Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial.
Клиническое исследование II фазыСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Tian Jun, Chen Jonathan H, Chao Sherry X, Pelka Karin, Giannakis Marios, Hess Julian, Burke Kelly, Jorgji Vjola, Sindurakar Princy, Braverman Jonathan, Mehta Arnav, Oka Tomonori, Huang Mei, Lieb David, Spurrell Maxwell, Allen Jill N, Abrams Thomas A, Clark Jeffrey W, Enzinger Andrea C, Enzinger Peter C, Klempner Samuel J, McCleary Nadine J, Meyerhardt Jeffrey A, Ryan David P, Yurgelun Matthew B, Kanter Katie, Van Seventer Emily E, Baiev Islam, Chi Gary, Jarnagin Joy, Bradford William B, Wong Edmond, Michel Alexa G, Fetter Isobel J, Siravegna Giulia, Gemma Angelo J, Sharpe Arlene, Demehri Shadmehr, Leary Rebecca, Campbell Catarina D, Yilmaz Omer, Getz Gad A, Parikh Aparna R, Hacohen Nir, Corcoran Ryan B
Аннотация
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. ClinicalTrials.gov registration: NCT03668431.