Confirmed durable efficacy of dabrafenib plus trametinib as first-line treatment for advanced BRAF-mutant cutaneous melanoma

Updated results of the COMBI-v study, in which the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is assessed in patients with BRAFV600–mutant advanced melanoma, confirm the previously reported findings of this study. The 3-year overall (OS) and progression-free survival (PFS) rates were shown to be 45% and 24% respectively for dabrafenib plus trametinib, compared to 31% and 10% for vemurafenib. A durable benefit was seen for the combination in all prognostic subgroups, but this was most pronounced in patients with normal LDH levels (and limited metastatic burden).

In the phase III, randomized, double-blind COMBI-v study, a total of 794 patients with histologically confirmed, unresectable, stage IIIC or IV BRAF^V600E/K–mutant melanoma were randomly assigned to receive either first-line dabrafenib (150 mg BID) in combination with trametinib (2 mg QD) or vemurafenib (960mg BID). Prior comparative analyses of COMBI-v showed significantly improved outcomes favoring the combination of dabrafenib and trametinib over vemurafenib. In these analyses, durable benefit and sustained tolerability was observed for a substantial proportion of patients treated with dabrafenib and trametinib, with a 2-year OS rate of 51%. This finding was confirmed in the COMBI-d study, comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy for patients with unresectable or metastatic BRAF^V600E/K mutant melanoma, where a 2- and 3 year OS rate of 52% and 44% was reported. During the 2016 annual ESMO meeting, updated results of the COMBI-v study were reported, with an additional follow-up of 16 months since the 2-year data cutoff (median follow-up 23 months for the combination).

Following the previously reported OS superiority of combined BRAF and MEK inhibition, a total of 34 vemurafenib-treated patients (9%) crossed over to the dabrafenib-trametinib arm. At the time of the presented analysis 66 patients in the combination arm (19%) and 10 patients in the vemurafenib arm (3%) was still on study treatment. The median duration of exposure was 12.2 months with dabrafenib + trametinib and 6.7 months with vemurafenib. With this additional follow-up, patients treated with dabrafenib and trametinib continued to achieve a durable OS and PFS benefit over patients receiving vemurafenib alone. After 3-years, the OS rate for patients treated with the combination was 45% as compared to 32% with vemurafenib. The HR for OS was 0.68 (95%CI: 0.56-0.83) with a median OS of 26.1 months for the combination and 17.8 months with vemurafenib. The 3-year PFS rate was 24% with the combination and 10% with vemurafenib alone (median PFS 12.1 vs. 7.3 months; HR[95%CI]: 0.61[0.51-0.73]).

In the subgroup of patients with an elevated LDH (> upper limit of normal, ULN) the 3-year OS rates with the combination and vemurafenib were 20% and 14% respectively (median OS 10.8 vs. 8.7 months; HR[95%CI]: 0.79[0.59-1.07). Of these patients 6% was free of progression after 3 years if they received the combination vs. 3% if they were treated with vemurafenib (HR[95%CI]: 0.70[0.53-0.93]). However, looking into subgroups of patients with more favorable prognostics, the benefit with the combination was much more pronounced. In patients with an LDH level ≤ULN, 56% was still alive after 3 years on the combination compared to 39% with vemurafenib alone (median OS: not reached vs. 21.6 months; HR[95%CI]: 0.61[0.47-0.79]). The 3-year PFS rate in these patients was 33% with dabrafenib + trametinib and 13% with vemurafenib (median PFS: 17.5 vs. 9.2 months; HR[95%CI]: 0.56[0.44-0.70]). Finally, of patients with LDH levels ≤ULN and less than 3 metastatic sites, 70% was still alive after 3 years if they received the combination as compared to 46% with vemurafenib alone (median OS: not reached vs. 26.4 months; HR[95%CI]: 0.47[0.33-0.67]). The PFS rate after 3 years in this population was 39% with the combination and 16% with vemurafenib (median PFS: 23.0 vs. 10.7 months; HR[95%CI]: 0.52[0.39-0.70]). The overall response rate with dabrafenib-trametinib was 67% as compared to 53% with vemurafenib. Nineteen percent of patients under the combination reached a complete response as compared to 12% with vemurafenib. Interestingly, the median duration of the complete responses with the combination was 39.6 months.

The safety profile of both treatment regimens was fairly similar, with less high-grade (grade 3 or more) toxicity for the combination (58% vs. 66%). Also the rate of adverse events leading to permanent treatment discontinuation was similar, with 16% for the combination and 15% with vemurafenib.

In summary, these updated results confirm the previously reported findings of COMBI-v, with a 3-year OS and PFS rate of 45% and 24% for the combination of dabrafenib and trametinib and 31% and 10% for vemurafenib, respectively. As such, these data support the long-term use of dabrafenib plus trametinib as the standard first-line targeted therapy for patients with BRAF-mutant advanced melanoma.

Reference

Robert C, Karaszewska B, Schacter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Presented at ESMO 2016; Abstract LBA40.