Combined BRAF, EGFR, and MEK Inhibition in Patients with <i>BRAF</i> V600E-Mutant Colorectal Cancer

Although BRAF inhibitor monotherapy yields response rates >50% in <i>BRAF</i>^V600-mutant melanoma, only approximately 5% of patients with <i>BRAF</i>^V600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in <i>BRAF</i>^V600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with <i>BRAF</i>^V600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of <i>KRAS</i> and <i>NRAS</i> mutations on disease progression. Thus, targeting adaptive feedback pathways in <i>BRAF</i>^V600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.<b>Significance:</b> This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with <i>BRAF</i>^V600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in <i>BRAF</i>^V600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. <i>Cancer Discov; 8(4); 428-43. ©2018 AACR.</i><i>See related commentary by Janku, p. 389</i><i>See related article by Hazar-Rethinam et al., p. 417</i><i>This article is highlighted in the In This Issue feature, p. 371</i>.