Oak Ridge Institute of Science and Education Fellowship at Office of Clinical Pharmacology, United States Food and Drug Administration, Silver Spring, MA, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
Sci Rep. 2021 Aug 30;11(1):17324. doi: 10.1038/s41598-021-96467-5.
Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.
针对 PD-1、PD-L1 和 CTLA-4 免疫检查点轴的抗体已被用于多种肿瘤类型。它们通过激活患者自身的免疫系统来靶向免疫逃避癌细胞，从而发挥抗肿瘤活性。然而，这种独特的作用机制可能会导致免疫相关不良反应（irAEs）。其中一种 irAE 是心肌炎，它与令人震惊的死亡率有关。在这项研究中，我们展示了从提交给美国食品和药物管理局（FDA）的安全试验数据集的心肌炎临床病例。此外，我们分析了超过 1400 万份 FDA 不良事件报告系统（FAERS）报告。FAERS 数据分析提供了证据，表明与接受化疗的患者相比，单独接受免疫检查点抑制剂、与另一种免疫检查点抑制剂（激酶抑制剂 axitinib）或化疗联合治疗的患者，所有癌症类型的心肌炎报告显著增加。所有联合疗法导致心肌炎报告的比值比进一步增加。我们进一步根据主要癌症免疫疗法疗效试验中的特定癌症类型和治疗/对照组将报告分层为亚队列，分析了心肌炎的发生情况，并确认了每个队列的观察到的趋势。
