85MO Management of Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAF V600E Mutant Metastatic Colorectal Cancer (BEACON CRC Study)

BRAF mutations occur in up to 15% of patients with metastatic colorectal cancer (mCRC) and the BRAF V600E mutation is a marker of poor prognosis. Inhibition of BRAF alone has not demonstrated clinical activity due to rapid feedback activation of EGFR that supports continued proliferation of BRAF V600E-mutated CRC tumor cells. In the BEACON CRC study, both triplet therapy with encorafenib (BRAF inhibitor) + binimetinib (MEK inhibitor) + cetuximab (epidermal growth factor receptor inhibitor), and doublet therapy with encorafenib + cetuximab demonstrated improved overall survival (OS) and objective response in patients with BRAF V600E mCRC compared with current standard of care (median OS: 9.3 months [triplet] and 9.3 months [doublet] vs 5.9 months [control]; objective response rate: 27% [triplet] and 20% [doublet] vs 2% [control], p< 0.0001 for both). Based on the efficacy and safety demonstrated in BEACON CRC, the doublet regimen has been submitted to the EMA for regulatory approval. Here, we focus on common adverse events (AEs) that occurred during the study with the doublet regimen, and best practices on managing and mitigating these events. BEACON CRC was a randomized, 3-arm, phase 3 study that evaluated triplet (n=224) or doublet (n=220) regimens versus investigator’s choice of irinotecan or FOLFIRI + cetuximab (n=221) in patients with BRAF V600E-mutated mCRC. The incidence and severity of AEs were assessed according to the NCI CTCAE, version 4.03. In the doublet arm, the most common AEs of any grade were diarrhea (38%), nausea (38%), fatigue (33%), and decreased appetite (31%). The most common skin-related AEs of any grade were dermatitis acneiform (30%), rash (15%), dry skin (13%), and pruritus (11%). grade ≥3 AEs occurred in 57% of patients (vs 64% in the control arm). The most common grade ≥3 AEs were anemia (6%), intestinal obstruction (5%), fatigue (4%), asthenia (4%), and abdominal pain (3%). Common laboratory abnormalities included low hemoglobin (any grade: 39%, grade 3–4: 6%) and high creatinine (any grade: 54%, grade 3–4: 3%). Arthralgia and myalgia (any grade), which are AEs associated with BRAF inhibitors, occurred in 23% and 15% of patients, respectively, and both led to dose reductions of either study drug in < 1% of patients; no patient discontinued either drug due to arthralgia or myalgia. Discontinuation of any study drug primarily due to an AE occurred in 12% of patients (vs 17% in the control arm). Management of AEs with the doublet regimen included treatment interruptions, dose reductions, and/or therapeutic interventions, when needed. Diarrhea, nausea, and headache were managed using standard supportive care. Management of skin toxicities will be described. The incidence, course, and management of class-based AEs will be described further. AEs that occurred with encorafenib + cetuximab during the BEACON CRC study were generally manageable, reversible, and infrequently associated with treatment discontinuation.