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Importance Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, setting, and participants This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main outcomes and measures Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and relevance In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

Importance Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. Objective To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. Design, Setting, and Participants Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. Exposure Ipilimumab therapy. Main Outcomes and Measures Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. Results Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. Conclusions and Relevance To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Importance The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. Objective To review the current evidence regarding the treatment of MBM from melanoma. Evidence Review The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included. Findings Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Conclusions and Relevance At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.