BRAF-Mutant and HER2+ mCRC Management Strategies Are Becoming Increasingly Tailored: With Chandler Park, MD, and Midhun Malla, MD

In this episode of MedNews Week's Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was rejoined by Midhun Malla, MD, a gastrointestinal oncologist at Allegheny Health Network in Pittsburgh, Pennsylvania, to discuss treatment personalization in metastatic colorectal cancer (mCRC), with a focus on BRAF V600E–mutant tumors, HER2-altered disease, and the clinical implications of tumor sidedness.

In part 2 of this conversation, Drs Park and Malla began by addressing treatment sequencing for patients with BRAF V600E–mutant CRC, particularly those who progress after adjuvant FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin)–based therapy. Dr Malla noted the lack of prospective data supporting rechallenge in this setting and advocated for shifting to a FOLFIRI (leucovorin, fluorouracil, and irinotecan)–based backbone, aligning with emerging real-world practices and evolving combination data involving encorafenib (Braftovi) and cetuximab (Erbitux). He referenced encouraging safety and tolerability findings from presentations at recent international meetings.

The conversation then turned to patients with microsatellite instability–high (MSI-H)/BRAF V600E–mutant tumors. Dr Malla discussed data from the phase 2 CheckMate 142 (NCT02060188) and phase 3 CheckMate 8HW (NCT04008030) trials, highlighting the consistent benefit of immunotherapy in this molecularly defined population, regardless of BRAF mutation status. He emphasized that MSI-H biology appears to outweigh the typically poor prognostic impact of BRAF mutations, supporting the use of checkpoint blockade in the frontline setting.

For left-sided, HER2-positive mCRC, Malla provided insight into second-line therapy selection following progression on FOLFOX and EGFR inhibition. He outlined the clinical rationale for selecting fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with concurrent RAS mutations and HER2 alterations, as well as reserving trastuzumab (Herceptin) plus tucatinib (Tukysa) for those with HER2 overexpression and RAS wild-type disease. He also highlighted key differences between the phase 2 DESTINY-CRC02 (NCT04744831) and MOUNTAINEER (NCT03043313) trials that inform treatment stratification in this setting.

Throughout the discussion, Malla emphasized the importance of early molecular profiling within the context of individualized treatment selection, as well as the evolving paradigm of targeted therapy for patients with advanced CRC.