Although monotherapy with a BRAF inhibitor is the current standard of care for patients with BRAF-mutated advanced melanoma, new data presented at the European Society for Medical Oncology (ESMO) 2014 Congress suggest that combination therapy should become the new standard systemic therapy for this patient population. 

In a study involving 495 treatment-naïve patients with BRAFV600 mutation­-positive, unresectable locally advanced or metastatic melanoma, researchers found that the BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib achieved greater progression-free survival (PFS) and response rates than vemurafenib plus placebo.1

Patients who received combination therapy showed significantly improved PFS compared with patients who received placebo (9.9 months vs 6.2 months, respectively). The combination arm also demonstrated a 49% reduction in risk of disease progression. The observed response rate was 68% in the combination arm and 45% in the control arm. There was a complete response in 10% of patients treated with combination therapy compared with 4% in the placebo arm.

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Lead study author Grant McArthur, MD, PhD, FRACP, MBBS, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre in Melbourne, Australia, said that these study findings show that using a combination approach to turn off two individual proteins (BRAF and MEK) may result in significantly improved outcomes.

In this study, combination therapy resulted in a greater incidence of grade 3 or higher adverse events (65% vs 59% for the placebo arm). However, there were no differences in the rates of adverse events leading to drug discontinuation and there was a reduced incidence of secondary cutaneous neoplasms with the combination therapy.

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In a separate study presented at the ESMO 2014 Congress, Caroline Robert and colleagues reported targeting BRAF V600E/K mutation-positive melanoma with a combination of dabrafenib and trametinib appears to achieve longer overall survival (OS) and PFS compared with treatment with vemurafenib alone.2

The researchers conducted an open-label phase 3 trial that randomly assigned 704 patients to receive either a combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) alone. The preplanned interim analysis presented at the ESMO 2014 Congress showed a 31% improvement in OS and 44% reduction in risk of disease progression in the combination arm compared with vemurafenib monotherapy. The median PFS was 11.4 months for patients in the combination therapy arm compared with 7.3 months for patients who received vemurafenib alone.

Patients in both arms had similar rates of adverse events. However, the combination therapy was associated with a much lower rate of cutaneous squamous cell carcinoma. The study was stopped in July 2014 and patients in the monotherapy arm were allowed to cross over to the combination arm.

Lead study author Caroline Robert, MD, PhD, who is head of Dermatology at the Institute Gustave Roussy in Paris, France, said the study findings further corroborate that a more complete blockade of the MAP kinase pathway delays the emergence of resistance and that appears to translate into improved survival.