A phase Ib study evaluating the c-MET inhibitor INC280 (capmatinib) in combination with bevacizumab in patients with high-grade glioma.

Background: To improve survival in patients with high-grade glioma, INC280 (capmatinib) a highly selective and potent oral inhibitor of the MET receptor with robust central nervous system (CNS) penetration, was evaluated in combination with bevacizumab (BEV). Methods: There were 2 phases, dose-escalation (3+3 design) and dose-expansion, which included patients (1) who progressed during or after first-line therapy (no prior BEV), (2) who progressed during or after second-line therapy with BEV, and (3) who had unresectable high-grade glioma (no prior BEV). Results: Sixty-four patients with high-grade glioma were treated; 18 in escalation cohorts and 46 in expansion Cohorts A (21), B (15), and C (10). The maximum-tolerated dose (MTD) was not reached and the RP2D was 400 mg capmatinib PO BID (800 mg daily). Treatment continued for a median of 14 weeks and up to ~6 years in one patient. Common treatment-related adverse events (65% ≤ Grade 2) included fatigue, peripheral edema, nausea, diarrhea, ALT increased, and constipation. Headaches and seizures occurred in 11 patients; Grade 3+ events included Grade 3 headache (1) and Grade 3 seizures (4). There were no treatment-related deaths. The 12 responders to treatment (2 CRs [1 pt in escalation and 1 pt in Cohort A] and 10 PRs [2 pts in escalation and A = 6, B = 1, and C = 1]) had a median duration of response of 9.2 months. Two patients with durable responses (CR >5 years, PR >1 year) did not harbor baseline c-MET alterations. Conclusion: Capmatinib + BEV was well-tolerated but had no clear signal of activity in c-MET non-activated high-grade glioma.