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

作者：Francesca Aroldi, Elena Élez, Thierry André, Géraldine Perkins, Hans Prenen, Vlad Popovici, Peter F. Gallagher, Jennifer Houlden, Linda Collins, Corran Roberts, Christian Rolfo, Federica Di Nicolantonio, Margaret Grayson, Ruth Boyd, Karolien Bettens, Jurgen Del‐Favero, Victoria Coyle, Mark Lawler, Hajrah Khawaja, Pierre Laurent‐Puig, Manuel Salto‐Tellez, Tim Maughan, Josep Tabernero, Richard Adams, Robin L. Jones, Bryan T. Hennessy, Alberto Bardelli, Marc Peeters, Mark R. Middleton, R. H. Wilson, Sandra Van Schaeybroeck · 发表于：BMC Cancer · 年份：2025 · DOI：10.1186/s12885-025-14068-1 · 被引用次数：5 · 研究领域：Colorectal Cancer Treatments and Studies、Liver physiology and pathology、Melanoma and MAPK Pathways

BACKGROUND: Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients. METHODS: In the dose escalation phase, patients with advanced solid tumours 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, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. RESULTS: Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1-21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) wer...