Dabrafenib and trametinib doubles the relapse-free survival in patients with stage III BRAF mutant melanoma

Surgery is curative for most patients with localized melanoma. However, patients with regional nodal involvement (stage III disease) are at a higher risk for relapse and death after resection. Results of the phase III COMBI-AD demonstrated that targeted adjuvant therapy with dabrafenib and trametinib doubles the relapse-free survival (RFS) in patients with stage III BRAF-mutant melanoma. The hazard ratio (HR) of 0.47 observed in this trial is the best result ever shown for an adjuvant treatment in stage III melanomas. Moreover, also the overall survival (OS) and the time to occurrence of distant metastases were significantly longer when patients received the combination in the adjuvant setting.

In Europe, there is no standard of care for the adjuvant treatment of stage III melanoma. Interferon is approved for these patients but this is a toxic therapy that improves the relative RFS by just 20% compared to placebo. Previous phase III trials have shown that the combination of dabrafenib and trametinib improved the OS and progression-free survival (PFS), and was well-tolerated, in patients with advanced, unresectable metastatic BRAF-mutant melanoma. COMBI-AD is the first clinical trial of targeted therapies for adjuvant treatment of stage III melanoma. All patients in the study had a BRAF mutation (91% V600E and 9% V600K). In total, 870 patients were randomized (1:1) within 12 weeks of complete surgical resection to receive dabrafenib (150mg twice daily) plus trametinib (2mg once daily), or matching placebos. Patients were treated for 12 months and stratification was done based on the type of BRAF mutation (V600E versus V600K) and the disease stage (IIIA versus IIIB versus IIIC). The primary endpoint of COMBI-AD was RFS, with OS, distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety as key secondary objectives.

At a median follow-up of 2.8 years, the combination therapy had significantly reduced the risk of disease recurrence or death by 53% compared to placebo (median RFS not reached versus 16.6 months; HR[95%CI]: 0.47[0.39–0.58]; p < 0.0001). At 3 years, 58% of patients in the combination arm were free of relapse as compared to only 39% in the placebo arm. This benefit in RFS with the combination was observed across all patient subgroups. Dabrafenib + trametinib adjuvant therapy also resulted in a statistically significant 43% reduced risk of death compared to placebo (median OS not reached in either arm; HR[95%CI]: 0.57[0.42-0.79]; p = 0.0006). At 3 years 86% of patients who received the adjuvant combination therapy was still alive, while this was only the case for 77% of patients treated with placebo. In addition to this, dabrafenib + trametinib also induced a significantly better distant metastases-free survival (HR: 0.51) and freedom from relapse (HR: 0.47) compared to placebo.

In total, 97% of patients on the combination had an adverse event of any kind and 41% experienced a serious (grade 3/4) adverse event. In the placebo arm these percentages were 88% and 14%, respectively. No treatment-related fatalities were reported. In 26% of the patients receiving dabrafenib + trametinib, therapy had to be stopped due an adverse event (versus 3% on placebo). This rate of treatment discontinuation is higher than what was seen in clinical trials with stage IV melanoma patients. According to the investigators, this could in part be related to the fact that 90% of patients had no progressive disease and were treated for the scheduled full year. The longer patients receive treatment, the more likely they are to have adverse events. Nevertheless, there were no new toxicities compared to those already seen in stage IV disease.

In summary, COMBI-AD convincingly demonstrated that the combination of dabrafenib and trametinib is a new and very effective adjuvant treatment option in stage III melanoma patients.

Reference

Hauschild A, Santinami M, Long G, et al. COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Presented at ESMO 2017; abstract LBA6_PR.