Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK.
J Clin Oncol. 2022 Oct 10;40(29):3439-3452. doi: 10.1200/JCO.22.00369. Epub 2022 Jun 4.
PURPOSE: Major adverse cardiac events (MACEs) because of immune checkpoint inhibitors (ICIs) are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACEs can lead to significant morbidity and mortality, hence the need to better define presentations of MACEs and their association with noncardiac irAEs in ICI-treated patients. METHODS: We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the National Cancer Institute-Cancer Therapy Evaluation Program for National Cancer Institute-sponsored investigational clinical trials between June 2015 and December 2019. Patients were eligible if they had been treated with anti-programmed cell death protein-1 (anti-PD-1)/programmed cell death-ligand 1 (anti-PD-L1) alone or with additional anticancer therapies. RESULTS: A total of 6,925 participants received anti-PD-(L)1-based therapies; 48% (n = 3,354) were treated with single-agent anti-PD-(L)1 therapy. Of 6,925 patients, 0.6% (n = 40) qualified as ICI-related MACE, with 77.5% (n = 31 of 40) being ≥ grade 3. Myocarditis accounted for 45% (n = 18 of 40) of total ICI-MACEs. Concurrent multisystem involvement with other noncardiac irAEs was seen in 65% (n = 26 of 40). Most patients with myocarditis (83%, n = 15 of 18) had one or more noncardiac irAEs associated. Incidence of MACE was higher with anti-PD-(L)1 + targeted therapies compared with anti-PD-(L)1 + anti-cytotoxic T-cell lymphocyte-4 combinations (2.1% 0.9%, = .08). There was a higher incidence of myocarditis with anti-PD-(L)1-based combination therapies versus single-agent anti-PD-(L)1 therapies (0.36%, n = 13 of 3,571 0.15%, n = 5 of 3,354, = .08). Deaths related to myocarditis were identified in 22.5% (n = 4 of 18). All four patients who died had concurrent myositis. CONCLUSION: Increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated noncardiac irAEs should be emphasized. Better characterization of the risk of MACE with the concurrent use of non-ICI-based anticancer therapies with anti-PD-(L)1 treatments is needed.
目的：免疫检查点抑制剂（ICI）引起的重大心脏不良事件（MACE）是罕见的免疫相关不良事件（irAE），包括一系列具有不同表现的心脏毒性。ICI 相关的 MACE 可导致显著的发病率和死亡率，因此需要更好地定义 MACE 的表现及其与接受 ICI 治疗的患者中非心脏 irAE 的关系。
方法：我们对 2015 年 6 月至 2019 年 12 月期间美国国家癌症研究所癌症治疗评估计划国家癌症研究所赞助的临床试验严重不良事件报告数据库中捕获的 MACE 进行了回顾性汇总分析。符合条件的患者需接受抗程序性细胞死亡蛋白-1（抗 PD-1）/程序性死亡配体 1（抗 PD-L1）单药或联合其他抗癌治疗。
结果：共有 6925 名参与者接受了抗 PD-（L）1 治疗；48%（n=3354）接受了单药抗 PD-（L）1 治疗。在 6925 例患者中，有 0.6%（n=40）为 ICI 相关 MACE，其中 77.5%（n=31/40）为≥3 级。心肌炎占总 ICI-MACE 的 45%（n=40/18）。65%（n=40/61）的患者并发其他非心脏 irAE 的多系统受累。大多数心肌炎患者（83%，n=15/18）存在一种或多种非心脏 irAE 相关。与抗 PD-（L）1+靶向治疗相比，抗 PD-（L）1+抗细胞毒性 T 淋巴细胞 4 联合治疗的 MACE 发生率更高（2.1%比 0.9%，=0.08）。与单药抗 PD-（L）1 治疗相比，抗 PD-（L）1 联合治疗的心肌炎发生率更高（0.36%，n=13/3571比 0.15%，n=5/3354，=0.08）。已确定与心肌炎相关的死亡有 22.5%（n=4/18）。所有死亡的 4 例患者均同时患有肌炎。
结论：应强调提高患者和处方者对 ICI-MACE 及其相关非心脏 irAE 模式的认识。需要更好地描述非 ICI 为基础的抗癌治疗与抗 PD-（L）1 治疗同时使用时 MACE 的风险。
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