Advances in the discovery and development of melanoma drug therapies

ABSTRACT

Introduction

Therapeutic strategies for melanoma have evolved significantly over the last decade shifting from cytotoxic chemotherapies like dacarbazine to targeted therapies and immunotherapies including immune checkpoint inhibitors. These new drug therapies have improved overall as well as progression-free survival, lowering the mortality of this cancer for melanoma patients with advanced disease. Newer strategies incorporate combination therapies that harness synergies between mechanisms of anticancer efficacy as well as help overcome resistance issues of monotherapies, which remain a challenge.

Areas covered

This review looks at each class of drug therapy for melanoma and provides an overview of the preclinical mechanism of action, the clinical efficacy data, and their applications in combination therapy regimens. NCCN treatment guidelines, safety, toxicity, and immune-related adverse events are also described as well as a note on cost.

Expert opinion

Numerous ongoing trials continue to evaluate the role of novel therapies and combinations for this challenging disease and understanding their mechanism of action, risks, benefits, and treatment guidelines can help care providers and patients have a more comprehensive and tailored discussion of treatment options and expectations.

KEYWORDS:

• Melanoma
• chemotherapy
• targeted therapies
• immunotherapy
• clinical trials
• immune checkpoint inhibitors
• BRAF
• MEK inhibitors

Article highlights

• The last several years has seen the greatest advances in melanoma treatments to date and include a host of novel therapies approved by the FDA for the treatment of advanced melanomas.

• For advanced melanomas, immunotherapy options include immune checkpoint inhibitors like pembrolizumab, nivolumab, or nivolumab with ipilimumab in combination.

• For patients with BRAF mutations, targeted therapy regimens will include combination of a BRAF inhibitor with a MEK inhibitor, such as combining vemurafenib with cobimetinib, or dabrafenib with trametinib.

• Second-line therapies include ipilimumab, high-dose interleukin-2 and cytotoxic chemotherapy such as dacarbazine, temozolomide, and paclitaxel.

• Resistance to BRAF inhibitors in metastatic melanoma includes both genetic and epigenetic mechanisms.

• There are over 100 active clinical trials for advanced melanoma in the U.S. and new Phase 3 agents include bempegaldesleukin, sargramostim, and a TLR9 agonist (IMO-2125).

• With many reasonable options currently available and many more being evaluated for the future, patients with metastatic melanoma now have choices for their disease as well as the possibility for improved outcomes over a longer duration.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by funds from the University of Michigan’s Comprehensive Cancer Center and the Department of Surgery. They are also supported by the National Institutes of Health (Grant No. R01 CA120458, R01 CA213566, and R01 CA216919).