One year of combination treatment with dabrafenib plus trametinib reduced the risk for disease recurrence or death by more than half in patients with stage III high-risk BRAF V600E/K melanoma, according to the results of a phase III study (abstract LBA6_PR) presented at the 2017 European Society for Medical Oncology (ESMO) Congress in Madrid.
The results of the COMBI-AD trial are “practice-changing,” according to presenter Axel Hauschild, MD, professor of dermatology at the University of Kiel in Germany.
“These are the best results ever shown for an adjuvant treatment in stage III 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 trial included 870 patients with treatment-naive high-risk, stage III, BRAF V600E/K–mutant melanoma. Patients were within 12 weeks of complete surgical resection and were randomly assigned to dabrafenib 150 mg twice daily plus trametinib 2 mg once daily or placebo. Treatment was given for 12 months. The primary endpoint was relapse-free survival.
With a median follow-up of 2.8 years, the combination significantly reduced risk for disease recurrence or death (hazard ratio [HR], 0.47; 95% CI, 0.39–0.58). The median relapse-free survival was not yet reached in patients assigned dabrafenib plus trametinib compared with 16.6 months for placebo. The relapse-free survival benefit was observed across all patient subgroups.
Compared with placebo, patients assigned to the combination therapy also had significant improvements in overall survival (HR, 0.57). The 3-year overall survival rate was 86% for combination therapy compared with 77% for placebo (P = .0006); however, this level of improvement “did not cross the prespecified interim analysis boundary of P = .000019. Distant metastasis–free survival (HR, 0.51; 95% CI, 0.40–0.65) and freedom from relapse (HR, 0.47; 95% CI, 0.39–0.57) were also significantly improved with combination treatment compared with placebo.
The majority (97%) of patients assigned to combination treatment had an adverse events; 41% of patients had grade 3/4 events. About one-quarter of patients (26%) had adverse events that led to discontinuation of treatment compared with 3% of patients assigned placebo.
“The number of treatment discontinuations was a little higher than in trials of stage IV melanoma patients,” said Hauschild. “This could be because 90% of patients had no progressive disease and were treated for the scheduled full year. 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 IV disease and overall we can say the treatment was well tolerated.”
The trial results were also published in the New England Journal of Medicine.
Commenting on the results, ESMO Melanoma Faculty Coordinator Olivier Michielin, MD, PhD, head of Personalised Analytical Oncology, Lausanne, Switzerland, said that COMBI-AD is the first trial reporting on the use of targeted therapies in the adjuvant setting for melanoma.
“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,” Michielin said. “The different toxicity profiles between immunotherapy and the targeted therapies will factor into decisions on which to use.”