ReviewResistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?
Introduction
Melanoma is the most lethal form of skin cancer and its incidence continues to increase worldwide [1]. Until recently, the 5-year survival for patients with advanced melanoma (including both lymph node and other metastases) was only 16% (Surveillance, Epidemiology, and End Results (SEER) data 2011), and no drug therapy improved overall survival (OS). Since 2010, both selective kinase and immune checkpoint inhibitors have demonstrated survival benefits (reviewed in [2]), and have been approved for use in patients with metastatic melanoma in many countries around the world.
Approximately 40% of melanomas carry oncogenic BRAF mutations that constitutively activate the mitogen-activated protein kinase (MAPK) [3]. The most common BRAF mutation is V600E, which accounts for approximately 75–90% of the BRAF mutations identified in melanoma [2]. Pre-clinical studies showed that BRAFV600-mutant melanomas require MAPK signalling for their survival (reviewed in http://www.sciencedirect.com/science/article/pii/S2211124713004646 [4]) and phase III clinical trials confirmed that inhibition of BRAF alone, or the combined inhibition of BRAF and its downstream target, MEK, improved the OS of patients with advanced BRAF-mutant melanoma [5], [6], [7], [8], [9]. Based on these trials, the BRAF inhibitors (BRAFi) dabrafenib and vemurafenib as single agents, and dabrafenib combined with the MEK inhibitor trametinib are now approved for the treatment of metastatic BRAF mutant melanoma (reviewed in [2]).
In this review, we describe the data leading to the approval of BRAF/MEK inhibitors (BRAF/MEKi) for BRAFV600-mutant metastatic melanoma, and we explore the three major effectors of BRAF/MEK inhibitor resistance which are potentially targetable and propose new treatment strategies to further improve outcomes for patients with BRAF-mutated metastatic melanoma.
Section snippets
Approved targeted therapies in BRAF-mutated melanoma
Two BRAFi have been approved for the treatment of BRAF-mutated metastatic melanoma. Vemurafinib was the first targeted agent to be approved worldwide as first line treatment for BRAFV600-mutated metastatic melanoma after the landmark phase III study (BRIM-3) at first interim analysis showed that vemurafenib resulted in a significant improvement in progression-free survival (PFS) compared with dacarbazine chemotherapy (hazard ratio [HR] 0.26; p < 0.001, median PFS 5.8 versus 1.6 months,
Potentially targetable resistance mechanisms to targeted therapy
Acquisition of melanoma resistance to BRAFi occurs after a median of 6–8 months in 50% of patients on vemurafenib or dabrafenib monotherapy [5], [6]. Although resistance to combined BRAFi and MEKi therapy is delayed compared to treatment with the single agents, resistance remains a significant problem [14]. Interestingly, in contrast to the acquired resistance observed with other small molecule kinase inhibitors, such as imatinib in chronic myeloid leukaemia and epidermal growth factor receptor
Conclusions
There has been dramatic progress in improving clinical outcomes for patients with melanoma in the past 5 years. Combined treatment with BRAF and MEK inhibitors has significantly improved OS but resistance continues to be problematic. In this review we have discussed three therapeutic strategies that may overcome or delay resistance to MAPKi based on both the changes observed in melanoma tissue early during treatment and the known resistance mechanisms. Clinical trials using agents which target
Conflict of interest statement
G.V.L. is a consultant advisor to Amgen, BMS, MERCK MSD, Novartis, Provectus, Roche. Other authors have no conflicts of interest.
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