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Drug · BRAF + MEK inhibitorNICE TA562

Encorafenib + binimetinib

Trade names: Braftovi (encorafenib) + Mektovi (binimetinib). Sometimes called Enco + Bini or COMBO450.

Second BRAF + MEK inhibitor combination approved for BRAF V600-mutant unresectable or metastatic melanoma. Approved by NICE in 2019 (TA562) on the strength of the COLUMBUS trial. Generally better tolerated than dabrafenib + trametinib for pyrexia, with a distinct but manageable ocular and creatine-kinase profile. An alternative first-line targeted option for BRAF-mutant disease, particularly where pyrexia has driven dose interruptions on dabrafenib + trametinib.

UK national guidance is the primary frame of reference; see about the author.

CurrentLast reviewed 27 April 2026

Mechanism

BRAF V600E / V600K activating mutations occur in ~50% of cutaneous melanoma. Encorafenib is a selective ATP-competitive inhibitor of mutant BRAF with a long dissociation half-life. Binimetinib is an allosteric MEK1/2 inhibitor. The combination blocks MAPK pathway reactivation that drives resistance to BRAF monotherapy and reduces the paradoxical activation that produces hyperproliferative cutaneous lesions (keratoacanthomas, well-differentiated cSCC) on BRAF monotherapy.

Indications (UK)

  • NICE TA Unresectable or metastatic BRAF V600-mutant melanoma — NICE TA562 (2019), first-line. Approved alongside dabrafenib + trametinib.
  • Adjuvant melanoma: encorafenib + binimetinib is not currently NICE-approved in the adjuvant setting (dabrafenib + trametinib has TA544 for that role).
  • Trial Brain metastasis activity: limited CNS data; discuss at neuro-oncology MDT.
  • Active in BRAF-mutant non-cutaneous melanoma (mucosal, occasionally uveal) but not specifically approved for these.

Dosing

  • Encorafenib 450 mg orally once daily (taken with or without food).
  • Binimetinib 45 mg orally twice daily (12-hour interval; with or without food).
  • Until disease progression or unacceptable toxicity.
  • Dose-reduction schedule per UK SmPC: encorafenib 450 mg OD (starting) → 1st reduction 300 mg OD → 2nd reduction 225 mg OD → discontinue if not tolerated. Binimetinib 45 mg BD (starting) → 1st reduction 30 mg BD → discontinue if not tolerated (no further reduction).
  • Encorafenib monotherapy dose if binimetinib permanently discontinued: 300 mg OD.

Adverse events

  • Less pyrexia than dabrafenib + trametinib (~18% vs ~50%) — major advantage in real-world tolerability.
  • Ocular: serous retinopathy / retinal pigment epithelial detachment (~20%; usually asymptomatic, reversible); rare retinal vein occlusion. Baseline and serial ophthalmology.
  • Creatine kinase rise (often asymptomatic; check baseline and serial); rhabdomyolysis rare.
  • Hepatic transaminitis; monitor LFTs.
  • Cardiac: LVEF reduction (baseline and serial echo).
  • GI: nausea, vomiting, diarrhoea, constipation.
  • Cutaneous: rash, photosensitivity, hyperkeratosis, palmar-plantar erythrodysaesthesia; cSCC / keratoacanthoma less frequent than on BRAF monotherapy.
  • Hypertension; peripheral oedema.
  • Resistance commonly emerges at median ~14–15 months in metastatic disease.

Evidence summary

  • Trial COLUMBUS Part 1 (Dummer 2018, Lancet Oncol): encorafenib 450 mg + binimetinib 45 mg vs vemurafenib in BRAF V600-mutant advanced melanoma. PFS 14.9 vs 7.3 months (HR 0.54); ORR 63% vs 40%.
  • Trial COLUMBUS 5-year update (Dummer 2022, J Clin Oncol): median OS 33.6 months vs 16.9 months (vemurafenib); 5-year OS ~35%. Durable benefit comparable to dabrafenib + trametinib.
  • No head-to-head trial vs dabrafenib + trametinib; cross-trial comparison suggests broadly similar efficacy with different toxicity profile.

Practical

  • BRAF V600 mutation testing on tumour tissue mandatory before prescribing.
  • Baseline ECG, echo (LVEF), ophthalmology assessment, LFTs, FBC, U&Es, CK, lipase, lipids.
  • Serial ophthalmology (per local protocol; common practice every 1–3 months for the first 6 months).
  • Pregnancy testing in childbearing potential; effective contraception throughout treatment and for at least 1 month afterwards.
  • Counsel about retinopathy symptoms (blurred vision, photopsia) and to seek review promptly.
  • Drug interactions: CYP3A4 substrates / inhibitors / inducers; check current SmPC.
  • Sequencing with immunotherapy: optimal sequencing remains debated; see related discussion. Local MDT decision.
  • Dabrafenib + trametinib is the alternative BRAF / MEK pair; choice between them is often driven by tolerability concerns (pyrexia → favour enco/bini) and clinician familiarity.

References

  1. Dummer R, Ascierto PA, Gogas HJ et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2018;19:603–15.
  2. Dummer R, Flaherty KT, Robert C et al. COLUMBUS 5-year update: long-term safety and overall survival in patients with advanced BRAF V600-mutant melanoma receiving encorafenib plus binimetinib. J Clin Oncol 2022;40:4178–88.
  3. NICE TA562. Encorafenib with binimetinib for unresectable or metastatic BRAF V600 mutation-positive melanoma. London: NICE; 2019.
  4. European Medicines Agency. Braftovi / Mektovi Summary of Product Characteristics.

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