학술논문
Combined PD-1, BRAF and MEK inhibition in BRAFV600Ecolorectal cancer: a phase 2 trial
Document Type
Article
Author
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.
Source
Nature Medicine; February 2023, Vol. 29 Issue: 2 p458-466, 9p
Subject
Language
ISSN
10788956; 1546170X
Abstract
While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600Ecolorectal 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 BRAFV600ECRC. 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.