Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study

Shuang Xia; Yi-Chang Zhao; Lin Guo; Hui Gong; Yi-Kun Wang; Rui Ma; Bi-Kui Zhang; Yue Sheng; Mayur Sarangdhar; Yoshihiro Noguchi; Miao Yan

doi:10.3389/fphar.2022.967017

Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study

Front Pharmacol. 2022 Nov 9:13:967017. doi: 10.3389/fphar.2022.967017. eCollection 2022.

Authors

Shuang Xia^{1

2

3}, Yi-Chang Zhao^{1

2

3}, Lin Guo^{1

2

3}, Hui Gong^{1

2

3}, Yi-Kun Wang^{1

2

3}, Rui Ma^{1

2

3}, Bi-Kui Zhang^{1

2

3}, Yue Sheng⁴, Mayur Sarangdhar^{5

6

7}, Yoshihiro Noguchi⁸, Miao Yan^{1

2

3}

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
² International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
³ Toxicology Counseling Center of Hunan Province (TCCH), Changsha, China.
⁴ Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
⁶ Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
⁸ Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan.

Abstract

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.

Keywords: FAERS; antibody–drug conjugates; data mining; pharmacovigilance; sepsis.