Latest Approved Therapies for Metastatic Melanoma: What Comes Next?

Abstract

Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. The recent oncogene-directed therapeutic, vemurafenib, usually produces high level of tumor shrinkage and survival benefits in many patients with B-RAF V600E mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T-cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of “melanoma stem cells” to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas.

Melanoma genotypes and phenotypes get personal

“…85 Hence, initial targeted therapies aimed at driver mutations/pathways and/or virulence-conferring cells are used to shrink down the bulk of tumors, coupled with immune enhancement in which both antigenic epitopes are created/exposed and more favorable microenvironments created that are conducive to immunocytic-mediated MM cell eradication. [114][115][116] The searches for better understanding of cancer genome landscapes and signaling pathway alterations, in concert with drug development efforts, present great opportunities and challenges for patient suffering from MM and many other malignant tumors. 117 …”

Burden of Illness for Metastatic Melanoma in Canada, 2011–2013

“…Patients with stage iv disease have a very poor prognosis, with fewer than 10% being alive at 5 years 2,[23][24][25][26] , although recent advances in targeted and immunotherapies have significantly improved those numbers [27][28][29][30][31][32] . Although the activity of targeted therapies and immunotherapies in melanoma has been promising, the prognoses for long-term disease-free survival among patients with metastatic and recurrent disease remain poor 33,34 . Thus, an urgent unmet medical need for effective therapies in patients with advanced melanoma still exists.…”

Bench to bedside: mechanistic principles of targeting the RAF kinase in melanoma

“…Significant inroads have been made in the last decade towards understanding the molecular underpinnings of melanoma, ushering in new therapeutic strategies. Melanoma is a molecularly heterogeneous disease with anomalies in melanocyte tumor cells, microenvironment of the cells, and in immune surveillance of the tumor . Understanding the specific defects leading to tumor initiation and progression allows for tailoring specific therapeutics, thereby maximizing efficacy while minimizing toxicity.…”