Managing Toxicity of Immunotherapy in Melanoma

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Although the toxicities associated with anti-PD-1 antibodies are not benign, they appear to be more easily managed compared with other immunotherapies used to treat malignant melanoma, such as ipilimumab and interleukin-2 (IL-2), Anna Pavlick, DO, explains. The leading concern has research continues to advance treatments for patients with melanoma is determining how to manage the toxicities associated with combinations.

The side effects associated with anti-PD-1 therapy include rash, thyroid-related problems, and fatigue, Richard Joseph, MD, adds; however, these adverse events are not dose limiting nor do they lead to stopping the drug. Pneumonitis can be a concern with PD-1 inhibition, primarily in patients with lung cancer. Despite this, pneumonitis should still be suspected in a patient with melanoma taking a PD-1 inhibitor who presents with respiratory symptoms, shortness of breath, cough, or difficulty breathing. In some areas, patients are given a card to bring to their local clinic or emergency department which explains that they are on an anti-PD-1 inhibitor and which side effects are associated, Robert Andtbacka, MD, adds.

The most mature combined immunotherapies data in melanoma are for ipilimumab with nivolumab. Other immunologic agents are now being combined, such as T-VEC with ipilimumab or pembrolizumab and ipilimumab with GM-CSF. With combined ipilimumab and nivolumab, a large percentage of patients developing profound, rapid-onset diarrhea, which is similar to what is experienced with single-agent ipilimumab. This adverse event requires early management, panelists note.

A phase II randomized trial assessed ipilimumab alone or in combination with GM-CSF, explains Howard Kaufman, MD. Treatment with the combination of ipilimumab and GM-CSF demonstrated a 1-year overall survival rate of 68.9% compared with 52.9% with ipilimumab monotherapy. Additionally, the rate of grade 3 or higher adverse events was 45% versus 58%, for the combination and single-agent, respectively (P = .04). Particularly, the gastrointestinal toxicities associated with ipilimumab were reduced with GM-CSF, Kaufman notes.

Another combination study looking at ipilimumab and IL-2 showed no increase in toxicities, Kaufman notes. Whether its 2 or 3 agents being combined, it will be important to understand how to combine them to achieve greater responses with the least amount of toxicity for patients.