BRAF Inhibitors versus Immunotherapy in Patients with BRAF V600-Mutant Metastatic Melanoma

SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. The approval of the combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced melanoma, was 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. However, Squamous Cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation (BRAF wild-type cells) 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 PFS. 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 PFS, RR and Overall Survival (OS), when compared to chemotherapy, in advanced melanoma patients with BRAF V600E/K mutations. A combination of BRAF inhibitor TAFINLAR® and MEK inhibitor MEKINIST®, significantly improved OS, as compared with monotherapy with BRAF inhibitor, 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. However, approximately 50% of patients progress after 12 months, although a significant number of patients experience long-term benefit without progression.

The purpose of this study was to identify the clinical predictors and analyze the clinical correlates of those who had prolonged survival. The authors in this manuscript report the updated OS results of a previously published study, in which BRAF inhibitor-naive patients were treated with a combination of TAFINLAR® and MEKINIST®. Additionally, the authors in this study also report the clinical factors associated with long term survival. The original open-label phase I and II study of combination therapy with TAFINLAR® and MEKINIST® (N Engl J Med. 2012;367:1694-1703) had four parts (parts A, B, C, and D). The present analysis evaluated the outcomes of a total of 78 BRAF inhibitor-naive patients, enrolled in part B (N= 24) and part C (N= 54), who received the phase III dose (optimal dose) of oral TAFINLAR® 150 mg twice daily combined with oral MEKINIST® 2 mg once daily. The remaining cohorts in parts B and C and all cohorts in parts A and D did not receive the phase III dose of the combination therapy and therefore are not described here.

It was noted that among patients in part B of the study, the 1 year Progression Free Survival (PFS) was 44%, 2 year PFS was 22% and 3 year PFS was 18%. Among patients in part C, the 1 year PFS was 41%, 2 year PFS was 25% and 3 year PFS was 21%. The median Overall Survival (OS) was 27.4 months in part B and 25 months in part C with an OS at 1, 2, and 3 years of 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with good prognostic factors such as metastases in fewer than three organ sites and lower baseline LDH (Lactate Dehydrogenase) levels. The 3 year OS was 62% in patients with normal baseline LDH levels and 63% in those who had a complete response.

The authors concluded that a combination of TAFINLAR® and MEKINIST® results in a median OS of more than 2 years in BRAF V600 mutation-positive metastatic melanoma, with approximately 20% of the patients remaining progression free at 3 years. Good prognostic features at baseline, were predictive of durable responses. With dilemma facing clinicians, whether to choose MAP Kinase inhibitors versus Immunotherapy, as first line therapy for this patient group, the longest follow up data presented, demonstrating durable benefit with a combination TAFINLAR® and MEKINIST®, should be very reassuring. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. Long GV, Weber JS, Infante JR, et al. JCO JCO629345; published online on January 25, 2016