Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

SUMMARY: It is estimated that in the US, approximately 76,000 new cases of melanoma were diagnosed and close to 8000 individuals died of the disease, in 2014. The incidence of melanoma has been on the rise for the past three decades. The FDA granted accelerated approval in January 2014, for a combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced melanoma, based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BREAK-3 randomized phase III trial, TAFINLAR® (Dabrafenib), a selective oral BRAF inhibitor demonstrated a statistically significant improvement in Progression Free Survival (PFS) and Response Rate (RR) compared to Dacarbazine (DTIC), in patients with advanced BRAF V600E/K mutated melanoma. In the BRIM 3 randomized, phase III study, ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF demonstrated significant improvement in Progression Free Survival and Overall Survival compared to Dacarbazine. Squamous cell carcinoma’s were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. The addition of a MEK inhibitor such as MEKINIST® (Trametinib) to a BRAF inhibitor such as TAFINLAR®, has addressed some of these limitations, in previously published studies, with improvement in Progression Free Survival. MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway and has been shown to significantly improve Progression Free Survival, Response Rate and Overall Survival, when compared to chemotherapy, in advanced melanoma patients with BRAF V600E/K mutations. The authors in this open label, randomized, phase III trial, evaluated the outcomes, comparing a combination of TAFINLAR® and MEKINIST® with single agent ZELBORAF® , in previously untreated and unresectable Stage IIIC or IV melanoma patients with BRAF V600E or V600K mutations. Eligible patients (N=704) were assigned in a 1:1 ratio to receive either a combination of TAFINLAR® (Dabrafenib), 150 mg PO BID and MEKINIST ® (Trametinib) 2 mg PO QD or ZELBORAF® (Vemurafenib) 960 mg PO BID, as first line therapy. The primary end point of this study was Overall Survival. Secondary end points included Progression Free Survival, Overall Response Rate, duration of response, and safety. At the preplanned interim analysis, the Overall Survival at 12 months was 72% in the combination therapy group and 65% in the single agent ZELBORAF® group (HR=0.69; P=0.005). The median Progression Free Survival was 11.4 months in the combination therapy group and 7.3 months in the ZELBORAF® group (HR=0.56; P<0.001). The objective response rate was 64% with combination therapy and 51% with single agent ZELBORAF® (P<0.001). There was no difference in the rates of severe adverse events and study drug discontinuations between the two groups. Skin cancers such as Squamous cell carcinoma and Keratoacanthoma occurred in 1% of patients in the combination therapy group and 18% of those treated with ZELBORAF® . The authors concluded that a combination of BRAF inhibitor TAFINLAR® and MEK inhibitor MEKINIST® significantly improved Overall Survival as compared with ZELBORAF® monotherapy, with a 31% relative reduction in the risk of death, in previously untreated patients with metastatic melanoma, with BRAF V600E or V600K mutations. This benefit was accomplished without increased overall toxicity. Robert C, Karaszewska B, Schachter J, et al. N Engl J Med 2015; 372:30-39