A 5-year analysis of the randomized COMBI-AD clinical trial confirms long-term relapse-free survival (RFS) in patients with resected stage III BRAF V600-mutation–positive melanoma who are treated with the combination of adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist) for 12 months.
Follow-up data at a minimum of 59 months showed that median RFS was not yet reached in the dabrafenib plus trametinib arm compared with 16.6 months in the placebo arm, as presented by Axel Hauschild, MD, PhD, Professor, Dermatology Oncology, University Hospital Schleswig-Holstein, Kiel, Germany, at the 2020 American Society of Clinical Oncology Virtual Scientific Meeting.
“This analysis represents the longest follow-up to date from a phase 3 study of a current standard of care adjuvant therapy, as it is approved and used in many countries for patients with resected stage III BRAF-mutant melanoma,” he said. “It shows that there is a more than 50% 5-year RFS, and RFS curves for both treatment arms appear to be reaching a plateau, which is a good sign if we are talking about cure.”
COMBI-AD is a randomized, phase 3 trial evaluating adjuvant dabrafenib 150 mg twice daily plus trametinib 2 mg once daily versus 2 matched placebo in 870 patients with stage III BRAF V600E/K-mutation–positive melanoma who had their tumors resected ≤12 weeks before randomization. Previous systemic therapy was not permitted. At baseline, approximately three-fourths of patients in each arm had involvement of 1 to 3 lymph nodes.
Median follow-up was 60 months in the active treatment arm and 58 months in the placebo arm, at which time 190 of 438 (43%) patients in the dabrafenib plus trametinib arm and 262 of 432 (61%) patients in the placebo arm had an RFS event, corresponding to a hazard ratio (HR) of 0.51 (95% confidence interval [CI], 0.42-0.61).
Ten patients in each arm had a secondary primary melanoma, which were counted as a relapse, said Dr Hauschild.
The difference in RFS was consistent across subgroups, including those with BRAF V600E or BRAF V600K mutations, aged <65 years or ≥65 years, those with micrometastasis, those with macrometastasis, and regardless of the number of lymph nodes involved.
The benefit to the combination treatment on RFS was evident across all American Joint Committee on Cancer (AJCC) 7 substages: HRs in favor of dabrafenib plus trametinib were 0.61 (95% CI, 0.35-1.07) in patients with stage IIIA disease, 0.50 (95% CI, 0.37-0.67) in those with stage IIIB, and 0.48 (95% CI, 0.36-0.64) in those with stage IIIC.
An analysis according to AJCC 8 yielded similar findings, including in a newly designated stage IIID group, in which the HR in favor of dabrafenib/trametinib was 0.34 (95% CI, 0.14-0.79).
Distant metastasis-free survival was not reached in either arm but favored dabrafenib plus trametinib (126 events vs 159 events; HR, 0.55; 95% CI, 0.44-0.70).
A larger proportion of patients in the placebo arm required any subsequent anticancer therapy (54% vs 40%) and subsequent systemic anticancer therapy (47% vs 34%). Some 56% in the placebo group versus 35% in the active treatment group were treated subsequently with a BRAF or MEK inhibitor.
Overall survival data are not yet mature, although the trend currently favors dabrafenib/trametinib, Dr Hauschild said.
These data suggest that a long-term survival benefit is conferred in patients with stage III BRAF V600-mutation–positive melanoma treated for 12 months with adjuvant dabrafenib plus trametinib.