DABRAFENIB-TRAMETINIB COMBINATION FOR MELANOMA NEAR APPROVAL IN EUROPE

The combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) for use in the treatment of melanoma has at last been given the go ahead by European authorities (the products were recently acquired by Novartis from GlaxoSmithKline).

Both drugs are already approved for use in melanoma in Europe, but for individual use.

The combination had previously been considered by the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) in March 2014, but at the time the committee said there were insufficient data.

In the meantime, the manufacturer has filed new data from phase 3 studies known as COMBI-d and COMBI-v, which both show a survival benefit, and the CHMP has now issued a positive opinion for use of the combination.

The European Commission will review the CHMP recommendation and is expected to deliver its final decision within 3 months. The decision will be applicable to all 28 EU member states, plus Iceland, Liechtenstein, and Norway.

Specifically, the combination of dabrafenib, a BRAF inhibitor, together with trametinib, a MEK inhibitor, is recommended for approval for use in the treatment of BRAF V600 mutation-positive melanoma, which accounts for about 40% of all melanoma and is particularly aggressive.

This use of the combination is already approved in the United States. The US Food and Drug Administration granted an accelerated approval in January 2014, and the agency has now designated priority review for the new phase 3 data to convert this into a full approval. A decision is expected by November. The combination also has breakthrough therapy designation.

Survival Benefit of 6 Months

The COMBI-d study used dabrafenib alone as the compactor, and shows a survival advantage of 6 months with the combination. The median overall survival with the combination was 25.1 months vs 18.7 months with dabrafenib alone (hazard ratio [HR], 0.71; P = .011). After 1 year, 74% of patients on the combination were still alive, compared with 68% on dabrafenib alone, while at 2 years these figures were 51% and 42%, respectively.

The COMBI-v study used another BRAF inhibitor, vemurafenib (Zelboraf, Plexxikon/Roche), as the comparator. This trial also showed a significant improvement in survival with the combination, with the median overall survival not reached for the combination vs 17.2 months on vemurafenib (HR, 0.69; P = .005). In this study, at 1 year, 72% of patients were still alive, compared with 65% on vemurafenib.

The most common adverse reactions seen for combination therapy in both studies at 20% or more include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, vomiting, hypertension, and cough.

After the results of the COMBI-v study were presented last year at the European Society for Medical Oncology Congress, melanoma experts said the combination of a BRAF and MEK inhibitor should become the standard of care in patients with advanced melanoma that is BRAF mutation-positive, and urged that the combination should be used instead of a BRAF inhibitor alone.