In lung cancer, the historic absence of clear biomarkers to identify patients who could derive benefit from MET-specific therapy has kept the field from moving forward with potential therapies.
In lung cancer, the historic absence of clear biomarkers to identify patients who could derive benefit from MET-specific therapy has kept the field from moving forward with potential therapies. Today, after years of preclinical and late-phase development, capmatinib (Tabrecta) is an FDA-approved treatment for patients with non–small cell lung cancer (NSCLC) with MET exon 14 skipping.1
The journey to this FDA approval began with investigations of capmatinib as monotherapy in cell line- or patient-derived xenograft lung models.
The activity of the highly selective and potent MET inhibitor, capmatinib, correlated with some plausible genomic features in lung models, an early study showed.2 However, as monotherapy, few models had a response to capmatinib, which signaled to investigators that proper patient selection is vital for use of capmatinib in clinical trials. In addition, any limited response rationalized the idea of combining capmatinib with other kinase inhibitors to better target MET-driven lung cancers. First, capmatinib required confirmation as a single-agent in humans.
Patients with NSCLC and MET exon 14 skipping mutations represent 3% to 4% of the NSCLC patient population. The standard of care for these patients is immunotherapy, but such treatments have not significantly improved the poor prognosis in this NSCLC subgroup. Targeted therapy with capmatinib is a good option for these patients, simply because of its mechanism of action, Juergon Wolf, MD, explained in a prior interview with Targeted Oncology.
“The MET exon 14 skipping mutations have an influence on the half-life of the MET protein, and this is an oncogenic transformation because it’s a lower degradation of the protein, which means a longer half-life. This is the mechanism of action of capmatinib,” said Wolf, medical director, University Hospital Cologne.
Although capmatinib is not the only MET inhibitor under investigation, Wolf provided an explanation of what sets the drug apart from the others.
“There are several MET inhibitors now in clinical evaluation. If you compare capmatinib with the other MET inhibitors, capmatinib seems to be the most potent of those MET inhibitors.”
At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, a presentation from Wolf showed that the potency of capmatinib was 0.6 IC50 (nM) compared with 2.1 for savolitinib (AZD-6094), 3.0 for tepotinib (EMD 1214063), 7.8 for cabozantinib (Cabometyx), and 22.5 for crizotinib (Xalkori). Thus, investigators explored the efficacy and safety of capmatinib for the treatment of patients with NSCLC and MET 14 exon skipping in a phase 2 clinical trial (GEOMETRY mono-1; NCT02414139).3
The final analysis of the multicenter, non-randomized, open-label, multicohort
GEOMETRY- mono-1 trial were published in the New England Journal of Medicine after being presented by Wolf at the 2020 ASCO Virtual Annual Meeting. The study showed significant antitumor activity in patients treated with capmatinib, particularly those who were treatment naïve.4
The study included 364 patients with NSCLC and MET exon 14 skipping mutations who were assessed on treatment with capmatinib for the primary end point of overall response rate (ORR). The secondary end points were duration of response (DOR), time to response, disease control, progression-free survival (PFS), safety, and pharmacokinetics. To evaluate the end points, patients were dividedinto 7 cohorts. Previously-treated individuals with up to 2 prior lines of therapy were included in cohorts 1 through 4. Cohorts 5a and 5b included treatment-naïve patients. Patients in cohort 6 had MET amplifications and had received 1 prior line of therapy. Finally, cohort 7 included patients with MET exon 14 skipping mutations who were treatment naïve.
For the 69 patients in the study who received 1 or 2 lines of prior therapy, the ORR achieved with capmatinib was 41% (95% CI, 29%-53%). The ORR was higher among the treatment-naïve population of 28 patients at 68% (95% CI, 48%-84%). In response to these efficacy findings, Wolf said “this is comparable with what we already know from established trials and mutation-directed therapies.”
The safety profile of capmatinib in this study was tolerable with the majority of adverse events (AEs) being grade 1 and 2 in severity. These AEs were observed in ≥20% of patients. The most frequently reported treatment-related AEs were peripheral edema (54%), nausea (46%), vomiting 26%), and increased blood creatinine (33%).
These data overall suggested that capmatinib is a potential new therapeutic option for patients with MET exon 14 skipping-positive NSCLC. It was noted in the interview with Wolf, the unexpected finding was how the efficacy persisted in the subgroup of patients with brain metastases.
In the GEOMETRY mono-1 trial, brain metastases were present in 11% to 23% of the population. Still, responses were observed in 7 out of the 13 patients in the NSCLC MET exon 14 skipping group. The study investigators noted in the NEJM report that this finding is important, considering the central nervous system stability is essential for disease response. Wolf also noted that this finding was significant and will be researched further.
“For the confirmation of the brain activity, there are more trials being planned. I think that this is a very relevant issue because there is a substantial proportion of patients with brain [metastases] and this is a major factor that influences quality of life in these patients.”
Beyond the overall data from GEOMETRY mono-1 and the brain metastases subgroup of the study, capmatinib has also demonstrated efficacy in MET amplifications, another unexpected accomplishment that Wolf considered notable. Moving forward with capmatinib in MET-mutant NSCLC may involve improving outcomes in highly amplified patients, as well as understanding why there is such a significant difference in response between patients who were previously treated and those who were treatment naïve.
“In the future, we will try to develop capmatinib to the highly amplified subgroup of patients, as we start to understand the biology.”
1. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. US Food and Drug Administration. May 6, 2020. Accessed May 4, 2021. https://bit.ly/2UgrJiH
2. Baltschukat S, Engstler BS, Huang A, et al. Capmatinib (INC280) Is Active against models of non–small cell lung cancer and other cancer types with defined mechanisms of MET activation. Clin Cancer Res. 2019;25(10): 3164-3175. doi: 10.1158/1078-0432.CCR-18-2814
3. Wolf J, Seto T, Han JY, et al. Capmatinib (INC280) in MET ex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019 37 (suppl; abstr 9004). doi: 10.1200/JCO.2019.37.15_suppl.9004
4. Wolf J, Seto T, Han JY, et al. Capmatinib in MET Exon 14–mutated or MET-amplified non–small-cell lung cancer. N Engl J Med. 2020;383(10):944-57. doi: 10.1056/NEJMoa2002787