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Abstract
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.
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Details
1 Oak Ridge Institute of Science and Education Fellowship at Office of Clinical Pharmacology, United States Food and Drug Administration, Silver Spring, USA (GRID:grid.417587.8) (ISNI:0000 0001 2243 3366); University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
2 University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
3 University of California San Francisco, Clinical Pharmacology and Therapeutics (CPT) Postdoctoral Training Program, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
4 Oak Ridge Institute of Science and Education Fellowship at Office of Clinical Pharmacology, United States Food and Drug Administration, Silver Spring, USA (GRID:grid.417587.8) (ISNI:0000 0001 2243 3366)
5 US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, USA (GRID:grid.417587.8) (ISNI:0000 0001 2243 3366)
6 UCSD Moores Cancer Center, Center for Personalized Cancer Therapy, Division of Hematology and Medical Oncology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)