Adjuvant Immunotherapy for Melanoma

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Clinical trials assessing adjuvant BRAF inhibitors, anti-PD-1 antibodies, and ipilimumab are under way for patients with melanoma. These trials are important, since treatments that are safe and effective in the metastatic setting are not always effective adjuvant therapies, Omid Hamid, MD, says. At this point, the checkpoint inhibitors should not be used as adjuvant therapy off-label, outside of a clinical trial, Hamid advises.

Data from a phase III clinical trial has shown some benefits with pegylated interferon alfa-2b in the adjuvant setting; however, Richard Joseph, MD, suggests that interferon is not an appropriate option for most patients. Findings from the phase III EORTC 18991 study demonstrated an improvement in recurrence-free survival (RFS) with adjuvant pegylated interferon alfa-2b compared with observation in patients with resected stage III melanoma, Hamid notes.

In the study, the 7-year RFS rate was 39.1% with interferon versus 34.6% with observation. However, there was not a significant difference in overall survival (P = .57). The greatest benefit with interferon was seen in patients with stage III N1 ulcerated melanoma, Hamid notes. In this population, overall survival was improved by 41% with interferon compared with observation. However, 37% of patients in the study discontinued treatment with interferon due to side effects.

It is important to manage expectations about the possible side effects of interferon in the adjuvant setting, stresses Robert Andtbacka, MD. Given the benefit seen with this agent, it is logical to think of interferon as an appropriate comparator for adjuvant trials of ipilimumab and PD-1 inhibitors in melanoma.

The conversation on adjuvant interferon can be difficult, notes Howard Kaufman, MD, since the FDA has approved this agent for this indication. Patients should be made aware of potential controversies surround the agent. Overall, the risk-benefit ratio seen with interferon enhances the need for more effective therapies and clinical trials, Kaufman notes.

Adjuvant ipilimumab at 10 mg/kg was explored in the phase III EORTC 18071 trial. This treatment showed a significant benefit in RFS compared with placebo, but at the cost of substantial toxicity and even treatment-related deaths, Andtbacka notes.

According to findings presented at the 2014 ASCO Annual Meeting and published in Lancet Oncology, RFS was improved by 25% with ipilimumab versus placebo (HR = 0.75; 95% CI, 0.64—0.90). The median RFS was 26.1 months among patients receiving ipilimumab versus 17.1 months in the placebo arm (P = .0013). In total, 52% of patients who started ipilimumab discontinued treatment due to adverse events. In total, 38.6% of patients discontinued within 12 weeks (n = 182) and 1.1% died (n = 5).

The phase III trial ECOG 1609 trial is assessing 10 mg/kg and 3 mg/kg of adjuvant ipilimumab in comparison with high-dose interferon α-2b, Hamid notes. The primary endpoints on the trial are RFS and overall survival, with secondary endpoints focused on toxicity and quality of life. The trial is ongoing and recruiting participants (NCT01274338).

In March 2014, the FDA accepted a supplemental Biologics License Application for ipilimumab as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.