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).

• Klíčová slova
• Binimetinib, Colorectal cancer, Crizotinib, CtDNA, MET biomarker, Pharmacodynamics, Pharmacokinetics, Phase I, RAS mutant,
• MeSH
• benzimidazoly * aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• dospělí MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• kolorektální nádory * farmakoterapie   genetika   patologie   MeSH
• krizotinib * aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• MAP kinasa-kinasa 1 antagonisté a inhibitory   MeSH
• MAP kinasa-kinasa 2 antagonisté a inhibitory   MeSH
• maximální tolerovaná dávka MeSH
• mutace MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   farmakokinetika   aplikace a dávkování   MeSH
• protoonkogenní proteiny c-met antagonisté a inhibitory   genetika   MeSH
• Ras proteiny genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• Názvy látek
• benzimidazoly * MeSH
• binimetinib MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• krizotinib * MeSH
• MAP kinasa-kinasa 1 MeSH
• MAP kinasa-kinasa 2 MeSH
• MAP2K1 protein, human MeSH Prohlížeč
• MAP2K2 protein, human MeSH Prohlížeč
• MET protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-met MeSH
• Ras proteiny MeSH