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).

Cardiff University and Velindre University NHS Trust Cardiff CF14 2 TL UK

Centre for Statistics in Medicine Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK

Department of GI Oncology Hôpital Européen Georges Pompidou 75015 Paris France

Department of Medical Oncology Sorbonne Université Hôpital Saint Antoine 75012 Paris France

Department of Medical Oncology University of Antwerp Antwerp University Hospital 2610 Wilrijk Belgium

Department of Molecular and Clinical Cancer Medicine University of Liverpool Ashton St Liverpool L69 3GE UK

Department of Oncology and University of Torino Candiolo Cancer Institute 10060 Candiolo TO Italy

Department of Oncology Molecular Biotechnology Center University of Torino Turin Italy

Department of Oncology University of Oxford Old Road Campus Research Building Roosevelt Drive Oxford OX3 7DQ UK

Faculty of Science RECETOX Masaryk University 625 00 Brno Czech Republic

Genomics Diagnostics and Genomics Group Agilent Technologies 1831 Diegem Belgium

IFOM ETS the AIRC Institute of Molecular Oncology Milan Italy

Institut National de La Sante Et de La Recherche Medicale Universite Paris Descartes 75006 Paris France

Northern Ireland Cancer Centre Belfast Health and Social Care Trust Belfast BT9 7 AB UK

Oncology Clinical Trials Office Department of Oncology University of Oxford Oxford OX3 7LJ UK

Patrick G Johnston Centre for Cancer Research School of Medicine Dentistry and Biomedical Science Queen's University Belfast Belfast BT9 7AE UK

Royal College of Surgeons in Ireland University of Medicine and Health Sciences 123 St Stephen's Green Dublin Ireland

Vall d'Hebron University Hospital and Institute of Oncology 08035 Barcelona Spain

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