Long-Term Benefit of Dabrafenib Plus Trametinib in Melanoma Confirmed in 5-Year Follow-Up of COMBI-AD Study

Axel Hauschild, MD, PhD

The long-term benefit of adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist) as treatment of patients with resected, stage III BRAF V600E/K-mutant melanoma were validated by 5-year data from the phase 3 COMBI-AD study, according to a presentation from the 2020 American Soceity of Clinical Oncology (ASCO) Virtual Scientific Program.

The 4- and 5-year relapse-free survival (RFS) rates were 55% (95% CI, 50-60) and 52% (95% CI, 48-58) with the doublet therapy versus 38% (95% CI, 34-43) and 36% (95% CI, 32-41) with placebo.

"There is a longer than 50% relapse-free survival," said lead study author Axel Hauschild, MD, during a presentation at the 2020 ASCO Virtual Scientific Program. "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."

These data, assessed at a median follow-up of 60 months in the dabrafenib and trametinib arm and 58 months in the placebo arm, correlated with RFS estimates provided by the Weibull mixture cure rate model, which approximated the fraction of patients who would remain RF long-term, said Hauschild, a professor of dermatology at the University Hospital Schleswig-Holstein, Campus Kiel, in Germany.¹

Data showed that 43% (190/438) of patients assigned to dabrafenib/trametinib had an RFS event compared with 61% (262/432) of patients assigned to placebo. At the data cutoff of November 8, 2019, the median RFS was not reached (NR) with the regimen (95% CI, 47.9-NR) versus 16.6 months (95% CI, 12.7-22.1) with placebo (HR, 0.51; 95% CI, 0.42-0.61).

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

Investigators observed a long-term RFS advantage associated with dabrafenib/trametinib across all AJCC 7 substages. The hazard ratio was 0.61 (95% CI, 0.35-1.07) for stage IIIA disease; 0.50 (95% CI, 0.37-0.67) for stage IIIB; and 0.48 (95% CI, 0.36-0.64) for stage IIIC.

In patients with stage IIIA disease, the 4-year RFS rate was 72% (95% CI, 62-83) with the doublet therapy versus 62% (95% CI, 51-76) with placebo. At 5 years, the RFS rate was 65% (95% CI, 55%-77%) and 58% (95% CI, 46%-72%), respectively.

In patients with stage IIIB disease, 5-year RFS rate also favored dabrafenib/trametinib, 55% versus 34% (HR, 0.50; 95% CI, 0.37-0.67). In patients with stage IIIC disease, the 5 -year RFS rate was 45% (95% CI, 38%-53%) in the dabrafenib/trametinib arm and 29% (95% CI, 23%-37%) in the placebo arm (HR, 0.48; 95% CI, 0.36-0.64).

Although "it is very clear that all patient groups [benefited] from dabrafenib and trametinib compared with placebo," the combination modality did not reach statistical significance in patients with a BRAF V600K mutation (n = 78) and the continent subgroup comprising Australia and New Zealand (n = 107). Hauschild said that result could be due to the small number of patients in these subgroups.

Notably, the median distant metastasis-free survival was NR in either arm, but favored the combination approach (HR, 0.55; 95% CI, 0.44-0.70). The 5 year DFS rate was 65% (95% CI, 61-71) in the dabrafenib plus trametinib group and 54% (95% CI, 49-60) 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. The event-driven final OS analysis will be reported in the future, Hauschild said. Safety data were also not updated in this 5 year analysis because all patients completed treatment.

COMBI-AD: The Primary Analysis

COMBI-AD (NCT01682083) enrolled 870 patients with completely resected, stage III cutaneous melanoma that harbored a BRAF V600E or V600K mutation. Eligible patients were required to have undergone resection 12 weeks or earlier prior to randomization, must not have received prior systemic therapy, and had an ECOG performance status of 0 to 1.

The 438 patients assigned to the doublet therapy were treated with 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. The remaining 432 patients received 2 matched placebo tablets. In both arms, treatment was administered for a period of 12 months.

At a median follow-up of 2.8 years, the estimated 3-year RFS rate was 58% with the regimen and 39% with placebo (HR, 0.47; 95% CI, 0.39-0.58; P <.001).²

The 3 -year OS rate was 86% among dabrafenib/trametinib-treated patients and 77% among placebo-receiving patients (HR, 0.57; 95% CI, 0.42-0.79; P = .0006), however, this improvement did not cross the prespecified interim analysis boundary of P = .000019. Rates of DMFS were also higher in the combination therapy group compared with the placebo group.

_Reference

_{1. Hauschild A, Dummer R, Santinami M, et al. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600-mutant melanoma: five-year analysis of COMBI-AD. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31. Abstract 10001.}

_{2. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813-1823. doi: 10.1056/NEJMoa1708539}