Efficacy and safety of combination therapy with binimetinib, encorafenib, and cetuximab for BRAF non-V600E mutated metastatic colorectal cancer: Results from a phase 2 BIG BANG trial (EPOC1703).

3585 Background: BRAF mutations which are found in 8-12% of metastatic colorectal cancer (mCRC) can be classified into three groups; Class 1 and 2 tumors do not respond to anti-EGFR antibody therapy because of the RAS independent activity, while previous studies suggested potential anti-tumor activity of anti-EGFR antibody for class 3 tumor. Combination therapy with binimetinib, encorafenib, and cetuximab showed the substantial efficacy for BRAF V600E mutated mCRC in the BEACON CRC trial, however, the clinical activity of these triplet therapy for BRAF non-V600E mutated mCRC is unknown. Here, we conducted a multicenter phase 2 trial to assess the efficacy and safety of combination therapy with binimetinib, encorafenib, and cetuximab in patients with BRAF non-V600E mutated mCRC. Methods: We enrolled patients with RAS wild-type and BRAF non-V600E mutated mCRC, refractory or intolerant to at least one fluoropyrimidine-based chemotherapy, and no prior history of anti-EGFR antibody (primary analysis cohort) or refractory to prior anti-EGFR antibody (anti-EGFR antibody refractory cohort). Enrolled patients receive binimetinib (45 mg BID), encorafenib (300 mg QD), and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, weekly) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed confirmed objective response rate (ORR) in the primary analysis cohort with sample size of 21 patients. Results: Between May 2018 and March 2023, 12 and 20 patients were enrolled in the primary analysis cohort and the anti-EGFR antibody refractory cohort, respectively (same order in the following abstract). 7 and 19 patients had a history of ≥ 2 lines of previous chemotherapy, respectively. The most frequent mutation overall was BRAF D594G (n=14, 43.8%). There were each 2 responders in both cohorts, resulting in 16.7% (95%CI, 2.1-48.4%) and 10.0% (95%CI, 1.2-31.7%) of confirmed ORR, respectively. Among 7 patients harboring class 1 or 2 tumors in both cohorts combined, there were 2 responders (ORR 28.6%). Median progression-free survival was 3.3 months and 3.0 months, respectively. Grade 3 or higher adverse events occurred in 4 and 10 patients, respectively, and no new safety signals were identified. Conclusions: The combination therapy with binimetinib, encorafenib, and cetuximab showed modest efficacy for BRAF non-V600E mutated mCRC, with a manageable safety profile, although there was not enough statistical power due to slow accrual. Circulating-tumor DNA analyses at the timepoint of before and after treatment are ongoing. Clinical trial information: UMIN000031857. Table: see text