Role of dabrafenib/trametinib combination therapy in BRAF-mutated melanoma
COMBI-AD study evaluating adjuvant therapy in stage III melanoma
The COMBI-AD study investigated whether adjuvant combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib would improve outcomes in stage III melanoma patients with confirmed BRAFV600 mutations following complete surgical resection. In this double-blind, placebo-controlled, phase III study, 870 patients with high-risk stage IIIA, stage IIIB or stage IIIC, BRAFV600E- or BRAFV600K-positive cutaneous melanomas were randomly assigned to receive oral dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) or two matched placebo tablets, for 12 months following complete resection. The primary endpoint was relapse-free survival (RFS). [N Engl J Med 2017;377:1813-1823]
At a median follow-up of 2.8 years, the estimated 3-year RFS rate was 58 percent in the combination therapy group vs 39 percent in the placebo group (hazard ratio [HR] for relapse or death, 0.47; 95 percent confidence interval [CI], 0.39 to 0.58; p<0.001). (Figure 1) The combination therapy was thus associated with a 53 percent reduction in the risk of relapse. In terms of overall survival (OS), 86 percent of patients in the dabrafenib plus trametinib group were alive at 3 years, compared with 77 percent of patients receiving placebo.
Longer follow-up confirmed the RFS benefit associated with adjuvant dabrafenib plus trametinib in patients with resected BRAFV600-mutant stage III melanoma. At a median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo group), the 3-year and 4-year RFS rates were 59 percent (95 percent CI, 55 percent to 64 percent) and 54 percent (95 percent CI, 49 percent to 59 percent) in the combination therapy arm vs 40 percent (95 percent CI, 35 percent to 45 percent) and 38 percent (95 percent CI, 34 percent to 44 percent) in the placebo arm, respectively (HR, 0.49; 95 percent CI, 0.40 to 0.59). Subgroup analysis of RFS demonstrated a similar treatment benefit regardless of baseline factors including disease stage, nodal metastatic burden and ulceration. [J Clin Oncol 2018;36:3441-3449]
Long-term survival in COMBI-v and COMBI-d studies in unresectable or metastatic melanoma
Two randomized phase III studies, COMBI-d and COMBI-v, evaluated the efficacy and safety of combination therapy with dabrafenib plus trametinib compared with BRAF inhibitor monotherapy (dabrafenib alone or vemurafenib alone, respectively) in patients with previously untreated, unresectable or metastatic melanoma with BRAFV600E or BRAFV600K mutations. [N Engl J Med 2014;371:1877-1888; Lancet 2015;386:444-451; N Engl J Med 2015;372;30-39] In a pooled analysis of the COMBI-d and COMBI-v studies, 3-year progression-free survival (PFS) rate was 23 percent and 3-year OS rate was 44 percent for patients treated with dabrafenib plus trametinib. [Eur J Cancer 2017;82:45-55]
Long-term COMBI-v study data demonstrated that PFS rates were consistently higher in the dabrafenib plus trametinib arm compared with the vemurafenib monotherapy arm at 2, 3, 4 and 5 years. (Figure 2) The 5-year OS rate was 36 percent in the combination therapy group vs 23 percent for patients receiving vemurafenib monotherapy. (Figure 3) [N Engl J Med 2019;381:626-636 & Supplementary Appendix]
A pooled analysis of data from 563 patients receiving combination therapy in the COMBI-d and COMBI-v trials showed PFS rates of 21 percent at 4 years and 19 percent at 5 years. The OS rates were 37 percent at 4 years and 34 percent at 5 years. [N Engl J Med 2019;381:626-636 & Supplementary Appendix]
The same pooled analysis showed an objective response rate (ORR) of 68 percent among patients treated with dabrafenib plus trametinib, with 19 percent of patients achieving complete response (CR). Among those patients with a CR, 5-year PFS rate was 49 percent and 5-year OS rate was 71 percent. The median duration of CR was 36.7 months (95 percent CI, 24.1 months to not reached).
Quality of life data from COMBI-v study
The COMBI-v study also assessed the effects of treatment with dabrafenib plus trametinib vs vemurafenib monotherapy on health-related quality of life (QoL). Three different validated tools were used to evaluate QoL: the European Organisation for Research and Treatment of Cancer QoL, EuroQoL-5D, and Melanoma Subscale of the Functional Assessment of Cancer Therapy. QoL assessments were completed at baseline, during study treatment, at disease progression and after disease progression. [Lancet Oncol 2015;16:1389-1398]
Questionnaire completion rates were high in both the combination therapy group and the monotherapy group, with similar QoL and symptom scores at baseline in both groups. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of combination therapy compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression. Patients treated with dabrafenib plus trametinib had the largest improvement in ability to function, with improved scores in physical, role and social functioning domains. The combination therapy group also had the largest decrease in symptom scores, with improvements in pain, fatigue and appetite loss scores. QoL improvements were observed as early as week 8 after commencing treatment and sustained through week 48, suggesting a clear QoL benefit with combination therapy over monotherapy for patients.
NCCN guidelines for targeted therapy in cutaneous melanoma
BRAF mutations are found in an estimated 50 percent of patients with melanoma and may be associated with poorer outcomes and shorter survival. [Clin Cancer Res 2011;17:1658-1663, JAMA Oncol 2015;1:359-368] As such, BRAF status is considered a critical factor for choosing first-line systemic therapy in stage III or IV cutaneous melanoma. The US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend BRAF mutation testing for patients with stage III or IV melanoma. [NCCN Clinical Practice Guidelines in Oncology, Cutaneous Melanoma, Version 2.2019]
The NCCN guidelines also recommend combination therapy with BRAF- and MEK-targeted agents as one of the preferred first-line regimens in the treatment of metastatic or unresectable cutaneous melanoma in the presence of a BRAFV600 mutation. The guidelines note that in the absence of comparative phase III clinical trial data, it is difficult to select between immunotherapy and targeted therapy in the first-line treatment of BRAF-mutant melanoma and that the choice should be determined by individual patient’s characteristics. The guidelines suggest that BRAF/MEK inhibitors may be preferred in patients with rapidly progressing disease or symptoms, as they have a shorter time to response compared with checkpoint immunotherapies.