Sistema de Salut de Catalunya
Institut Català de la Salut
[Elez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Cubillo A] Centro Integral, Oncológico Clara Campal, HM CIOCC, Madrid, Spain. Facultad HM Hospitales de Ciencias de La Salud UCJC, Madrid, Spain. [Garcia Alfonso P] Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain. [Middleton MR] Department of Oncology, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. [Chau I] Gastrointestinal Unit, Royal Marsden Hospital, London & Surrey, UK. [Alkuzweny B] Formerly Pfzer, Inc, San Diego, CA, USA
Vall d'Hebron Barcelona Hospital Campus
2024-04-17T06:21:02Z
2024-04-17T06:21:02Z
2024-04-11
Binimetinib; Colorectal cancer; Ipilimumab
Binimetinib; Càncer colorectal; Ipilimumab
Binimetinib; Cáncer colorrectal; Ipilimumab
Background In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). Methods In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. Results In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. Conclusions The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.
This study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019, in collaboration with Bristol Myers Squibb.
Article
Published version
English
Anomalies cromosòmiques; Còlon - Càncer - Tractament; Recte - Càncer - Tractament; Quimioteràpia combinada; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation; DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms; Other subheadings::Other subheadings::Other subheadings::/drug therapy; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada
BMC
BMC Cancer;24(1)
https://doi.org/10.1186/s12885-024-12153-5
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
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