Credit: David A Litman | stock.adobe.com
A final analysis of the Phase III COMBI-AD trial (NCT01682083) show that over eight years of follow-up, 12 months of adjuvant therapy with the combination of Tafinlar (dabrafenib) plus Mekinist (trametinib) produced improved relapse-free survival (RFS) and distant metastasis–free survival (DMFS) compared to placebo in patients with resected stage III melanoma. Although the combination was found to reduce the risk of death overall by 20%, with a 25% reduction among patients with a BRAF V600E mutation, the overall survival (OS) benefit was not found to be statistically significant, according to the study, published by The New England Journal of Medicine.1,2
“The analysis of [OS] showed that the risk of death was 20% lower with [Tafinlar plus Mekinist] than with placebo, but the benefit was not significant,” the study authors wrote. “The analysis of melanoma-specific survival suggested that the risk of death from melanoma was 22% lower with combination therapy than with placebo. It is notable that among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. Owing to a slow rate of death, the required number of events had been reduced from the originally planned number (597) to the current number (260), although the power of the trial (80% for a hazard ratio for death of 0.70) was not affected.”1
Tafinlar and Mekinist inhibit different growth-promoting signals located in tumor cells that are activated by the V600E BRAF mutation. While Tafinlar blocks signaling from the BRAF protein, Mekinist blocks signals from the MEK protein. Tumors that initially respond to Tafinlar monotherapy may become resistant to the drug via activating signals from the MEK protein, therefore the combination therapy is thought to stop tumors from using this escape mechanism.3
The combination is currently indicated to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test; adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and with involvement of lymph nodes following a complete resection; treatment of patients with metastatic non-small cell lung cancer with BRAF V600E mutation as detected by an FDA-approved test; treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and with no satisfactory locoregional therapeutic options; treatment of patients aged 1 year and older with unresectable or metastatic solid tumors with BRAF V600E mutation who progressed following prior treatment and who have no satisfactory alternative treatment options; and treatment of pediatric patients aged 1 year and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy.4
For the two-arm, randomized, double-blind trial, investigators randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations in a 1:1 ratio to receive Tafinlar 150 mg twice daily plus Mekinist 2 mg once daily or two matched placebos. Patients continued on the Tafinlar and Mekinist combination for 12 months or until occurrence of disease relapse, unacceptable toxic adverse effects (AEs), withdrawal of consent, or death, whichever occurred first. Investigators followed patients for disease relapse until observation of first relapse, after which they were followed for survival.
The trial’s median duration of follow-up was 8.33 years for the combination therapy and 6.87 years for placebo. Kaplan–Meier OS estimates were in favor of the combination therapy compared with placebo; however, the survival benefit was not deemed significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P=0.06 by stratified log-rank test).
Investigators observed a consistent survival benefit across several prespecified subgroups, including 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). RFS results were in favor of the combination therapy over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as was DMFS (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). In terms of safety, AEs were consistent with findings from prior clinical trials and no new safety signals were reported.
“The final analysis of this trial had more than 8 years of follow-up for an approved adjuvant therapy in patients with resected stage III melanoma,” the study authors concluded. “One year of adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis–free survival than placebo, no long-term safety concerns, and a 20% lower risk of death than placebo (although the benefit was not significant), as well as a 25% lower risk of death among patients with melanoma with a BRAF V600E mutation. Whether or how therapies administered after relapse may have reduced the effect of adjuvant therapy on overall survival is unclear.”1
References
1. Long G., et al. Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med 2024;391:1709-1720. DOI: 10.1056/NEJMoa2404139. Vol. 391 No. 18
2. Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD). ClinicalTrials.gov. Updated August 30, 2023. Accessed November 11, 2024.
3. Winstead E. Dabrafenib–Trametinib Combination Approved for Solid Tumors with BRAF Mutations. National Cancer Institute. Website. Published July 21, 2022. Accessed November 11, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors
4. TAFINLAR and MEKINIST Prescribing Information. https://us.tafinlarmekinist.com/. Accessed November 11, 2024.