Targeting BRAF V600E/K mutation-positive melanoma with a combination of dabrafenib plus trametinib achieves longer overall survival and progression-free survival as well as better response rates, compared to treatment with vemurafenib alone, according to data from an open-label phase III trial presented at ESMO 2014 in Madrid.

“We knew from previous studies of dabrafenib plus trametinib that the response rates were higher than those observed with dabrafenib monotherapy and that the progression-free survival was also significantly longer,” says lead author Dr Caroline Robert, head of Dermatology at the Institute Gustave Roussy, Paris, France.

The ongoing two-arm study has randomised 704 patients with advanced BRAF V600E/K mutation-positive melanoma either to a combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily), or to vemurafenib (960 mg, twice daily) alone.

The primary endpoint is overall survival, with secondary endpoints of progression-free survival, objective response rate, duration of response, and safety.

A pre-planned interim analysis shows a 31% improvement in overall survival among patients on combination therapy, and a 44% reduction in the risk of disease progression compared to vemurafenib monotherapy.

Researchers found a median progression-free survival of 11.4 months for dabrafenib plus trametinib, and 7.3 months for vemurafenib.

Patients in both arms of the study had similar rates of severe adverse events, although treatment with combination therapy was associated with a much lower rate of cutaneous squamous cell carcinoma.

In July this year, the study was stopped, and patients originally randomised to the vemurafenib arm of the trial were allowed to cross over to the combination arm.

In summary, Robert says, “These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for the patients.”

Commenting on the results from this study, Dr Reinhard Dummer, from the University of Zurich Hospital, ESMO Faculty Coordinator for melanoma, says: “While monotherapy with a BRAF inhibitor is currently considered as a standard of care for patients with BRAF mutated advanced melanoma, the data from these two trials [this one and this one], along with trial data presented earlier this year, provide convincing evidence that combination therapy with either dabrafenib and trametinib, or vemurafenib and cobimetinib will be the standard systemic therapy for this patient population.”

“The combination provides more efficacy concerning response rate and progression-free survival and overall survival documented for the trametinib and dabrafenib combination with a similar to lower load of adverse reactions,” Dummer says.

“Of special relevance is the lower risk for new cutaneous malignancies which might be a surrogate for other secondary malignancies associated with the use of monotherapy BRAF inhibitors.”

Source: ESMO