Background
Phase III randomized open-label trial. 665 patients with BRAF V600E-mutated metastatic colorectal cancer after 1–2 prior lines of therapy. Three-arm design: triplet (encorafenib + binimetinib + cetuximab), doublet (encorafenib + cetuximab), and control (irinotecan/FOLFIRI + cetuximab). Co-primary endpoints assessed triplet vs control. BRAF V600E occurs in ≈8–10% of mCRC; prognosis on chemotherapy is historically poor (mOS 4–5 months after 1 prior line).
Interventions and follow up
Arm A (Triplet): Encorafenib 300 mg PO daily + binimetinib 45 mg PO bid + cetuximab 400 mg/m² loading then 250 mg/m² weekly, until progression or unacceptable toxicity
Arm B (Doublet): Encorafenib + cetuximab
Arm C (Control): Investigator-choice irinotecan/FOLFIRI + cetuximab
Primary endpoint: Confirmed ORR and OS — triplet vs control
Median follow-up: 7.8 months (primary analysis)
Arm B (Doublet): Encorafenib + cetuximab
Arm C (Control): Investigator-choice irinotecan/FOLFIRI + cetuximab
Primary endpoint: Confirmed ORR and OS — triplet vs control
Median follow-up: 7.8 months (primary analysis)
Results
ORR (triplet vs control): 26% vs 2%, P<.001
mOS (triplet vs control): 9.0 vs 5.4 months, HR 0.52 (95% CI 0.39–0.70), P<.001
mPFS (triplet vs control): 4.3 vs 1.5 months, HR 0.38 (95% CI 0.29–0.49), P<.001
ORR (doublet vs control): 20% vs 2%
mOS (doublet vs control): 8.4 vs 5.4 months, HR 0.60 (95% CI 0.45–0.79), P<.001
mOS (triplet vs control): 9.0 vs 5.4 months, HR 0.52 (95% CI 0.39–0.70), P<.001
mPFS (triplet vs control): 4.3 vs 1.5 months, HR 0.38 (95% CI 0.29–0.49), P<.001
ORR (doublet vs control): 20% vs 2%
mOS (doublet vs control): 8.4 vs 5.4 months, HR 0.60 (95% CI 0.45–0.79), P<.001
Adverse events
Overall grade ≥3: 58% (triplet), 50% (doublet), 61% (control)
Most common grade ≥3 (triplet): acneiform dermatitis 7%, fatigue 7%, nausea 5%, paronychia 5%; CPK increased 9% (binimetinib)
Discontinuation due to toxicity: 7% triplet, 8% doublet, 11% control
Most common grade ≥3 (triplet): acneiform dermatitis 7%, fatigue 7%, nausea 5%, paronychia 5%; CPK increased 9% (binimetinib)
Discontinuation due to toxicity: 7% triplet, 8% doublet, 11% control
Conclusions
The encorafenib + binimetinib + cetuximab triplet produced a landmark improvement in OS (HR 0.52) and ORR (26% vs 2%) vs irinotecan-based control in BRAF V600E mCRC, more than doubling median OS vs prior chemotherapy standards (∼5 months). The doublet (without binimetinib) showed similar OS benefit (HR 0.60), albeit with lower ORR, raising questions about the incremental value of binimetinib.
Key Limitations
Relatively short median follow-up (7.8 months) for primary OS analysis; PFS gains are modest in absolute terms. The doublet performed similarly to the triplet for OS in later analyses, and the benefit of adding binimetinib remains uncertain — longer follow-up favors the doublet for comparable efficacy and better tolerability. Control arm was irinotecan-based rather than modern third-line standards. Limited data in patients with prior anti-EGFR exposure. BRAF V600E status must be confirmed — applicable to only ∼8% of mCRC.
Clinical Context
BEACON CRC established encorafenib + cetuximab (doublet) as a standard of care for BRAF V600E mCRC after 1–2 prior lines, with FDA approval in April 2020. The doublet has largely supplanted the triplet in practice due to equivalent OS, lower toxicity, and simpler administration. First-line BRAF-targeted therapy is under investigation (SEAMARK). ESMO endorses encorafenib + cetuximab in this setting; ESMO-MCBS score: 4.