Importance Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.

Objective To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.

Design, Setting, and Participants We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti–programmed death-1/ligand-1 (PD-1/PD-L1) and anti–cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.

Exposures Anti–CTLA-4 (ipilimumab or tremelimumab), anti–PD-1 (nivolumab, pembrolizumab), or anti–PD-L1 (atezolizumab, avelumab, durvalumab).

Main Outcomes and Measures Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects.

Results Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti–CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti–PD-1/PD-L1–related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti–PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti–PD-1), 0.38% (anti–PD-L1), 1.08% (anti–CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).

Conclusions and Relevance In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

重要性 免疫检查点抑制剂 (ICI) 现在是癌症治疗的中流砥柱。尽管罕见、暴发和致命的毒性作用可能会使这些原本具有变革意义的疗法复杂化；表征这些事件需要整合全球数据。

目的 确定致命 ICI 相关毒性作用的范围、时间和临床特征。

设计、设置和参与者 我们回顾性查询了世界卫生组织 (WHO) 的药物警戒数据库 (Vigilyze)，该数据库包含超过 16,000,000 条药物不良反应，以及来自 7 个学术中心的记录。我们对已发表的抗程序性死亡 1/配体 1 (PD-1/PD-L1) 和抗细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 试验进行了荟萃分析，以使用来自的数据评估它们的发生率大型学术医疗中心、全球 WHO 药物警戒数据，以及国际上所有已发表的接受 ICI 治疗的癌症患者的 ICI 临床试验。

暴露 抗-CTLA-4（ipilimumab 或 tremelimumab）、抗-PD-1（nivolumab、pembrolizumab）或抗-PD-L1（atezolizumab、avelumab、durvalumab）。

主要结果和措施 ICI 相关毒性作用的时间、范围、结果和发生率。

结果 在国际上，从 2009 年到 2018 年 1 月，Vigilyze 报告了 613 起致命的 ICI 毒性事件。方案之间的范围差异很大：在总共 193 例抗 CTLA-4 死亡中，大多数通常死于结肠炎 (135 [70%])，而抗 PD-1/PD-L1 相关死亡通常死于肺炎 ( 333 [35%])、肝炎 (115 [22%]) 和神经毒性作用 (50 [15%])。PD-1/CTLA-4 联合死亡通常死于结肠炎 (32 [37%]) 和心肌炎 (22 [25%])。联合疗法、抗 PD-1 和易普利姆玛单药疗法的致命毒性作用通常发生在治疗开始后的早期（中位时间分别为 14.5、40 和 40 天）。心肌炎的死亡率最高（131 例报告病例中有 52 例 [39.7%]），而内分泌事件和结肠炎的死亡率仅为 2% 至 5%；报告的其他器官系统毒性作用中有 10% 至 17% 会导致致命后果。对来自 7 个学术中心的 3545 名接受 ICI 治疗的患者进行的回顾性研究显示，死亡率为 0.6%；心脏和神经系统事件尤为突出 (43%)。从出现症状到死亡的中位时间为 32 天。一项涉及 19217 名患者的 112 项试验的荟萃分析显示，毒性相关的死亡率为 0.36%（抗 PD-1）、0.38%（抗 PD-L1）、1.08%（抗 CTLA-4）和 1.23 %（PD-1/PD-L1 加 CTLA-4）。

结论和相关性 据 我们所知，在迄今为止发表的对致命性 ICI 相关毒性作用的最大评估中，我们观察到早发死亡的原因和频率因治疗方案而异。跨学科的临床医生应该意识到这些不常见的致命并发症。