Rone, Kelley

The recent approval of encorafenib, cetuximab, and FOLFOX based on the phase III BREAKWATER trial has introduced a new standard of care for the first-line treatment of BRAF V600E–mutated metastatic colorectal cancer (mCRC). However, its safety and efficacy in patients with significant liver dysfunction remains unclear and, as such, patients are often excluded from pivotal clinical trials. This report presents a case of BRAF V600E–mutated mCRC presenting with extensive hepatic involvement and liver dysfunction. Despite the absence of guidelines, the patient was initiated on full-dose encorafenib, cetuximab, and FOLFOX. He experienced a rapid clinical and biochemical response, with near-normalization of liver enzymes after cycle 1, and complete functional recovery by cycle 3. Treatment was well tolerated, with no significant adverse events throughout 9 cycles. He subsequently transitioned to maintenance 5-FU, cetuximab, and encorafenib. Posttreatment blood-based next-generation sequencing revealed no residual actionable mutations. The patient then successfully underwent complete surgical resection of his primary tumor and metastatic disease with negative margins. This case highlights the importance of considering encorafenib-based therapy in select patients with BRAF V600E–mutated mCRC in the setting of compromised liver function.