From the Guest Editors: Recent Advances and Evolving Challenges in Treating Unresectable Melanoma.

Abstract

The dramatic progress recently made in the treatment of metastatic melanoma seemed unachievable only 10 years ago. Until 2011, few effective therapies existed for metastatic melanoma, and overall survival was on the order of months. Dacarbazine was US Food and Drug Administration (FDA) approved in 1975 and remains the only chemotherapy ever approved for melanoma, with response rates of up to 15%, but with limited durability.1 Approval of high-dose interleukin 2 followed in 1998, with the potential for long-term durable responses in a minority of patients (up to 15%), but at the expense of significant toxicity.2 After decades of drought, the advent of genomic profiling combined with breakthroughs in understanding immune escape mechanisms has led to approval of more effective therapies based on immunologic manipulation and identification of targetable oncogenic drivers.3 Optimism in the field has soared since the 2011 FDA approval of the CTLA-4 inhibitor ipilimumab and the BRAF inhibitor vemurafenib, both of which provided unmatched options for disease control. Since then, dual immune checkpoint blockade with CTLA-4 and PD-1 inhibitors and vertical mitogen-activated protein kinase pathway inhibition with BRAF and MEK inhibitors are now standards of care. The challenges in melanoma therapeutics have shifted from finding an effective drug to understanding which drug to use first, how to combine drugs to induce a synergistic anti-tumor effect, how to overcome primary or acquired drug resistance, and how to mitigate treatment-related toxicity. This comprehensive special issue is composed of thoughtful perspectives from leading melanoma experts. Beginning with a focus on immunotherapy, Loo et al. review the use of single and dual-agent immune checkpoint blockade in advanced melanoma and the ongoing research efforts to personalize these approaches. Hu-Lieskovan et al. build off this chapter to explore combination therapy strategies using CTLA-4 and/or PD-1 inhibitors as a backbone, whereas Giuroiu et al. segue into a discussion of novel drugs in early clinical development that target new immune molecules. An exploration of adjunctive therapies follows, including radiation’s role in amplifying the antitumor immune response by Escorcia et al. and the use of and rationale for intratumoral approaches by Bommareddy et al. Merhavi-Shoham et al. review the experience with adoptive cell therapy including use of tumor infiltrating lymphocytes, T-cell receptor gene manipulation, and T cells with genetically modified chimeric antigen receptors. The edition’s focus then shifts to an update on molecularly targeted therapies by Iams et al. and Gibney et al. and transitions to current investigations for the management of melanoma brain metastases by Oliva et al. Despite the groundbreaking progress that has transpired in systemic therapies for advanced melanoma over the past decade, multiple barriers remain, as highlighted in Izar and colleagues’ commentary on clinical trial design and Sznol’s reflection on the challenges of clinical research in melanoma. We have reached an unprecedented era in advanced melanoma in which objective response rates to frontline combination CTLA-4 and PD-1 immunotherapy reach 57.7%, whereas response rates to monotherapy PD-1 inhibitors reach 43.7%.4 This success has stimulated the rapid investigation and/or FDA approval of these drugs in other immunogenic malignancies. However, no reliable predictive biomarkers currently exist to aid in patient selection, and the rate of grade 3-4 toxicity remains high, potentially precluding patients from receiving subsequent immunotherapies. Even after melanoma progression on immunotherapy, other options include BRAF/MEK inhibition in the setting of a driver BRAF mutation, immunotherapy reinduction, or alternative immune therapies. Therefore, as patient and clinician access to numerous effective standard-of-care treatment options has dramatically increased, the pool of melanoma clinical trial participants can decrease.