Advanced-Stage Cutaneous Melanoma: Current Treatment and Future Directions

Arielle Thal, MD, Liana Puscas, MD, and Vikas Mehta, MD, MPH, on behalf of the Head and Neck Surgery Education Committee

Advanced-stage melanomas are difficult to cure, with high recurrence rates and poor long-term survival. Treatment of resectable cutaneous melanoma has historically included surgical resection followed by pathologically directed adjuvant therapy. Over the past 15 years, many immune-modulating agents have been trialed in the treatment of advanced melanoma such as interferon alpha-2B, interleukin-2 (IL-2), BRAF/MEK inhibition, and, more recently, anti-CTLA-4 (ipilimumab) and anti-PD1 (pembrolizumab and nivolumab) therapy. Here we will identify the agents currently in use, review their history, and explore future directions for immunotherapy in the treatment of advanced melanoma.

Ipilimumab 

In 2011, ipilimumab was approved for use in metastatic melanoma based on the results of a Phase III randomized controlled trial showing improved overall survival.¹ In 2015, it was approved for use in the adjuvant setting for patients with stage III disease because of data demonstrating improved recurrence free survival in this population. These results were promising, but there was a significant rate of adverse events resulting in discontinuation of treatment in over half of patients. The most common side effects included gastrointestinal, hepatic, and endocrine disturbances.²

Pembrolizumab/Nivolumab

Nivolumab was introduced into the treatment of advanced melanoma as second line treatment for patients who progressed through first line therapy.³ Later studies demonstrated improved outcomes for patients treated with pembrolizumab compared to ipilimumab with improved two-year survival (55% vs. 43%) and progression free survival (30% vs. 14%).⁴ With both agents showing promise in this setting and having different mechanisms of action, combination anti-PD1/anti-CTLA-4 therapy was assessed. This was done in a three-arm trial comparing ipilimumab alone, nivolumab alone, and ipilimumab/nivolumab in combination for patients with unresectable disease. Patients treated with nivolumab (in combination or alone) had improved progression free survival. Combination therapy was particularly beneficial for patients with PD-1 negative tumors. As a result of these studies, anti-PD1 with or without ipilimumab became the immunotherapy of choice for melanoma.⁵ 

Transition to Neoadjuvant Treatment

The rationale for neoadjuvant immunotherapy is based on the hypothesis that a more robust anti-tumor response is possible prior to resection due to the presence of an intact tumor microenvironment via tumor-infiltrating lymphocytes and intact lymph nodes. Based on this hypothesis, the SWOG Cancer Research Network trial tested neoadjuvant pembrolizumab against adjuvant pembrolizumab in patients with resectable Stage III/IV melanoma. The neoadjuvant group had improved two-year event free survival compared to the adjuvant group, 72% vs. 49%.⁶ The NADINA trial, which evaluated neoadjuvant ipilimumab/nivolumab versus adjuvant ipilimumab/nivolumab in this population, further supported the benefit of neoadjuvant therapy by showing an increase in event-free survival, 83.7% vs. 57.2%. There was also a positive correlation between the rate of pathologic response and recurrence free survival, indicating durable responses. Approximately 59% of patients had a major pathologic response which correlated with a 95.1% recurrence free survival at 12 months. Of note, adverse events were increased in the neoadjuvant group, 29.7% compared to 14.7%.⁷ 

Other anti-PD1 combination therapies in the neoadjuvant setting have been investigated to optimize responses and reduce adverse events. Relatlimab is a monoclonal antibody to LAG-3 and has been investigated in combination with nivolumab in the neoadjuvant setting. It appears to be better tolerated than ipilimumab/nivolumab and has comparable levels of pathologic response: 63% major pathologic response correlating to 100% recurrence free survival at 12 months.⁸ Although this is promising, the data supporting this combination is scarce, with only a few small studies available at the current time. 

Conclusions and Future Directions

Currently, neoadjuvant nivolumab, with or without ipilimumab, is recommended for patients with resectable Stage III/IV disease. Ideal dosing for efficacy and reduction in adverse events is still under investigation.⁹ Patients should be counseled that adverse events are not uncommon and can be life threatening. Relatlimab in combination with anti-PD1 therapy is a promising alternative to ipilimumab with the potential for decreased toxicity. Fewer studies investigating this approach exist and therefore it is less commonly used at the current time. Pathologic response is clearly correlated with survival outcomes, and there is a need for early identification of responders vs. non-responders. An evaluation of biomarker expression, with a specific interest in IFN-Y (DONIMI trial) and tumor mutational burden, based on previous data is the next step.¹⁰

Overall, this is an exciting shift in the paradigm of melanoma management with a quantum leap in survival from advanced disease. However, many questions still exist that necessitate further research including the optimal therapeutic combination and dose, pre-treatment identification of possible responders versus non-responders, evaluation of pathologic response, timing of surgery after neoadjuvant treatment, and indications for de-escalation of care in both the surgical and adjuvant setting.

References

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