2026-04-13T02:42:20Zhttps://recercat.cat/oai/requestoai:recercat.cat:11351/113332024-12-20T03:24:11Zcom_2072_378070com_2072_378040col_2072_378092
RECERCAT
author
Middleton, Mark
author
Chau, Ian
author
Alkuzweny, Baha
author
Elez, Elena
author
Cubillo, Antonio
author
García-Alfonso, Pilar
2024-06-06T08:37:48Z
2024-06-06T08:37:48Z
2024-04-17T06:21:02Z2024-04-17T06:21:02Z2024-04-11
http://hdl.handle.net/11351/11333
Binimetinib; Colorectal cancer; IpilimumabBinimetinib; Càncer colorectal; IpilimumabBinimetinib; Cáncer colorrectal; IpilimumabBackground
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.
Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
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
Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion