biostudies-literatureTian JNIDDK NIH HHSEIF | Stand Up To CancerU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS458-466https://www.ebi.ac.uk/biostudies/studies/S-EPMC9941044biostudies-literatureUnknown29(2)While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF^V600E 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^V600E 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.Nature medicineCombined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: a phase 2 trial.PMC9941044R01 CA208756SU2C-AACR-DT22-17U54 CA224068T32 CA207021K99 CA259511U54CA224068P50 CA127003R00 CA259511P30 DK043351Spurrell MHess JSiravegna GCorcoran RBHuang MChen JHMcCleary NJChi GMichel AGYurgelun MBClark JWOka TWong EGemma AJPelka KRyan DPBraverman JBaiev IBurke KLeary RJorgji VTian JAllen JNFetter IJSindurakar PAbrams TAGiannakis MCampbell CDYilmaz OEnzinger PCVan Seventer EEDemehri SKlempner SJKanter KChao SXBradford WBSharpe AMehta AJarnagin JParikh ARHacohen NGetz GALieb DEnzinger ACMeyerhardt JAfalseCombined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: a phase 2 trial.While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF^V600E 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^V600E 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: NCT03668431.2023-01-01T00:00:00Z2023 Feb2026-05-29T13:01:00.305Z2025-02-19T04:46:24.8ZS-EPMC99410443670294910.1038/s41591-022-02181-8