Confirmed long-term benefit of adjuvant dabrafenib-trametinib in patients with resected stage III BRAF V600-mutant melanoma
The COMBI-AD trial was the first prospective phase III trial evaluating a BRAF inhibitor and MEK inhibitor combination therapy as adjuvant treatment in patients with completely resected BRAF V600-mutated stage III melanoma. The five-year follow-up data of this trial, presented at ASCO 2020, further solidifies the relapse-free survival (RFS) benefit of adjuvant dabrafenib plus trametinib in this setting. Compared to placebo, adjuvant dabrafenib-trametinib was associated with a 49% reduced risk of having a relapse. Importantly, a pre-planned subgroup analysis of COMBI-AD demonstrates that adjuvant dabrafenib plus trametinib benefits patients irrespective of baseline patient and disease factors.
The COMBI-AD trial is a randomised phase III trial enrolling 870 patients with completely resected cutaneous melanoma and a BRAFV600E/K mutation. All patients had stage IIIA, IIIB or IIIC melanoma, as classified by the 7th edition of the American Joint Committee on Cancer Staging Manual (AJCC 7). Tumour resection was performed ≤ 12 weeks before randomisation. Patients could not have received any prior systemic treatment and had an ECOG performance status (ECOG PS) of 0 or 1. Patients were randomly assigned (1:1) to twelve months of adjuvant dabrafenib 150 mg, twice daily plus trametinib 2 mg, once daily or two matched placebo. Stratification was performed based on BRAF mutation and disease stage. Primary endpoint of the trial was RFS.
Previous results of the COMBI-AD trial showed a significant RFS benefit for patients treated with adjuvant dabrafenib plus trametinib compared to placebo. In the primary analysis, the three-year RFS rate with dabrafenib plus trametinib was 58%, as compared to 39% for patients who received placebo (HR [95%CI]: 0.47 [0.39-0.58], p<0.001). In addition, an interim analysis of overall survival (OS) indicated a three-year OS rate of 86% with dabrafenib plus trametinib versus 77% for placebo (HR [95%CI]: 0.57 [0.42-0.79]). At ASCO 2020, the five-year analysis of RFS was presented.
As reported earlier, the median age of the patients in the study was 50 years. Most patients (91%) had a BRAFV600E mutation and 92% had an ECOG performance status (PS) of 0. In total, 19% of the patients had stage IIIA disease while other patients had stage IIIB or IIIC disease. Baseline characteristics were well balanced between both treatment arms. At the data cut-off on November 8th, 2019, the minimum study follow-up was 59 months and 63% of the patients in the dabrafenib plus trametinib arm were still in follow-up (versus 54% in the placebo arm). In total, 21% of the patients in the dabrafenib plus trametinib arm had died as compared to 28% in the placebo arm. At the five-year analysis, patients in the combination arm had a 49% reduced risk of having a relapse (5-year RFS rates: 52% versus 36%, HR [95%CI]: 0.51 [0.42-0.61]). The RFS was significantly in favour of dabrafenib plus trametinib across all subgroups, although the difference did not reach statistical significance for patients with a BRAFV600K mutation and for the group of patients originating from Australia and New Zealand. However, according to the authors, this lack of significance is mainly the result of the small sample sizes of these patient groups (78 and 107 patients, respectively). The RFS benefit obtained with dabrafenib plus trametinib was evident across all AJCC 7 sub-stages (HR [95%CI]: IIIA, 0.61 [0.35-1.07]; IIIB, 0.50 [0.37-0.67]; IIIC, 0.48 [0.36-0.64]). The median distant-metastasis-free survival (DMFS), defined as first relapse only, was not reached in either arm but also this endpoint was clearly in favour of dabrafenib plus trametinib (HR [95%CI]: 0.55 [0.44-0.70]). In total, 43% of the patients in the dabrafenib plus trametinib arm and 60% of the patients in the placebo arm relapsed. Of the patients treated with dabrafenib plus trametinib, 34% received any systemic anticancer therapy, of which immunotherapy (26%) and small molecule-targeted therapy (20%) were used most frequently. For patients who received placebo, 47% received any systemic anticancer therapy (28% immunotherapy and 35% small molecule-targeted therapy). Safety data were not updated in this analysis because all patients had completed the study treatment. The final OS analysis is event driven and will be reported in the future.
The five-year analysis of the COMBI-AD trial represents the longest follow-up to date from a phase III study of a current standard-of-care adjuvant therapy for patients with resected stage III BRAFV600-mutant melanoma. These long-term data show that adjuvant dabrafenib plus trametinib can provide patients with a long relapse free survival, with more than half of the patients remaining free of relapse after 5 years. Interestingly, the Kaplan Meier curves for RFS seem to reach a plateau suggesting a cure for a substantial proportion of patients. The RFS benefit was consistently seen across all AJCC 7 stage III subcategories.
Hauschild A, Dummer R, Santinami M, et al. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD. Presented at ASCO 2020; Abstract 10001.