Metastatic Colorectal Cancer — BRAF V600E-Mutant

Sequencing for BRAF V600E-mutant metastatic colorectal cancer: first-line BRAF-targeted triplet (encorafenib + cetuximab + mFOLFOX6, per BREAKWATER) or chemotherapy + bevacizumab, with encorafenib + cetuximab given second line (per BEACON-CRC) after chemotherapy-first, then a later-line cytotoxic/oral option or clinical trial.

First-line strategy (confirm BRAF V600E and test mismatch-repair status first)

1L: Encorafenib + cetuximab + mFOLFOX6 (BRAF-targeted triplet)

BREAKWATER established encorafenib + cetuximab + mFOLFOX6 as a preferred first-line option for BRAF V600E-mutant metastatic CRC, improving response and survival over chemotherapy. Note: MSI-high/dMMR tumors should receive first-line pembrolizumab instead (checkpoint blockade takes priority).

Evidence: BREAKWATER

1L: Chemotherapy + bevacizumab (FOLFOX or FOLFIRI + bevacizumab)

Conventional intensive first-line chemotherapy backbone with bevacizumab, still appropriate when the BRAF-targeted triplet is not used. Anti-EGFR monotherapy is not effective in BRAF V600E-mutant disease without concurrent BRAF inhibition.

2L: Encorafenib + cetuximab (BRAF-targeted doublet)

For patients who received chemotherapy first: BEACON-CRC established encorafenib + cetuximab after progression on prior therapy, improving overall survival versus chemotherapy. Monitor for acneiform rash (cetuximab) and arthralgia/fatigue.

Evidence: BEACON CRC

2L: Chemotherapy ± bevacizumab (FOLFIRI-based)

For patients who received the BRAF-targeted triplet first: switch to a non-cross-resistant chemotherapy backbone (FOLFIRI-based) with bevacizumab on progression.

3L+: Later-line therapy (trifluridine-tipiracil or regorafenib) or clinical trial

After both chemotherapy and BRAF-targeted therapy: trifluridine-tipiracil (± bevacizumab) or regorafenib are standard refractory-line options; prioritize a clinical trial where available.