JMIR Publications

ABSTRACT

Cutaneous melanoma has always been a dreaded diagnosis due to its high mortality rate and its proclivity for invasiveness and metastasis. Historically, advanced melanoma treatment was limited to chemotherapy and nonspecific immunotherapy agents that displayed poor curative potential and high toxicity. However, during the last decade, the evolving understanding of the mutational burden of melanoma and the immune system evasion mechanisms has led to the development of targeted therapy and specific immunotherapy agents that have transformed the landscape of advanced melanoma treatment. Targeted therapy comprises of agents that directly inhibit mutated kinases, namely BRAF and MEK, which have been implicated in the growth and survival of cancerous melanocytes. However, the efficacy of BRAF and MEK inhibitor monotherapies was limited by early resistance and an upsurge in treatment-associated skin tumours. Consequently, a combined BRAF/MEK inhibitor approach was trialled, which resulted in superior survival rates while minimising the aforementioned limitations. On the other hand, specific immunotherapy agents were developed on the heels of Nobel Prize-winning discoveries that outlined the pivotal role of certain immune downregulatory signals that facilitate tumour growth. Despite the considerable strides in understanding the clinical implication of these agents, there is a scarcity in randomised clinical trials that directly compare the efficacy of the aforementioned agents, hence there are no clear-cut preferences among the available first-line options. This paper attempts to summarise the current understanding of first-line treatments. Additionally, it describes the indirect comparative evidence that aids in bridging the gap in the literature.