Metastatic melanoma: therapeutic agents in preclinical and early clinical development

ABSTRACT

Introduction: Advanced melanoma historically had a very poor outcome but targeted therapies and immune checkpoint inhibitors (IC) have changed the course of the disease and made durable responses possible. However, most patients will develop progressive disease, so further strategies to overcome treatment resistance are needed.

Areas covered: Current treatment strategies and landmark trials are discussed.

Novel targeted agents, immune checkpoint inhibitors, and further immune-modulatory drugs, cancer vaccines and tumor infiltrating lymphocytes and their potential role in the treatment of melanoma are described. Current trials investigating these emerging agents and treatment strategies were searched for on ClinicalTrials.gov and are presented on the background of the current literature explaining the rationale for employing these new agents and strategies. Combinations of tumor-directed agents with those causing immune augmentation as well as a new adjuvant and neoadjuvant strategies are discussed.

Expert opinion: Questions regarding treatment combination, personalization, and sequence of treatment will become increasingly important and will be guided by new biomarkers. New treatment settings will broaden the patient selection and will highlight the need for further discussions regarding toxicity in long-term survivorship.

KEYWORDS:

• Advanced melanoma
• adjuvant treatment
• Bempegaldesleukin
• emerging agents
• immunotherapy
• immune checkpoints
• neoadjuvant treatment
• personalization
• tumor infiltrating lymphocytes
• targeted therapy

Article highlights

• Melanoma treatment has been revolutionized by immune checkpoint (IC) inhibitors and targeted agents; 5-year survival for metastatic melanoma treated with combined IC is 52%.

• Several new inhibitory and co-stimulatory IC are under investigation, early trials of anti-TIM 3, anti-LAG3 and CD-122 agonists showed promising results.

• Targeted drug and IO combinations have shown efficacy but also notable toxicity; initial trials suggested an improved ORR and there are ongoing phase III trials of anti-PD1 combined with targeted therapy.

• Tumour Infiltrating Lymphocyte (TIL) trials are currently limited to a certain subgroup of patients but show a comparatively high response rate and a lot of work is going into further exploration as well as setting up new centers.

• Durable responses achieved with immunotherapy and its use in the adjuvant setting have led to a consideration of long-term survivorship issues, highlighting the need for strategies to reduce toxicity.

• A personalized approach regarding the choice of therapy is becoming increasingly feasible and is explored further in several forms such as individual neoantigens in melanoma vaccines, usage of TILs, and genetic analysis of IC expression.

This box summarizes key points contained in the article.

Declaration of interest

J Larkin has received honoraria from and has acted in a consultant and advisory capacity for AstraZeneca, Achilles, Boston Biomedical, Bristol Myers Squibb (BMS), Elsai, EUSA Pharma, GSK, Ipsen, Imugene, Incyte, IOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Roche, Secarna and Vitaccess, and has received research funding from BMS, MSD, Achilles, Novartis, Pfizer, Aveo, Roche, Nektar, and Covance. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has engaged in BMS, Merck, Checkmate Pharmaceuticals, Tesaro, Amgen, Medpacto sponsored research. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.