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

Aroldi, Francesca, Elez, Elena, André, Thierry, Perkins, Geraldine, Prenen, Hans, Popovici, Vlad, Gallagher, Peter, Houlden, Jennifer, Collins, Linda, Roberts, Corran, Rolfo, Christian, Di Nicolantonio, Federica, Grayson, Margaret, Boyd, Ruth, Bettens, Karolien, Delfavero, Jurgen, Coyle, Victoria, Lawler, Mark, Khawaja, Hajrah, Laurent-Puig, Pierre, Salto-Tellez, Manuel, Maughan, Tim S., Tabernero, Josep, Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Hennessy, Bryan T., Bardelli, Alberto, Peeters, Marc, Middleton, Mark R., Wilson, Richard H. and Van Schaeybroeck, Sandra 2025. A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC). BMC Cancer 25 (1) , 658. 10.1186/s12885-025-14068-1

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Abstract

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) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency. Conclusions: Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	BioMed Central
Date of First Compliant Deposit:	20 May 2025
Date of Acceptance:	1 April 2025
Last Modified:	20 May 2025 10:51
URI:	https://orca.cardiff.ac.uk/id/eprint/178373

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