Abstract
Capmatinib may be effective in patients with advanced non–small cell lung cancer who have MET exon 14 skipping mutations. In the phase II GEOMETRY mono-1 trial, the drug elicited high overall response rates and relatively durable responses in newly diagnosed and previously treated patients, including those with brain metastases.
Capmatinib (INC280; Novartis) may soon be an option for patients with advanced non–small cell lung cancer (NSCLC) who have MET exon 14 skipping mutations: In a phase II trial, the drug elicited high overall response rates (ORR) and relatively durable responses in newly diagnosed and previously treated patients, including those with brain metastases. Because it may be significantly more effective than existing therapies, capmatinib has been granted priority review by the FDA.
The findings were presented at the American Association for Cancer Research Virtual Annual Meeting I: April 27–28, 2020.
The 3% to 4% of patients with NSCLC who have MET exon 14 skipping mutations tend to have poor responses to standard treatments—including chemotherapy and immunotherapy—compelling researchers to investigate new therapeutic options. A highly selective MET inhibitor, capmatinib demonstrated anticancer activity in preclinical models and appeared to cross the blood–brain barrier in rats and monkeys. “The in vitro and in vivo activity has been impressive,” said Edward Garon, MD, of the University of California, Los Angeles, who presented the results.
The GEOMETRY mono-1 trial enrolled patients with MET-altered advanced NSCLC who lacked EGFR and ALK mutations, including those with stable or asymptomatic brain metastases. Garon reported on two cohorts with MET exon 14 skipping mutations: one included patients who had received prior therapies, and patients in the other were newly diagnosed.
The 69 previously treated patients had an ORR of 40.6% and a disease control rate (DCR) of 78.3%; responses lasted for a median of 9.7 months. The 28 newly diagnosed patients had an ORR rate of 67.9%, with a DCR of 96.4%; responses lasted for a median of 11.1 months. Of 13 evaluable patients with brain metastases, seven had a response in the brain, including four patients with complete resolution of brain lesions. A safety analysis of 334 patients in the trial revealed that 35.6% experienced side effects classified as grade 3 or 4, most commonly swelling of the extremities.
Based on these findings, capmatinib was granted a breakthrough therapy designation by the FDA last year for patients with NSCLC and MET exon 14 skipping mutations, and it could soon be approved for this indication.
“The results of the GEOMETRY study will undoubtedly change the therapeutic landscape for patients with MET exon 14 skipping mutations—in the study, capmatinib elicited meaningful and durable responses,” said Benjamin Levy, MD, of Johns Hopkins University in Baltimore, MD, and Washington, DC, who was not involved in the trial. He added that he was most impressed by the high response rate in newly diagnosed patients. “While these numbers are small, these results highlight the critical role of identifying MET exon 14 skipping mutations through next-generation sequencing in all patients with advanced NSCLC,” he said.
Study discussant Taofeek Owonikoko, MD, PhD, of the Winship Cancer Institute at Emory University in Atlanta, GA, emphasized that capmatinib “also showed a very encouraging signal of efficacy against intracranial metastases.” He's now curious to know whether the drug can prevent or delay development of new brain metastases.
Although cross-trial comparisons are difficult, Levy noted that response rates for capmatinib in patients with NSCLC and MET exon 14 skipping mutations appear comparable to those elicited by the multikinase inhibitor crizotinib (Xalkori; Pfizer). Future studies should investigate optimal drug sequencing in these patients, he said.
Another area for further study, Owonikoko said, is drug resistance. He pointed out that most responses to capmatinib lasted less than a year, which “highlights the need to better understand mechanisms of resistance.” One possible route for overcoming resistance, he added, is combining capmatinib with drugs in other classes, such as angiogenesis inhibitors, immune checkpoint inhibitors, and agents that target EGFR or RAS. Trials for some of these combinations are under way. –Catherine Caruso
