Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma

Abstract

Melanoma is the most dangerous form of skin cancer owing to its metastatic potential and is an important public health concern. The melanoma incidence has been increasing worldwide. Although potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blocking antibodies, as well as combination strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review was to summarize the evolution of and recent advances in the treatment of metastatic melanoma. Therefore, we conducted a comprehensive PubMed search between January 1, 1960, and February 1, 2014, using the search term melanoma or metastatic melanoma combined with terms such as chemotherapy, immunotherapy, CTLA-4, PD-1, PD-L1, adoptive T cell, targeted therapy, MAPK, molecular biology, and survival.

Figure 1

MAPK pathway signaling in malignant melanoma leads to phosphorylation and activation of RAS, RAF, MEK, and ERK, a process that ultimately regulates the cell cycle, differentiation, and apoptosis. Mutated BRAF, which is 500-fold activated, stimulates constitutive signaling, proliferation, and survival, making it an excellent target for vemurafenib and dabrafenib. Trametinib inhibits MEK, situated downstream. MAPK = mitogen-activated protein kinase

Figure 2

Timeline depicting FDA approvals and landmark clinical trials in metastatic melanoma. HR = hazard ratio; N = number randomized; OS = overall survival; RR = response rate; PFS = progression-free survival

Figure 3

Figure 3.a. T-cell activation with positive co-stimulation. Figure 3.b. CTLA-4 is a negative regulator of T-cell activation. CTLA-4 inhibitors binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligand, B7. Blockade of CTLA-4 augments T-cell activation and proliferation. Figure 3.c. Engagement of PD-1 expressed on T cells with PDL-1 expressed on APC or tumor cells results in T-cell suppression and tumor protection. Blockade of this interaction with either PD-1 or PDL-1 blocking antibodies can “wake up” exhausted T cells, resulting in a T-cell response against tumor. APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte antigen-4; MHC = major histocompatibility complex; PD-1 = programmed death 1; PDL-1 = programmed death ligand-1; TCR = T-cell receptor