Improved response rate and survival with dabrafenib plus trametinib versus vemurafenib alone in advanced melanoma
Targeting BRAFV600E/K mutation-positive melanoma with a combination of dabrafenib plus trametinib achieves longer overall survival (OS) and progression-free survival (PFS) as well as better response rates, compared to treatment with vemurafenib alone. These results reconfirm previous preclinical data that a more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival of these patients.
Previously reported studies indicated that combining dabrafenib with trametinib results in higher response rates in advanced melanoma as compared to BRAF inhibition alone. Moreover, these studies demonstrated a significantly longer PFS with the combination. During ESMO 2014, the final analysis of the phase III COMBI-v study were presented. In this ongoing, two-arm study, 704 patients with advanced BRAFV600E/K mutation-positive melanoma were randomised to either a combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily), or to vemurafenib alone (960 mg, twice daily). The primary endpoint of the study was OS, with secondary endpoints being PFS, objective response rate (ORR), duration of response (DoR) and safety.
The pre-planned interim analysis demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for the combination therapy after which the IDMC recommended to stop the study. In this analysis, a 31% improvement in OS was shown among patients on combination therapy and a 44% reduction of the risk of disease progression compared to vemurafenib monotherapy. The median OS was not reached in the combination arm vs. 17.2 months in the vemurafenib arm (HR[95%CI]: 0.69 [0.53-0.89]; p = 0.005). The median PFS in the combination arm was 11.4 months compared to 7.3 months for vemurafenib alone (HR[95%CI]: 0.56 [0.46-0.69]; p < 0.001). In addition, the combination of dabrafenib and trametinib was associated with a significantly higher ORR as compared to vemurafenib monotherapy (64% vs. 51%; p < 0.001). Finally, researchers also indicated that the DoR was longer with the combination at a median of 13.8 months versus 7.5 months with vemurafenib.
In general, patients in both arms of the study had similar rates of severe adverse events. The incidence of pyrexia and ejection fraction decrease was higher with the combination. Interestingly, treatment with the combination therapy was associated with a much lower rate of cutaneous squamous cell carcinoma and other typical skin toxicity seen with BRAF inhibition.
In summary, these results indicate that combining dabrafenib with trametinib results in a significantly better OS, PFS and ORR as compared to vemurafenib alone, the current standard therapy in this setting. The data of this study together with the results of the coBRIM study provide convincing evidence that combination therapy with either dabrafenib and trametinib, or vemurafenib and cobimetinib will become the new standard systemic therapy for this patient population. Of special relevance is the lower risk for new cutaneous malignancies seen with the combination strategy in this study, which might be an extra advantage.
Robert C, Karaszewska B, Schachter J, et al. COMBI-v: A randomised, open-label, Phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at ESMO 2014; Abstract LBA4.