Early Activity Observed With Capmatinib in Advanced NSCLC

Todd Bauer, MD

The c-MET inhibitor capmatinib (INC280) demonstrated early signals of efficacy with an overall response rate (ORR) of 20% when administered to patients with advanced c-MET—dysregulated non–small cell lung cancer (NSCLC), according to results of an ongoing phase I trial that were presented during the 2016 International Association for the Study of Lung Cancer (IASLC) Multidisciplinary Symposium on Thoracic Oncology.¹

In the open-label study, which includes dose-escalation and dose-expansion phases, researchers are exploring the highly potent selective c-MET inhibitor across multiple settings (NCT01324479). Following the completed dose-escalation phase for the NSCLC indication, the recommended phase II dose was 400 mg twice daily of capmatinib.

The 2 expansion cohorts, which assessed the predictive value of both c-MET overexpression and amplification through a range of gene copy numbers (GCN), were comprised of all-comer patients with NSCLC dysregulated in c-MET (n = 26) and EGFR wild-type c-MET immunohistochemistry (IHC) 3+ disease (n = 29).

“By looking at those different biomarkers, we can really push the development of capmatinib ahead, we can spare patients who aren’t likely to respond to the drug from going on it, and we can find the patients who are more likely to respond to capmatinib and put them on it,” said study author Todd Bauer, MD, associate director of Drug Development, Sarah Cannon Research Institute, in an interview with OncLive during the IASLC meeting.

The primary endpoint was maximum-tolerated dose, safety, and tolerability, while secondary endpoints were overall response rate (ORR) in the EGFR wild-type cohort; the type, frequency, and severity of adverse events (AEs); and progression-free survival (PFS), duration of response, and disease-control rate. Enrolled patients harbored c-MET dysregulation, which was defined as an H-score >150, a ratio of c-MET/centromere >2.0, c-MET GCN >5, >50% of tumor cells with IHC score 2+ or 3+.

As of the data cut-off date on March 15, 2016, 55 patients had been enrolled in the expansion groups. The median age was 60.

Through investigator assessment, partial responses were observed in 11 evaluable patients with NSCLC with a 20% ORR (95% CI, 10.4-33). In the patients with c-MET IHC 3+ disease, the ORR was 24% (95% CI, 11.8-41.2). Patients with a c-MET gene copy number >6 had a 47% ORR (95% CI, 21.3-73.4).

“This suggests that gene copy number is a stronger predictor of response to capmatinib than simply c-MET IHC disease,” said Bauer during a presentation of the results at the meeting.

The median PFS for all patients with NSCLC was 3.6 months (95% CI, 1.84-7.33), and 7.4 months for patients with c-MET GCN >6 (95% CI, 3.84-22.11).

Through a retrospective next-generation sequencing analysis, 4 patients were identified to have a c-MET exon 14 skipping mutation. Three of these patients had a confirmed PR and 1 patient had stable disease.

“One of the unique things about this study is we looked at different ways to measure dysregulation of c-MET, whether it was just by overexpression, through IHC gene copy number looking at amplification, or whether it was by mutation,” said Bauer during the interview. “We were able to look back at the majority of patients on the study and determined what was most important to tell us who is going to respond. In looking for biomarker-driven therapies, does it matter if you can find it on IHC? Maybe some. Does it matter if you find it with gene copy number? Absolutely. Does it matter if you find it in a mutation? Most definitely.”

Forty-two patients (76%) discontinued treatment. Reasons for stopping treatment included disease progression (51%), AEs (18%), or withdrawal of consent (7%). Treatment is ongoing in 13 patients (24%).

The most common AEs were of low grade and grade 3/4 AEs occurred in less than 10% of patients. Grade 3/4 treatment-related AEs consisted of nausea (4%), peripheral edema (2%), and fatigue (4%). All-grade treatment-related toxicities included nausea (40%), peripheral edema (26%), vomiting (29%), decreased appetite (16%), fatigue (20%), and blood creatinine increase (9%).

“Capmatinib is a very specific c-MET inhibitor,” Bauer said. “Crizotinib (Xalkori), we know, is designed as a c-MET inhibitor and happens to hit ALK pretty well, also. It’s a good c-MET inhibitor, also, but the precision of which capmatinib hits c-MET is pretty high, and that really reduces the side effects that we don’t want to see that sometimes the other TKIs demonstrate.”

c-MET dysregulation, commonly reported as c-MET amplification, overexpression, or mutation leading to deletion of exon 14, is a negative prognostic factor in patients with NSCLC.

The efficacy of capmatinib in c-MET dysregulated advanced NSCLC is being explored prospectively in the ongoing international phase II GEOMETRYmono-1 trial (NCT0241439).

Reference

1. Schuler M, Berardi R, Lim WT, et al. Phase I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients with advanced cMET+ NSCLC. Presented at: 2016 IASLC Multidisciplinary Symposium on Thoracic Oncology; Chicago, Illinois, September 22-24, 2016.