Advances in Intralesional Therapy for Locoregionally Advanced and Metastatic Melanoma: Five Years of Progress

SIMPLE SUMMARY: The prognosis for patients with locoregionally advanced and metastatic melanoma remains poor despite advances in systemic therapy. By delivering therapeutics directly to the site(s) of disease, intralesional therapies have the advantage of delivering the oncolytic agent directly into the metastatic melanoma while minimizing systemic side effects and resistance. Within the past 5 years, numerous potential intratumoral therapies have been investigated, though few have reached phase 2 clinical trials. We present a discussion of the scientific rationale for and status of intralesional therapies that have reached phase 2 or later clinical trials within the past 5 years in order to inform providers about current and upcoming intralesional therapeutic options for advanced melanoma. ABSTRACT: Locoregionally advanced and metastatic melanoma are complex diagnoses with a variety of available treatment options. Intralesional therapy for melanoma has been under investigation for decades; however, it has advanced precipitously in recent years. In 2015, the Food and Drug Administration (FDA) approved talimogene laherparepvec (T-VEC), the only FDA-approved intralesional therapy for advanced melanoma. There has been significant progress since that time with other oncolytic viruses, toll-like receptor agonists, cytokines, xanthene dyes, and immune checkpoint inhibitors all under investigation as intralesional agents. Further to this, there has been exploration of numerous combinations of intralesional therapies and systemic therapies as various lines of therapy. Several of these combinations have been abandoned due to their lack of efficacy or safety concerns. This manuscript presents the various types of intralesional therapies that have reached phase 2 or later clinical trials in the past 5 years, including their mechanism of action, therapeutic combinations under investigation, and published results. The intention is to provide an overview of the progress that has been made, discuss ongoing trials worth following, and share our opinions on opportunities for further advancement.