Combined BRAF, EGFR, and MEK Inhibition in Patients with -Mutant Colorectal Cancer.

Although BRAF inhibitor monotherapy yields response rates >50% in -mutant melanoma, only approximately 5% of patients with colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in 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 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 and mutations on disease progression. Thus, targeting adaptive feedback pathways in colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with colorectal cancer. Our findings highlight the MAPK pathway as a critical target in colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. .