More Positive Data for BRAF/MEK Combo in Melanoma, But Debate Continues

Jeffrey S. Weber, MD, PhD

The combination of trametinib (Mekinist) and dabrafenib (Tafinlar) improved overall survival (OS) compared with vemurafenib alone in patients with unresectable (stage IIIC) or metastatic (stage IV) BRAFV600E/K mutation-positive cutaneous melanoma. These results from the phase III COMBI-v trial were announced by GlaxoSmithKline (GSK), the company developing the drugs, and published in The New England Journal of Medicine.¹

Risk of death was 31% lower among patients receiving the combination compared with those receiving vemurafenib (HR = 0.69; 95% CI, 0.53-0.89; P <.005). Median OS had not been reached for the combination arm but was 17.2 months for the vemurafenib arm. At 12 months, the OS rate was 72% and 65% for the combination and vemurafenib arms, respectively.

“COMBI-v is the first phase III study that demonstrated a statistically significant improvement in overall survival for a combination of targeted MEK and BRAF therapies compared to a single agent in patients with BRAF V600-mutant melanoma,” Rafael Amado, MD, Head of Oncology R&D at GSK, said in a statement, adding that the data “reinforce confidence in the efficacy of this combination treatment.”

While the combination is certainly efficacious, there is some debate regarding its curative potential, Jeffrey S. Weber, MD, PhD, a senior member at Moffitt Cancer Center, said in an interview with OncLive.

For the treatment of patients with relatively indolent-growing disease, with low tumor burden and normal LDH levels, Weber said some oncologists would prescribe ipilimumab and/or nivolumab because they believe a cure is not possible with a BRAF/MEK inhibitor combination.

“Many of my colleagues go with immunotherapy,” Weber said. “They want to give the patient a curative chance first—if that doesn’t work, they can always go to BRAF/MEK.”

However, some patients treated with a BRAF/MEK combination have been in remission for at least 4 years, and may, in fact, be cured, he said, adding that it is a common belief that patients who fail treatment with a BRAF/MEK combination would not see benefit from immunotherapy afterwards, he continued.

“The problem with treating BRAF/MEK failures is often they will progress very rapidly—and some proportion of those patients will,” he said. “It’s a bit of an urban legend that they will just progress so rapidly, they’re all going to die, and not come to any other treatment.”

“And certainly, a modest proportion of patients will have rapidly progressive disease. You’re not going to get a chance to do very much.”

The FDA has approved dabrafenib and trametinib (both alone and in combination). Though the curative potential of the combination is unknown, Weber said the future is bright for these agents.

Weber said they could be used in triple combinations with p53 inhibitors, PI3K inhibitors, and HSP90 inhibitors. Combining these agents with immunotherapies is another interesting area, Weber said, and a combination of nivolumab, dabrafenib, and trametinib is particularly intriguing.

According to clinicaltrials.gov, there are 23 trials that are recruiting or will begin recruiting looking at dabrafenib and trametinib in melanoma. One trial, led by the National Cancer Institute, will evaluate dabrafenib and trametinib followed by ipilimumab and nivolumab or ipilimumab and nivolumab followed by dabrafenib and trametinib for stage III-IV BRAFV600 mutated melanoma.²

“You’re going to see a lot of combinations,” Weber said. “That’s where the good stuff is going to come.”

References

1. Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med 2015;372(1):30-39.
2. Clincaltrials.gov. Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma. https://clinicaltrials.gov/ct2/show/NCT02224781?term=dabrafenib+trametinib+melanoma&rank=15