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Rationale for Combining a Modified IL-2 and Nivolumab in Melanoma

Nikhil I. Khushalani, MD
Published Online:1:28 PM, Mon July 8, 2019


Nikhil I. Khushalani, MD, vice chair, Department of Cutaneous Oncology, Moffitt Cancer Center, discusses the rationale for combining nivolumab (Opdivo) with bempegaldesleukin (NKTR-214) for the treatment of patients with newly diagnosed, unresectable or metastatic melanoma in a randomized, open-label phase III trial.

Bempegaldesleukin is essentially a pegylated version of interleukin (IL)-2. High-dose IL-2 has been around for over 20 years and has been approved by the FDA for the treatment of advanced melanoma. However, this treatment is limited by its toxicity profile, says Khushalani.

The response rates for this patient population to IL-2 have typically been around 15%, but patients who achieved a complete response maintained their response for a long period of time. As a modified IL-2, bempegaldesleukin causes signaling in the intermediate-affinity IL-2 beta-gamma receptor. This results in an increase in CD8-positive lymphocytes on both T and natural killer (NK) cells within the tumor microenvironment.

By increasing signaling through the cells, bempegaldesleukin potentially increases the antitumor effect in the patient as well. This agent is being combined with nivolumab, an anti–PD-1 agent, which has become the standard of care for patients with advanced melanoma and has been approved for patients with stage III or resected disease. However, the response rates with nivolumab alone are approximately 40%, and that bar has not been broken by combining this with other agents.

The ongoing phase III CA045-001 trial (NCT03635983) is an attempt to prove that a second agent could be added to nivolumab to improve survivorship while decreasing toxicity. Because bempegaldesleukin is a slow-release version of IL-2, the hope is that this combination will improve efficacy at a less toxic level, concludes Khushalani.
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