Capmatinib showed substantial antitumor activity in patients with advanced non-small cell lung cancer (NSCLC) with a MET exon 14 skipping mutation, particularly in those who were not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumours with a high gene copy number than in those with a low gene copy number. Low-grade peripheral oedema and nausea were the main side effects. The results from the GEOMETRY mono-1 study are published by Dr. Jürgen Wolf of the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne in Cologne, Germany and colleagues on 3 September 2020 in The New England Journal of Medicine.
The authors wrote in the study background that MET exon 14 skipping mutations occur in approximately 3-4% of patients with NSCLC, typically in the absence of other driver mutations and are associated with a poor prognosis. MET amplification occurs in 1-6% of patients with NSCLC.
Capmatinib is a highly potent and selective inhibitor of the MET receptor. It has shown activity in cancer models with various types of MET activation. In addition, capmatinib crosses the blood–brain barrier. Preliminary clinical data showed low grade side effects and a promising efficacy as monotherapy in patients with MET dysregulated NSCLC.
The GEOMETRY mono-1 study investigators conducted a multiple-cohort, phase II study to evaluate capmatinib in patients with MET dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status, in particular with MET exon 14 skipping mutation or MET amplification according to gene copy number in tumour tissue. The primary endpoint was overall response (complete or partial response) and the key secondary endpoint was response duration. Both endpoints were assessed by an independent review committee.
The study team assigned 364 patients to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was 41% (95% confidence interval [CI], 29 to 53) in patients who had received one or two lines of therapy previously and 68% (95% CI, 48 to 84) in patients who had not received treatment previously. 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 7-12% 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 activity of capmatinib in the brain was encouraging; responses were observed in 7 of 13 patients with NSCLC with a MET exon 14 skipping mutation, including complete resolution of brain metastases in 4 patients. A total of 3 of the 7 patients with a response had received radiotherapy previously, which could have contributed to responses in brain metastases. Confirmation of these findings in larger populations of patients are needed.
The most frequently reported adverse events were peripheral oedema (51%) and nausea (45%). However, these events were mostly of grade 1 or 2 and were reversible with dose adjustments.
The study results confirm that MET exon 14 skipping mutations constitute a valid biomarker for the selection of patients for MET directed treatment. Previously crizotinib led to a response in 32% of patients with advanced NSCLC with a MET exon 14 skipping mutation, tepotinib recently led to a response in 46% of patients and savolitinib has also shown activity in this NSCLC subgroup.
Patients who have tumours with a MET exon 14 skipping mutation have a poor prognosis with standard therapies, including immunotherapies. The efficacy of capmatinib is significant because these patients are generally elderly and are thus more challenging to treat owing to a greater risk of side effects from first-line multidrug regimens.
The authors also commented that high concordance of detection of MET exon 14 skipping mutations by both RT-PCR testing and next-generation sequencing is particularly important.
The results of the GEOMETRY mono-1 study suggest that capmatinib may be a new therapeutic option in patients with advanced NSCLC with a MET exon 14 skipping mutation.
The study was funded by Novartis Pharmaceuticals.
Wolf J, Seto T, Han J-Y, et al. Capmatinib in MET Exon 14–Mutated or MET-Amplified Non–Small-Cell Lung Cancer. N Engl J Med 2020;383:944-57. DOI: 10.1056/NEJMoa2002787.