Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

中文翻译：

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Nivolumab 和 Ipilimumab 联合治疗晚期黑色素瘤患者的汇总分析安全性概况

目的 在晚期黑色素瘤患者中，将纳武单抗（抗程序性死亡 1 抗体）添加到易普利姆玛（抗细胞毒性 T 细胞淋巴细胞相关 4 抗体）可提高抗肿瘤反应和无进展生存期，但不良事件发生率更高（AE）。这项跨黑色素瘤研究描述了已批准的纳武单抗加伊匹单抗方案的安全性。方法 这项对三项试验（I、II 和 III 期）数据的回顾性安全性审查包括接受至少一剂纳武单抗 1 mg/kg 加伊匹单抗 3 mg/kg 每 3 周 × 4 然后接受纳武单抗的晚期黑色素瘤患者每 2 周 3 mg/kg，直到疾病进展或出现不可接受的毒性，同时遵循既定的 AE 管理指南。分析针对所有治疗相关 AE、选择（免疫相关）AE、发病和消退的时间，以及免疫调节剂的使用及其对结果的影响。结果 在 448 名患者中，中位随访时间为 13.2 个月。55.5% 的患者发生与治疗相关的 3/4 级 AE；35.7% 的治疗相关 AE 导致停药。最常见的任何级别的治疗相关选择 AE 是皮肤 (64.3%) 和 GI (46.7%)，3/4 级是肝脏 (17.0%) 和 GI (16.3%)；30.1% 的患者在一个以上的器官类别中出现了 2 至 4 级特定 AE。3/4 级治疗相关特定 AE 发生的中位时间范围为 3.1（皮肤）至 16.3（肾）周，并且不包括内分泌 AE，发生后消退的中位时间范围为 1.9（肾）至 4.5（肺）周，使用免疫调节剂时的解决率在 79% 到 100% 之间。四 (< 1%) 研究期间的死亡归因于治疗。结论 纳武单抗联合易普利姆玛的 3/4 级治疗相关 AE 的频率更高，并且比单独使用任何一种药物的历史经验发生得更早，但解决率相似。