BRAF +/- MEK inhibition in patients (pts) with BRAF-mutant (mut) metastatic colorectal cancer (mCRC): The Sarah Cannon Research Institute UK’s experience.

Abstract

645 Background: Activating V600 BRAF mutations are detectable in around 10% of mCRC pts and are associated with poor prognosis. Low response rates have been reported with anti-BRAF monotherapy in this subset of pts while encouraging data exist on enhanced MAPK pathway inhibition with combination therapy (anti-BRAF + anti-MEK and/or anti-EGFR). Methods: We performed a pooled analysis of BRAF-mut mCRC pts enrolled into different phase 1 trials involving the use of anti-BRAF monotherapy alone (Group A) or in combination with a MEK inhibitor (Group B) at therapeutic doses between June 2012 and August 2016. Demographic, baseline, toxicity and efficacy data were retrospectively reviewed. Results: Twenty BRAF-mut mCRC pts were identified in either Group A (n = 13) or Group B (n = 7). All pts had an ECOG performance status ≤ 1. Median age was 54 years (range 33-74). The primary tumor was right-sided in 10 (50%) pts, left-sided in 9 (45%) pts, and unknown in 1 (5%) subject. Median number of previous treatment lines was 1 (range 1-4). The disease control rate was 55%, with 3 (15%) pts experiencing partial response (PR) and 8 (40%) with stable disease. No complete responses were observed, 8 (40%) pts had progressive disease and 1 subject was considered not evaluable. All PRs were achieved in Group B and had duration of 2-4 months (mo). Median PFS was 3.73 mo (95% confidence interval [CI] 3.06-6.79) in the overall population, and showed a trend favoring the combination arm (2.80 mo for Group A vs. 5.03 mo for Group B, hazard ratio 0.71 [CI 0.26-1.95], p = 0.503). Most common toxicities were skin-related side effects (n = 10; 50%), myalgia/arthralgia (n = 5; 25%), nausea (n = 3; 15%), and pyrexia (n = 3; 15%). Grade 3/4 toxicities were uncommon and manageable: neutropenia (n = 1; 5%), hypophosphatemia (n = 1; 5%), pyrexia (n = 1; 5%), and abdominal pain (n = 1; 5%). Conclusions: Our cohort of pts treated with BRAF +/- MEK inhibitors showed a favorable safety profile. An encouraging activity level was found in the combination arm. In line with existing literature data, our findings supporting further development of combined MAPK inhibition in V600-positive mCRC.