Tafinlar and Mekinist Improve Long-Term Survival in Patients with BRAF Positive Melanoma

Adjuvant Tafinlar (dabrafenib) and Mekinist (trametinib) elicited a greater than 50% relapse-free survival (RFS) rate in patients with resected, stage 3 BRAF V600E/K-mutant melanoma, according to findings from a five-year analysis of the phase 3 COMBI-AD trial presented during the 2020 ASCO Virtual Scientific Program.

The trial involved a total of 870 patients with completely resected, stage 3 cutaneous melanoma with a BRAF V600E or V600K mutation. Patients were required to have undergone resection 12 weeks or earlier prior to randomization and must not have received prior systemic therapy.

The 438 patients assigned to the combination therapy arm received a combination of 150 milligrams (mg) of Tafinlar twice daily and 2 mg of Mekinist once daily. The remaining 432 patients in the placebo arm received two matched placebo tablets. Treatment was administered for a period of 12 months in both arms.

Previous data, during a median follow-up of 2.8 years, demonstrated that the two-drug combination had an estimated three-year RFS rate of 58% compared to 39% with the placebo. The overall survival (OS) rate, or the length of survival from the start of treatment, at three years was 86% in the treatment arm and 77% in the placebo arm.

The results presented during ASCO included five-year follow-up data, which found that the Tafinlar/Mekinist group saw four- and five-year RFS rates of 55% and 52% respectively. The placebo arm saw RFS rates of 38% and 36%.

“The relapse-free survival curves for both treatment arms appear to be reaching a plateau, which is a good sign if we are talking about cure,” said lead study author Dr. Axel Hauschild, of University Hospital Schleswig-Holstein in Germany.

Data was assessed at a median follow-up of 60 months in the Tafinlar and Mekinist arm and 58 months in the placebo arm; and demonstrated that 43% (190) of patients who received treatment had an RFS event compared with 61% (262) of patients who received placebo.

"I don't need to say that this is a highly statistically significant difference," added Hauschild.

Investigators observed a long-term RFS advantage with Tafinlar/Mekinist across all seven substages of disease. Notably:

• in patients with stage 3A disease, the four-year RFS rate was 72% with the two-drug combination compared to 62% with placebo. At five years, the RFS rate was 65% and 58%, respectively;
• the five-year RFS rate also favored the treatment arm in patients with stage 3B disease, at 55% vs. 34%;
• in patients with stage 3C disease, the five-year RFS rate was 45% in the Tafinlar/Mekinist arm and 29% in the placebo arm.

Hauschild noted that while "it is very clear that all patient groups [benefited] from dabrafenib and trametinib compared with placebo," the combination did not reach statistical significance in patients with a BRAF V600K mutation (of which there were 78) and the continent subgroup comprising Australia and New Zealand (which included 107 patients). Hauschild credited this failure to the small number of patients in these subgroups.

Additionally, the median distant metastasis-free survival (DMFS) was not reached in either arm but favored the combination approach. The five-year DMFS rate was 65% in the combination group and 54% in the placebo group. "DMFS was counted only if this was the patient's first relapse," Hauschild said. "If this was distant relapse after a local relapse, it was not counted in this analysis."

Overall survival was not updated at this data cutoff because the prespecified number of events for the final OS analysis had not yet occurred. According to Hauschild, the event-driven final OS analysis will be reported in the future, and safety data were also not updated in this five-year analysis because all patients completed treatment.

A version of this story originally appeared on OncLive® as “5-Year Follow-Up of COMBI-AD Confirms Long-Term RFS Benefit With Dabrafenib/Trametinib in BRAF+ Melanoma.”