Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083).,We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term.,In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo.,We report updated RFS (primary end point) and distant metastasis-free survival.,RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status.,The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model.,At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59).,Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67).,The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm.,Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.,Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib.,Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.
Anti-CTLA-4 antibody induces selective depletion of T reg cells within tumor lesions in a manner that is dependent on the presence of Fc gamma receptor-expressing macrophages within the tumor microenvironment.,Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma.,Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression.,We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions.,Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner.,Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.