2026-04-14T05:41:36Zhttps://recercat.cat/oai/requestoai:recercat.cat:11351/131182025-06-14T04:13:30Zcom_2072_378070com_2072_378040col_2072_378092
RECERCAT
author
Aroldi, Francesca
author
Elez, Elena
author
Perkins, Géraldine
author
Popovici, Vlad
author
André, Thierry
author
Prenen, Hans
author
Tabernero, Josep
2025-06-14T04:13:30Z
2025-06-14T04:13:30Z
2025-05-22T08:01:50Z2025-05-22T08:01:50Z2025-04-10
http://hdl.handle.net/11351/13118
Colorectal cancer; MET biomarker; PharmacokineticsCáncer colorrectal; Biomarcador MET; FarmacocinéticaCàncer colorectal; Biomarcador MET; FarmacocinèticaBackground
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).Supported by MErCuRIC, funded by the European Commission’s Framework Programme 7 (contract #602901), grants from Pfizer and the Tom Simms Memorial Fund (QUB/SVS). Cancer Research UK (C13749/A7261) (SVS).
Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
Còlon - Càncer - Tractament
Recte - Càncer - Tractament
Avaluació de resultats (Assistència sanitària)
Anomalies cromosòmiques
Posologia
Quimioteràpia combinada
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Prognosis::Treatment Outcome
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols
DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::pronóstico::resultado del tratamiento
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada
A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC)
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion