A combination of Tafinlar (dabrafenib) and Mekinist (trametinib) nearly halved the risk of relapse or death among patients with advanced melanoma with high-risk mutations, according to trial results presented at the recent European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain.
Axel Hauschild, MD, from the University Hospital Schleswig-Holstein in Germany presented data from the Phase 3 COMBI-AD trial (NCT01682083), showing that the combination also improved overall survival and the development of distant metastases compared to a placebo combination treatment.
Trial data also were published in the New England Journal of Medicine in the report, “Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.”
“There is no standard of care for the adjuvant treatment of stage III melanoma,” Hauschild, who is a professor of dermatology at the University of Kiel in Germany and a study co-author, said in a press release. “Interferon is approved for this situation but improves relative relapse-free survival by just 20% compared to placebo,” he added.
The study, which was supported by GlaxoSmithKline and Novartis, recruited 870 patients with stage 3 malignant myeloma. In stage 3, the cancer has spread to the lymph nodes. All patients had a mutation in the BRAF gene. In addition, 91 percent had a so-called V600E mutation and 9 percent had a V600K mutation.
This is a typical distribution of mutations among melanoma patients encountered in clinical practice, researchers said. When the treatment started, patients recently had their lymph metastases surgically removed.
Patients received Tafinlar, which blocks BRAF, and Mekinist, an inhibitor of the MEK molecular pathway, for 12 months.
At a median follow-up of 2.8 years, researchers estimated a three-year rate of relapse-free survival of 58 percent in patients on the Tafinlar and Mekinist combination, and 39 percent in the placebo group.
This translated to a 53 percent lower risk of relapse or death with the combo treatment, making the study meet its primary goal of improving relapse-free survival. And the benefits were seen in all types of patients.
But the therapy also improved overall survival: At three years, 86 percent were still alive in the combination group, compared to 77 percent in the placebo group, making the risk of death 43 percent lower with the treatment. The risk of developing distant metastases was lowered by 49 percent.
“These are the best results ever shown for an adjuvant treatment in stage 3 melanomas,” said Hauschild. “Combination treatment with dabrafenib and trametinib more than doubled the relapse-free survival time compared to placebo and the improvement in overall survival was impressive, too.”
The Tafinlar and Mekinist treatment is, however, not free from complications. The majority, 97 percent, experienced some kind of adverse events, and 41 percent had adverse events judged to be serious. In the placebo group, the figures were 88 percent and 14 percent for any adverse events and serious adverse events, respectively.
“The number of treatment discontinuations was a little higher than in trials on stage 4 melanoma patients,” said Hauschild, who explained that this could be because 90 percent of the patients had no progressive disease while they received a full year of treatment.
“The longer patients receive treatment, the more likely they are to have adverse events. But there were no new toxicities compared to those already seen in stage 4 disease and overall we can say the treatment was well-tolerated,” said Hauschild.
He believes that the results might change the way stage 3 melanoma is managed in clinical practice.
“This was the first big breakthrough in the adjuvant setting,” said Olivier Michielin, MD, PhD, head of Personalized Analytical Oncology, Lausanne, Switzerland, and ESMO Melanoma Faculty Coordinator.
Michielin explained that researchers have been trying, with little success, to develop adjuvant therapies for melanoma for years.
A study showed that immunotherapies interferon and Yervoy (ipilimumab) had a good effect in this patient group, but the treatment was fairly toxic.
“The improvements in progression-free survival and overall survival are both very significant, making this new treatment an attractive option for patients with BRAF mutations, who constitute around half of the melanoma population. The different toxicity profiles between immunotherapy and the targeted therapies will factor into decisions on which to use,” said Michielin.
“Both ipilimumab and the combination of dabrafenib plus trametinib have improved overall survival compared to placebo. We now need to determine which adjuvant strategy is best suited for which patient, factoring in also the upcoming results of PD-1 blockade in that setting,” he added.
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