DataSheet2_Do antibody–drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study.xlsx

Introduction: Antibody–drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies.
Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis.
Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses.
Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p <0.001); however, age did not exert influence on the risk of sepsis. We identified that 973 of 2,441 (39.9%) cases had acute myeloid leukemia (AML), and 766 of 2613 (29.3%) cases on ADCs died during therapy. Time-to-onset analysis indicated ADC-related sepsis is prone to occur within a month after administration. Co-administration of ADCs with colony-stimulating factors, proton pump inhibitors, H2-receptor antagonists, or CYP3A4/5 inhibitors showed to synergistically increase the risk of sepsis-related toxicities.
Conclusion: Antibody–drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

引言：抗体药物偶联物（Antibody–drug conjugates, ADCs）在难治性肿瘤中展现出卓越的抗肿瘤疗效，但同时也可能引发严重不良反应。尽管已有ADC相关脓毒症的相关报道，但真实世界研究中对其临床特征的刻画仍不够充分。
研究目的：本研究旨在利用美国食品药品监督管理局不良事件报告系统（FAERS）数据，明确ADC与脓毒症之间的关联，并阐明ADC相关脓毒症的临床特征。
研究方法：本研究采用FAERS数据开展比例失衡分析，对比接受ADC治疗与其他治疗方案的癌症患者的脓毒症发生率。通过报告比值比（reporting odds ratios, RORs）与信息成分（information component, IC）评估ADC与脓毒症之间的关联。针对每个治疗组，我们检测了药物相互作用信号，并开展了亚组分析（按年龄、性别、治疗方案分组）与敏感性分析。
研究结果：2004年第一季度至2021年第三季度期间，共报告涉及ADC的病例24618例。本数据库中，脓毒症、感染性休克、多器官功能障碍综合征及其他脓毒症相关不良反应与ADC的关联显著高于其他药物。与其他抗肿瘤单药治疗相比，脓毒症与多器官功能障碍综合征是ADC相关安全性风险最高的不良事件。吉妥珠单抗奥佐米星与奥英妥珠单抗的安全性风险高于其他ADC药物。在排名前九位的ADC相关脓毒症病例中，男性的脓毒症安全性风险显著高于女性（p<0.001）；但年龄并未对脓毒症风险产生影响。我们发现，2441例接受ADC治疗的病例中，有973例（39.9%）为急性髓系白血病（AML），其中766例（29.3%）在治疗期间死亡。发病时间分析显示，ADC相关脓毒症多在给药后1个月内发生。ADC与集落刺激因子、质子泵抑制剂、H2受体拮抗剂或CYP3A4/5抑制剂联合使用时，会协同增加脓毒症相关不良反应的发生风险。
研究结论：抗体药物偶联物可能会增加癌症患者的脓毒症风险，进而导致较高的死亡率。未来仍需开展进一步研究以阐明ADC相关脓毒症的潜在机制，并制定相应的预防措施。