The combination of dabrafenib and trametinib leads to a median survival exceeding 2 years in advanced melanoma

An update of the phase III COMBI-v trial demonstrates that the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib results in a median overall survival (OS) of 25,6 months in patients with advanced melanoma. This survival seen with the combination is significantly longer than the 18 months seen with vemurafenib monotherapy, the comparator therapy in this study. In addition to this, the updated analysis confirms the longer progression-free survival (PFS) and the superior response rate (RR) of the combination therapy as compared to vemurafenib monotherapy.

COMBI-v was an open-label, randomized, phase III trial comparing the combination of dabrafenib and trametinib with vemurafenib monotherapy in the first-line treatment of 704 patients with BRAF^V600E/K mutation-positive, metastatic melanoma. At the time of the presented analysis, approximately 50% of patients in the study had deceased (349/703) and the median follow-up was 18 months.

The updated results of the study indicates that the combination therapy was associated with a reduction of 34% in the risk of dying as compared to vemurafenib monotherapy. The median OS with the combination was 25.6 months as compared to 18 months when vemurafenib was given (HR[95%CI]: 0.66[0.53-0.81]; p< 0.001). Looking at the evolution of the OS in this study, it becomes clear that the OS advantage of dabrafenib plus trametinib increased over time. In fact, after one year, 73% of patients treated with the combination was still alive as compared to 64% with vemurafenib. After 2 years, the survival rate with the combination therapy was 51% as compared to 38% with vemurafenib monotherapy. In addition to this, patients receiving the combination also remained progression-free for a longer period of time. In fact, the median PFS was 12.6 months with the dabrafenib-trametinib combination as compared to 7.3 months with vemurafenib (HR[95%CI]: 0.61[0.51-0.73]; p< 0001). The updated analysis of COMBI-v also confirmed the higher response rate of the combination as compared to vemurafenib (66% vs. 53%; p= 0.0008) and confirmed the longer duration of response seen with the dual inhibition (13,8 vs. 8,5 months). With respect to safety, no new toxicity signals were reported during the 8 additional months of follow-up.

Finally, Robert et al. reported on a subgroup analysis of COMBI-v in function of the lactate dehydrogenase (LDH) level at baseline. This analysis reveales that patients with an LDH level below, or equal to the upper limit of normal (ULN) had the largest benefit of the combined treatment with dabrafenib and trametinib. In this subgroup of patients, the median PFS with the combination therapy was 17.5 months, while the median OS was not reached after 32 months.

In summary, this updated analysis of the COMBI-v study demonstrates that combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib results in a median OS of more than 2 years in patients with BRAF-mutation positive, advanced melanoma. This is the longest median OS ever reported in a clinical trial in this setting. These results of the COMBI-v trial are in line with what was reported from the COMBI-d trial at the ASCO meeting earlier this year and underline the fact that combining a BRAF inhibitor with a MEK inhibitor should be the way forward in the treatment of these patients.

Referentie

Robert C, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma . Presented at ECC 2015; Abstract #3301.