Adjuvant Therapy for Melanoma: Past, Current, and Future Developments

Abstract

This review describes the progress that the concept of adjuvant therapies has undergone in the last 50 years and focuses on the most recent development where an adjuvant approach has been scientifically evaluated in melanoma clinical trials. Over the past decade the development of immunotherapies and targeted therapies has drastically changed the treatment of stage IV melanoma patients. These successes led to trials studying the same therapies in the adjuvant setting, in high risk resected stage III and IV melanoma patients. Adjuvant immune checkpoint blockade with anti-CTLA-4 antibody ipilimumab was the first drug to show an improvement in recurrence-free and overall survival but this was accompanied by high severe toxicity rates. Therefore, these results were bypassed by adjuvant treatment with anti-PD-1 agents nivolumab and pembrolizumab and BRAF-directed target therapy, which showed even better recurrence-free survival rates with more favorable toxicity rates. The whole concept of adjuvant therapy may be integrated with the new neoadjuvant approaches that are under investigation through several clinical trials. However, there is still no data available on whether the effective adjuvant therapy that patients finally have at their disposal could be offered to them while waiting for recurrence, sparing at least 50% of them a potentially long-term toxic side effect but with the same rate of overall survival (OS). Adjuvant therapy for melanoma has radically changed over the past few years—anti-PD-1 or BRAF-directed therapy is the new standard of care.

Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients

“…Thus, alternative non-immunological based therapies may be more appropriate. This strategy can be applied to the usage of the modern day immunotherapies such as checkpoint inhibitor immunotherapies versus targeted therapies such as BRAF/MEK inhibitors for melanoma patients before treatment [ 1 ].…”

“…Melanoma is an antigenic cancer, whereby activated host anti-tumor immunity has been shown to control tumor progression. Adjuvant immunotherapies that have been used in melanoma clinical trials are: Interferon-α-2b (IFN-α-2b), Interleukin (IL)-2, melanoma cell vaccines, BCG (Bacillus Calmette-Guérin), and immune checkpoint inhibitors (ICI) immunotherapy in post-surgical, disease-free AJCC (American Joint Committee on Cancer) stage III and IV patients [ 1 , 2 , 3 , 4 ]. Newer immunotherapies using monoclonal antibodies, such as ICIs, which target against CTLA-4, PD-1, or PD-L1 [ 5 , 6 , 7 ], have improved overall survival time when used as both adjuvant and neo-adjuvant therapies in AJCC stage III/IV melanoma patients [ 8 , 9 , 10 , 11 ].…”

“…Newer immunotherapies using monoclonal antibodies, such as ICIs, which target against CTLA-4, PD-1, or PD-L1 [ 5 , 6 , 7 ], have improved overall survival time when used as both adjuvant and neo-adjuvant therapies in AJCC stage III/IV melanoma patients [ 8 , 9 , 10 , 11 ]. ICI agents, nivolumab and pembrolizumab therapies, which are less toxic and have better recurrence-free survival rates, are the most effective and current standard of care for the treatment of melanoma patients [ 1 ]. However, predicting which patients will respond to these different immunotherapies still remains unknown.…”

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

“…Furthermore, a substantial fraction of long-term survivors seems to remain disease-free even after discountinuation of treatment. In fact, ICI-based immunotherapy is approved by the FDA as a standard treatment for patients with advanced or recurrent melanoma [ 116 , 117 , 118 ].…”

The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients

“…Adjuvant immune checkpoint blockade with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a different type of inhibition and shows an increase in overall survival (OS) and recurrence-free survival in several cancers, but this was also associated with great toxicity percentages [ 79 ]. Both checkpoint inhibitors (anti-CTLA-4 and the PD-1 antibodies) can cause pruritus in 18–34% of treated subjects [ 80 ], with differences between the latter two forms of therapy.…”