{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tian J"],"funding":["NIDDK NIH HHS","EIF | Stand Up To Cancer","U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute","NCI NIH HHS"],"pagination":["458-466"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9941044"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(2)"],"pubmed_abstract":["While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF<sup>V600E</sup> colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF<sup>V600E</sup> CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431."],"journal":["Nature medicine"],"pubmed_title":["Combined PD-1, BRAF and MEK inhibition in BRAF<sup>V600E</sup> colorectal cancer: a phase 2 trial."],"pmcid":["PMC9941044"],"funding_grant_id":["R01 CA208756","SU2C-AACR-DT22-17","U54 CA224068","T32 CA207021","K99 CA259511","U54CA224068","P50 CA127003","R00 CA259511","P30 DK043351"],"pubmed_authors":["Spurrell M","Hess J","Siravegna G","Corcoran RB","Huang M","Chen JH","McCleary NJ","Chi G","Michel AG","Yurgelun MB","Clark JW","Oka T","Wong E","Gemma AJ","Pelka K","Ryan DP","Braverman J","Baiev I","Burke K","Leary R","Jorgji V","Tian J","Allen JN","Fetter IJ","Sindurakar P","Abrams TA","Giannakis M","Campbell CD","Yilmaz O","Enzinger PC","Van Seventer EE","Demehri S","Klempner SJ","Kanter K","Chao SX","Bradford WB","Sharpe A","Mehta A","Jarnagin J","Parikh AR","Hacohen N","Getz GA","Lieb D","Enzinger AC","Meyerhardt JA"],"additional_accession":[]},"is_claimable":false,"name":"Combined PD-1, BRAF and MEK inhibition in BRAF<sup>V600E</sup> colorectal cancer: a phase 2 trial.","description":"While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF<sup>V600E</sup> colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF<sup>V600E</sup> CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Feb","modification":"2026-05-29T13:01:00.305Z","creation":"2025-02-19T04:46:24.8Z"},"accession":"S-EPMC9941044","cross_references":{"pubmed":["36702949"],"doi":["10.1038/s41591-022-02181-8"]}}