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Ref Type Journal Article
PMID (36702949)
Authors Tian J, Chen JH, Chao SX, Pelka K, Giannakis M, Hess J, Burke K, Jorgji V, Sindurakar P, Braverman J, Mehta A, Oka T, Huang M, Lieb D, Spurrell M, Allen JN, Abrams TA, Clark JW, Enzinger AC, Enzinger PC, Klempner SJ, McCleary NJ, Meyerhardt JA, Ryan DP, Yurgelun MB, Kanter K, Van Seventer EE, Baiev I, Chi G, Jarnagin J, Bradford WB, Wong E, Michel AG, Fetter IJ, Siravegna G, Gemma AJ, Sharpe A, Demehri S, Leary R, Campbell CD, Yilmaz O, Getz GA, Parikh AR, Hacohen N, Corcoran RB
Title Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial.
Abstract Text While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E 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 BRAFV600E 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. registration: NCT03668431.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Dabrafenib + Spartalizumab + Trametinib Phase II Actionable In a Phase II trial, the combination of Spartalizumab (PDR001), Tafinlar (dabrafenib), and Mekinist (trametinib) was well tolerated and resulted in a confirmed objective response rate of 24.3% (9/37, 2 complete responses), disease control rate of 70.3% (26/37), median progression-free survival of 4.3 months, median duration of response of 7.4 months, and median overall survival of 13.6 months in patients with metastatic colorectal cancer harboring BRAF V600E (PMID: 36702949; NCT03668431). 36702949