment previously remains unexplained, although it is important to consider the limited number of patients and the overlapping 95% confidence intervals,” the authors noted. “An overall decline in health during longer durations of disease, as well as the evolution of resistant clones during first-line therapy, might contribute to this observation.”

Further, 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). Of the 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 adverse events (AEs) most frequently reported in the overall study population were peripheral edema (51%) and nausea (45%). However, the majority of these events were mostly of grade 1 or 2.

Senior author Rebecca Suk Heist, MD, an investigator in the MGH Cancer Center and associate professor of Medicine at Harvard Medical School, indicated that these study findings emphasize the importance of broad molecular profiling before deciding on the first line of therapy in this patient population.²

“There are many advances in NSCLC treatment that are helping people live longer and better with their disease, and it is really important that all newly diagnosed patients with NSCLC get broad molecular profiling to determine what their optimal first-line therapy should be,” Heist said in a press release. “If we don’t test, we don’t know.”

Heist also explained that MET exon 14 skipping and amplification join a number of other drivers of NSCLC for which targeted therapies have been developed. “It is critically important that all patients have their lung cancers tested for these to know whether there is a targeted treatment option or not,” she concluded.

References:

1. Wolf J, Seto T, Han JY, et al. Capmatinib in MET Exon 14–Mutated or MET-Amplified Non–Small-Cell Lung Cancer. The New England Journal of Medicine. doi: 10.1056/NEJMoa2002787

2. Clinical trial finds targeted drug effective in patients who have lung cancer with certain gene mutations [news release]. Boston. Published September 8, 2020. Accessed September 9, 2020. https://www.massgeneral.org/news/press-release/Clinical-trial-finds-targeted-drug-effective-in%20patients-who-have-lung-cancer-with-certain-gene-mutations