EU approval for Tafinlar (dabrafenib) + Mekinist (trametinib) for treatment of BRAF V600 mutation metastatic melanoma- Novartis

Novartis announced that the European Commission has approved the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. This is the first targeted therapy combination approved in the EU to treat patients with the most aggressive form of skin cancer, demonstrating improved overall survival versus the current standard of care with BRAF inhibitor monotherapy in two Phase III studies.

Marketing authorization is based on results from the Phase III COMBI-d and COMBI-v studies, in which the dabrafenib/trametinib combination demonstrated overall survival (OS) benefit compared to dabrafenib and vemurafenib (Zelboraf) monotherapies respectively in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

The COMBI-d study showed that the combination of dabrafenib and trametinib achieved a statistically significant OS benefit compared to dabrafenib monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55–0.92], p=0.011). In those who received dabrafenib in combination with trametinib, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received dabrafenib only, respectively. Safety results from the COMBI-d study were consistent with the profile observed to date for the combination; no new safety concerns were observed. The most common adverse events (≥20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application. Updated results from COMBI-v will be presented at an upcoming medical congress.

Comment: The dabrafenib + trametinib combination is seen as an answer to resistance problems faced by the monotherapies. The commercial limitations on the combination are its narrow market- BRAF V600E mutation patients (half the melanoma patients) and competition from Keytruda (pembrolizumab) and Opdivo (nivolumab) with their impressive data across all melanoma types.