As reported at the 2024 ASCO Annual Meeting (Abstract 9500) and in The New England Journal of Medicine by Georgina V. Long, MD, PhD, and colleagues, the final, 8-year follow-up analysis of the phase III COMBI-AD trial has shown continued improvements in relapse-free and distant metastasis–free survival—as well as a 20% lower risk of death—with adjuvant dabrafenib plus trametinib vs placebo in patients with resected stage III melanoma and BRAF V600E or V600K mutations.
“The 5-year results of this trial showed that adjuvant therapy with [this approved combination] resulted in longer relapse-free survival and distant metastasis–free survival than the placebos,” the investigators remarked. “Longer-term data were needed, including data regarding overall survival.”
Georgina V. Long, MD, PhD
Study Details
In the double-blind trial, a total of 870 patients were randomly assigned 1:1 to receive either 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily (n = 438) or two matched placebos (n = 432) for 12 months. Follow-up data were provided for median durations of 8.3 and 6.9 years, respectively.
The investigators reported the final results of the trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis–free survival.
8-Year Outcomes
At 8 years, dabrafenib plus trametinib vs the placebos seemed to confer a nonsignificant overall survival benefit (estimated rate = 71% vs 65%; hazard ratio [HR] for death = 0.80, stratified log-rank P = .06). The investigators reported consistent results across several prespecified subgroups, including the 792 patients harboring a BRAF V600E mutation (HR for death = 0.75).
The median duration of relapse-free survival was 93.1 months with dabrafenib plus trametinib and 16.6 months with the placebos (HR for relapse or death = 0.52). A total of 28% and 37% of the patients who received these interventions, respectively, experienced a relapse with distant metastasis (HR for distant metastasis or death = 0.56).
KEY POINTS
- Relapse-free and distant metastasis–free survival appeared to favor dabrafenib plus trametinib over the placebos.
- The overall survival analysis revealed a 20% lower risk of death with dabrafenib plus trametinib vs the placebos, but the benefit was not found to be significant.
Adverse Events
Adverse events were documented in 97% of the patients treated with dabrafenib plus trametinib and in 88% of those who received the placebos. A total of 41% and 13% of patients in these treatment arms, respectively, experienced a serious adverse event. The investigators observed no new safety signals.
A higher incidence of primary or secondary cancer was reported with dabrafenib plus trametinib vs the placebos (events per 100 patient-years = 4.0 vs 2.6); however, none of these malignancies led to death in the investigational arm. Skin cancers—including basal cell carcinoma, new primary malignant melanoma, and squamous cell carcinoma—were the most frequently documented secondary malignancies.
After more than 8 years of follow-up, the investigators concluded: “One year of adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis–free survival than the placebos, no long-term safety concerns, and a 20% lower risk of death than the placebos (although the benefit was not significant), as well as a 25% lower risk of death among patients with melanoma with a BRAF V600E mutation.”
Dr. Long, of the Melanoma Institute Australia and the University of Sydney, is the corresponding author of the The New England Journal of Medicine article.
Disclosure: The study was funded by GlaxoSmithKline and Novartis. For full disclosures of the study authors, visit nejm.org.
