Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): Updated efficacy and biomarker analysis.

3517 Background: BRAF V600 mutations occur in 5-15% of metastatic CRC and predict poor prognosis. Although highly effective in BRAF mutant melanoma, BRAF inhibitor monotherapy has shown poor efficacy in BRAF mutant CRC. Preclinical data suggest that improved MAPK pathway suppression with combined inhibition of BRAF and MEK may improve efficacy. Methods: 43 patients (pts) with BRAF V600 mutant stage IV CRC were treated with D (150mg BID) and T (2mg QD), 17 of whom were enrolled in a pharmacodynamic cohort with tumor biopsies pre-treatment and after 2 weeks of therapy. Archival tissues were analyzed for microsatellite instability (MSI), PTEN loss, and 487-gene sequencing (Illumina). Results: Of 43 pts, 5 (12%) achieved partial response (PR) or better (with or without confirmation), including 1 (2%) pt with complete response (CR) ongoing >22 months. An additional 22 (51%) pts achieved stable disease (SD) at first restaging, of which 11 (26%) pts had a minor response (10% to 30% tumor reduction). 10 (23%) pts...