1. After almost 10 years of follow-up, adjuvant dabrafenib and trametinib improved relapse-free and metastasis-free survival compared to placebo in patients with resected stage III melanoma.
2. Overall survival, however, did not differ significantly between the combination adjuvant therapy versus placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Melanoma is a deadly form of skin cancer, hallmarked by early invasion and metastasis carrying a significant risk of recurrence by the time of diagnosis. A 12-month adjuvant therapy with the BRAF-targeting agent dabrafenib and the MEK inhibitor trametinib was previously shown to reduce the risk of recurrence and prolong relapse-free survival in patients with resected stage III melanoma BRAF-V600 mutations, leading to its approval. This study was a follow-up to the original therapy trial. With the median follow-up of 8.33 years for the dabrafenib plus trametinib (adjuvant) group and 6.87 years for the placebo group, there was no significant difference in overall survival, despite the adjuvant group being favored. Nevertheless, the adjuvant therapy was associated with improved relapse-free and metastasis-free survival. Furthermore, within patients with the specific BRAF-V600E mutation, survival benefit over placebo was observed. No new safety concerns arose from the follow-up. The study was limited by underpowered subgroup analyses and a small number of patients at risk after 100 months. Notwithstanding, these results reaffirmed the efficacy and safety of adjuvant dabrafenib and trametinib in treating BRAF-V600-mutated stage III melanoma.
Click here to read the study in NEJM
Relevant Reading: Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
In-Depth [randomized controlled trial]: The original trial was a randomized placebo-controlled trial investigating the efficacy of adjuvant therapy with dabrafenib and trametinib in treating patients with BRAF-V600-mutated resected stage III melanoma. The trial regimens were continued for 12 months or until the occurrence of disease relapse, intolerable toxic effects, withdrawal of consent, or death. Patients were first followed for relapse until the first relapse, then they were followed for survival. The primary outcome was relapse-free survival. Secondary outcomes included metastasis-free survival, overall survival, and safety. In total, 870 patients were randomized 1:1 to receive the adjuvant therapy or matched placebo. The estimated overall survival at 8 years was 71% with the adjuvant group and 65% with placebo (hazard ratio for death 0.80, 95% confidence interval [CI] 0.62-1.01, p=0.06), which favored the adjuvant group but was not significant statistically. Twenty-three percent of patients in the adjuvant group and 26% in the placebo group had died from melanoma (hazard ratio for death from melanoma 0.78, 95% CI 0.59-1.02). Relapse-free survival (hazard ratio for relapse or death 0.52, 95% CI 0.43-0.63) and metastasis-free survival (hazard ratio for metastasis or death 0.56, 95% CI 0.44-0.71) were both improved in the adjuvant group, compared to placebo. The analysis found survival benefits across several prespecified subgroups, including the majority of patients who had a BRAF V600E mutation (hazard ratio for death 0.75, 95% CI 0.58-0.96), those with primary tumor ulceration, and those with macrometastasis, although the trial was not powered to assess these subgroups. No new safety signals arose during this follow-up after the original trial, where serious adverse events were reported in 41% of patients in the adjuvant group and 13% in the placebo group. These results corresponded with other trials and clinical practice since, and these benefits are comparable to immunotherapy, further reaffirming the benefits of adjuvant dabrafenib-trametinib therapy in treating BRAF-V600-mutated stage III melanoma.
Image: PD
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