Dabrafenib + trametinib
Trade names: Tafinlar (dabrafenib) + Mekinist (trametinib).
Combined BRAF (dabrafenib) and MEK (trametinib) inhibition is the standard targeted therapy for BRAF V600-mutant cutaneous melanoma. The combination produces rapid, deep responses in metastatic disease and improves recurrence-free survival as adjuvant therapy in resected stage III. Toxicity profile differs markedly from immunotherapy.
Mechanism
BRAF V600E/K activating mutations are present in approximately 50% of cutaneous melanoma. Dabrafenib selectively inhibits mutant BRAF. Trametinib inhibits MEK1/2 downstream — the combination overcomes resistance via reactivation of the MAPK pathway and reduces cutaneous toxicity (hyperproliferative SCC) seen with BRAF monotherapy.
Indications (UK)
- Adjuvant melanoma stage III with BRAF V600 mutation — NICE TA544 (2018), 12 months.
- Metastatic BRAF V600-mutant melanoma — combination dabrafenib + trametinib is recommended by NICE TA396. Dabrafenib monotherapy (TA321, 2014) is no longer standard and is reserved for situations where the MEK inhibitor is contraindicated. The alternative cobimetinib + vemurafenib combination (TA414) is not recommended by NICE; the other recommended BRAF + MEK pair is encorafenib + binimetinib (TA562).
- Brain-metastasis-active in BRAF-mutant disease (variable response).
Dosing
- Dabrafenib 150 mg orally twice daily.
- Trametinib 2 mg orally once daily.
- Take dabrafenib at least 1 hour before or 2 hours after meals; trametinib timing flexible.
- Adjuvant: 12 months.
- Metastatic: until progression or unacceptable toxicity.
Adverse events
- Pyrexia (~50%) — characteristic; may need dose interruption / steroid; rule out infection.
- Fatigue, nausea, headache.
- Cutaneous: rash, hyperkeratosis, photosensitivity, second cutaneous neoplasms (cSCC, KA — much less frequent than BRAF monotherapy).
- Cardiac: LVEF reduction (trametinib) — baseline echo, repeat as per protocol.
- Ocular: chorioretinopathy, retinal vein occlusion (trametinib).
- Hepatic transaminitis, anaemia, hypertension.
- Resistance typically emerges in metastatic disease at median 12–15 months.
Practical
- BRAF mutation testing on tumour tissue mandatory before prescribing.
- Baseline ECG, echo (LVEF), eye exam (low threshold), LFTs, FBC.
- Counsel about pyrexia management — dose interruption, paracetamol, NSAIDs; corticosteroids if recurrent or severe.
- Encorafenib + binimetinib is the alternative BRAF/MEK pair (NICE TA562) — slightly different toxicity profile.
References
- Long GV et al. Adjuvant dabrafenib + trametinib in stage III BRAF-mutated melanoma (COMBI-AD). N Engl J Med; 2017.
- Robert C et al. Five-year outcomes with dabrafenib + trametinib in metastatic melanoma (COMBI-d / COMBI-v). N Engl J Med; 2019.
- NICE TA544 (adjuvant dabrafenib + trametinib, 2018); TA396 (metastatic dabrafenib + trametinib combination, 2016); TA321 (dabrafenib monotherapy, 2014); TA562 (encorafenib + binimetinib, 2019); TA414 (cobimetinib + vemurafenib, 2016 — not recommended).
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