COPENHAGEN, Denmark — Dabrafenib plus trametinib demonstrated long-term safety and efficacy in patients with unresectable, metastatic BRAF V600–mutated melanoma, according to updated safety and efficacy results from the COMBI-v trial presented at the European Society for Medical Oncology Congress.
Previous results from the phase 3, randomized double blind study showed the combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) yielded better survival outcomes at 2 years than treatment with vemurafenib (Zelboraf, Hoffmann La Roche).
“The 2014 interim analysis became the ‘primary’ analysis, because it was already showing a benefit in terms of OS, and patients in the single-agent arm were allowed to crossover to the more efficient combination arm,” Caroline Robert, MD, PhD, head of the dermatology unit at the Institut Gustave-Roussy in Paris, France, said during her presentation. “Last year, I presented the 2-year data, with more than 50% of patients alive at 2 years after a follow-up of 19 months for the combination arm.”
In the current analysis, Robert presented results from long-term follow-up of the study to determine safety and efficacy at 3 years.
The trial included 704 patients with histologically confirmed unresectable stage IIC or IV BRAF V600E/K–mutated melanoma. Patients received first-line 150 mg dabrafenib twice daily with 2 mg trametinib once daily (n = 352) or 960 mg vemurafenib once daily (n = 352).
The updated analysis occurred after 16 additional months of follow-up since the 2-year analysis. By that time, 411 deaths had occurred and 34 patients had crossed over to the dabrafenib and trametinib arm. In total, 134 patients in the combination arm, 66 of whom were still receiving treatment, and 61 patients in the single-agent arm, 10 of whom were still receiving treatment, were on the study at the time of the analysis.
Results showed that the survival benefit persisted at 3 years.
Rates of 3-year OS were 45% (95% CI, 39-50) in the dabrafenib–trametinib arm and 32% (95% CI, 27-37) in the vemurafenib arm. Median OS was 26.1 months in the combination arm and 17.8 months in the single-agent arm (HR = 0.61; 95% CI, 0.51-0.73).
The greatest OS benefits were observed in patients with baseline lactate dehydrogenase less than or equal to the upper limit of normal and fewer than three organ sites of metastasis (3-year OS, 70% vs. 46%; median OS, not reached vs. 26.4 months; HR = 0.47; 95% CI, 0.33-0.67).
Patients in the dabrafenib–trametinib arm also demonstrated superior rates of 3-year PFS (25% vs. 11%), overall response (67% vs. 53%) and complete response (19% vs. 12%), as well as longer median duration of response (13.8 months vs. 7.9 months).
Researchers noted the dabrafenib–trametinib combination continued to appear safe, with no new safety signals at the updated analysis. Further, the rate of discontinuation due to adverse events in the combination arm appeared stable over time, from 13% in 2014 to 16% in both 2015 and 2016.
“This confirms the improved outcomes after this additional follow-up with the combination dabrafenib–trametinib compared with vemurafenib, despite the crossover,” Robert said. “The benefit is seen across all groups, but is more obvious in patients with favorable baseline characteristics. These data support the long-term use of the combination as a standard first-line targeted agent for patients with BRAF–mutated melanoma.” – by Alexandra Todak
Robert C, et al. Abstract LBA40. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: The study was funded by GlaxoSmithKline. Robert reports consultant roles with and Honoria from Amgen, Bristol-Myers Squibb, Merck, Novartis and Roche.