A Phase Ia/b study of MEK1/2 inhibitor Binimetinib with MET inhibitor Crizotinib in patients with RAS mutant colorectal cancer (MErCuRIC)

Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. This dose escalation/expansion study aimed to assess safety and initial efficacy of the MEK1/2 inhibitor Binimetinib with MET inhibitor Crizotinib in RASMT CRC patients. Methods: In the dose escalation phase, patients with advanced solid tumors received Binimetinib with Crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics and skin/tumor biopsies were collected. Results: Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was Binimetinib 30mg B.D, days 1-21 every 28 days, with Crizotinib 250mg O.D continuously. Dose-limiting toxicities included grade 3 or greater transaminitis, creatinine phosphokinase increases, and fatigue. Thirty-six RASMT CRC patients were enrolled in the dose expansion. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhea (51.8%) with grade 3 or greater TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Conclusions: Combination Binimetinib/PF-02341066 showed poor tolerability with no objective responses observed in RASMT CRC patients.