Tang Linlin, Sun Cuicui, Liu Wenshan, Wu Haiyan, Ding Chuanhua
Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, China.
Department of Pharmacy, Qilu Hospital of Shandong University, Ji'nan, China.
Front Pharmacol. 2024 Feb 7;15:1362484. doi: 10.3389/fphar.2024.1362484. eCollection 2024.
Antibody-drug conjugates (ADCs) are a relatively new class of anticancer agents that use monoclonal antibodies to specifically recognize tumour cell surface antigens. However, off-target effects may lead to severe adverse events. This study evaluated the neurotoxicity of ADCs using the FDA Adverse Event Reporting System (FAERS) database. Data were extracted from the FAERS database for 2004 Q1 to 2022 Q4. We analysed the clinical characteristics of ADC-related neurological adverse events (AEs). We used the reporting odds ratio (ROR) and proportional reporting ratio (PRR) for the disproportionality analysis to evaluate the potential association between AEs and ADCs. A total of 562 cases of neurological AEs were attributed to ADCs. The median age was 65 years old [(Min; Max) = 3; 92]. Neurotoxic signals were detected in patients receiving brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, and trastuzumab deruxtecan. The payloads of brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and trastuzumab emtansine were microtubule polymerization inhibitors, which are more likely to develop neurotoxicity. We also found that brentuximab vedotin- and gemtuzumab ozogamicin-related neurological AEs were more likely to result in serious outcomes. The eight most common ADC-related nervous system AE signals were peripheral neuropathy [ROR (95% CI) = 16.98 (14.94-19.30), PRR (95% CI) = 16.0 (14.21-18.09)], cerebral haemorrhage [ROR (95% CI) = 9.45 (7.01-12.73), PRR (95% CI) = 9.32 (6.95-12.50)], peripheral sensory neuropathy [ROR (95% CI) = 47.87 (33.13-69.19), PRR (95% CI) = 47.43 (32.93-68.30)], polyneuropathy [ROR (95% CI) = 26.01 (18.61-36.33), PRR (95% CI) = 25.75 (18.50-35.86)], encephalopathy [ROR (95% CI) = 5.16 (3.32-8.01), PRR (95% CI) = 5.14 (3.32-7.96)], progressive multifocal leukoencephalopathy [ROR (95% CI) = 22.67 (14.05-36.58), PRR (95% CI) = 22.52 (14.01-36.21)], taste disorder [ROR (95% CI) = 26.09 (15.92-42.76), PRR (95% CI) = 25.78 (15.83-42.00)], and guillain barrier syndrome [ROR (95% CI) = 17.844 (10.11-31.51), PRR (95% CI) = 17.79 (10.09-31.35)]. The mortality rate appeared to be relatively high concomitantly with AEs in the central nervous system. ADCs may increase the risk of neurotoxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADC drugs, combining the FAERS data with other data sources is crucial for monitoring the neurotoxicity of ADCs. Further studies on the potential mechanisms and preventive measures for ADC-related neurotoxicity are necessary.
抗体药物偶联物（ADCs）是一类相对较新的抗癌药物，它利用单克隆抗体特异性识别肿瘤细胞表面抗原。然而，脱靶效应可能导致严重的不良事件。本研究使用美国食品药品监督管理局不良事件报告系统（FAERS）数据库评估了ADCs的神经毒性。数据从FAERS数据库中提取，涵盖2004年第一季度至2022年第四季度。我们分析了与ADCs相关的神经系统不良事件（AEs）的临床特征。我们使用报告比值比（ROR）和比例报告比（PRR）进行不成比例分析，以评估AEs与ADCs之间的潜在关联。共有562例神经系统AEs归因于ADCs。中位年龄为65岁[（最小值；最大值）=3；92]。在接受本妥昔单抗、恩杂鲁胺、泊洛妥珠单抗、曲妥珠单抗、吉妥珠单抗、伊奈妥单抗和曲妥珠单抗德卢替康的患者中检测到神经毒性信号。本妥昔单抗、恩杂鲁胺、泊洛妥珠单抗和曲妥珠单抗的有效载荷是微管聚合抑制剂，更有可能产生神经毒性。我们还发现，与本妥昔单抗和吉妥珠单抗相关的神经系统AEs更有可能导致严重后果。八个最常见的与ADCs相关的神经系统AE信号是周围神经病变[ROR（95%置信区间）=16.98（14.94 - 19.30），PRR（95%置信区间）=16.0（14.21 - 18.09）]、脑出血[ROR（95%置信区间）=9.45（7.01 - 12.73），PRR（95%置信区间）=9.32（6.95 - 12.50）]、周围感觉神经病变[ROR（95%置信区间）=47.87（33.13 - 69.19），PRR（95%置信区间）=47.43（32.93 - 68.30）]、多发性神经病变[ROR（95%置信区间）=26.01（18.61 - 36.33），PRR（95%置信区间）=25.75（18.50 - 35.86）]、脑病[ROR（95%置信区间）=5.16（3.32 - 8.01），PRR（95%置信区间）=5.14（3.32 - 【此处原文疑似有误，多了个“7.96”，推测应是“7.96”的前半部分】）]、进行性多灶性白质脑病[ROR（95%置信区间）=22.67（14.05 - 36.58），PRR（95%置信区间）=22.52（14.01 - 36.21）]、味觉障碍[ROR（95%置信区间）=26.09（15.92 - 42.76），PRR（95%置信区间）=25.78（15.83 - 42.00）]和格林 - 巴利综合征[ROR（95%置信区间）=17.844（10.11 - 31.51），PRR（95%置信区间）=17.79（10.09 - 31.35）]。中枢神经系统出现AEs时死亡率似乎相对较高。ADCs可能会增加癌症患者神经毒性的风险，导致严重的死亡。随着新上市的ADCs药物广泛应用，将FAERS数据与其他数据源相结合对于监测ADCs的神经毒性至关重要。有必要对ADCs相关神经毒性的潜在机制和预防措施进行进一步研究。
