Multicenter phase 2 trial of combined inhibition of PD-1, BRAF and MEK for BRAF V600E mutated colorectal cancer
Prof. Nir Hacohen
BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer. However, respons rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. A multicenter phase 2 trial evaluated combined inhibition of PD-1, BRAF, and MEK with spartalizumab, dabrafenib, and trametinib in patients with BRAFV600E CRC. The primary end point was overall response rate. This end point was met with a confirmed response rate of 24.3% and durability of response that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of paired pretreatment an 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. The authors conclude that these data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response.