Mosca, Paul J.

Abstract Purpose: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma. Patients and Methods: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550–4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy. Results: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%–83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4+ T-cell subsets. Conclusions: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.

Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host’s immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.