Metastatic melanoma is an aggressive form of skin cancer with poor prognosis. Targeted therapies such as BRAF and MEK inhibitors have demonstrated clinical benefits in patients with advanced BRAF-mutant melanoma.1,2 As such, there are now three approved BRAF and MEK inhibitor combination therapies for the treatment of advanced BRAF-mutant melanoma. However, there is lack of data defining the long-term clinical outcomes of these therapies in this patient population. A recent study published in the New England Journal of Medicine which collectively investigated the extended survival data from two clinical trials, showed that first-line treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in patients with unresectable or metastatic melanoma resulted in 5-year survival in approximately one third of patients.3
Despite relatively higher prevalence in western countries, metastatic melanoma is the most serious form of skin cancer with poor prognosis and accounts for 10% of skin cancer cases in Hong Kong.4 Mutations of the BRAF gene are observed approximately half of all melanomas which led to the development of drugs targeting BRAF or related proteins such as MEK, known as BRAF or MEK inhibitors.5 Due to clinical studies that have demonstrated enhanced clinical benefits of using BRAF and MEK inhibitors concurrently, there are three BRAF and MEK inhibitor combination therapies which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced BRAF-mutant melanoma to date.
Although several clinical studies show improved progression-free survival (PFS) and overall survival (OS) in patients receiving BRAF and MEK inhibitor combination therapy compared with either type of inhibitor alone, long-term clinical outcomes remain unclear. Recently, a study collectively analyzed the extended survival data from two phase 3 clinical trials, COMBI-d and COMBI-v, which included a total of 563 patients, to define 5-year survival rates and clinical characteristics of patients in which sustainable benefits were observed.3
The study reported a PFS rate of 19% (95% CI: 15-22) and OS rate of 34% (95% CI: 30-38) at 5 years after first line treatment with dabrafenib plus trametinib.3 Patients who showed a complete response (383 of 536 patients) had PFS and OS rates of 49% (95% CI: 39-58) and 71% (95% CI: 62-79) respectively, suggesting that having a complete response to combination therapy is a good indicator of long-lasting treatment benefits.3 Furthermore, PFS and OS rates appeared to stabilize from 3 to 5 years.5 No unexpected adverse events were reported in the extended follow-up.3
A multivariate analysis of baseline factors identified that female sex, better ECOG performance status scores, normal lactate dehydrogenase levels and fewer than three organ sites with metastasis were associated with significantly longer PFS and OS. For instance, the 5-year OS rate among patients with high lactate dehydrogenase level at baseline was 16% (95% CI: 11-22), compared to 43% (95% CI: 38-49) in those with normal lactate dehydrogenase levels.3 Patients who were alive or remained progression free at 5 years after treatment randomization were more likely to have baseline factor characteristics associated with lower disease burden than those in the overall patient population.3
The findings in this study suggested that first-line treatment with dabrafenib plus trametinib demonstrates long-lasting clinical outcomes in a moderate proportion of patients with advanced BRAF-mutant melanoma. Interestingly, several ongoing clinical trials are now investigating the addition of immune checkpoint inhibitors targeting PD1 and PD-L1 to BRAF and MEK inhibitor combination therapy. The evaluation of baseline factors which appear to be associated with PFS and OS may be used as an end point in future studies.3 Identification of further biomarkers for the selection of patients who best benefit from treatment may enhance survival improvement in patients with advanced melanoma.