Multiple Adverse Events of anti-PD1/PDL1 Therapy: A Case- control Study using a Japanese Prescription-diagnostics Database

Purpose Accumulation of data on patient response to immune checkpoint inhibitors (ICIs) has enabled the analysis of adverse events (AEs) that have been difficult to analyze to date. The development of multiple AEs is often fatal; therefore, their characterization is important. Hence, we retrospectively investigated anti-programmed cell death protein 1 (PD1)/ programmed death-ligand 1 (PDL1) therapy by conducting a case-control study to determine the clinical characteristics of AEs associated with multiple ICIs. Methods We utilized the Japan Medical Data Center claims database, a prescription-diagnostics database, to obtain records of patients treated with PD1/PDL1 inhibitors, which were then analyzed. A total of 116,091 ICI-associated prescription-diagnostics data reports were retrieved. ICI-associated safety reports of individual cases till November 2020 were also analyzed. Furthermore, a narrowed search for immune-related AEs (irAEs) yielded 3,173 cases from the prescription-diagnostics data. Results There was a high incidence of concomitant AEs, and endocrine dysfunctions (hypophysitis, thyroiditis, and adrenal complications) had a high co-occurrence rate. Diabetes mellitus, hepatitis, and colitis overlapped in patients who developed thyroid dysfunction. In addition, there was a high incidence of myositis, myasthenia gravis, and myocarditis co-occurrence. Further analysis revealed a high mortality rate for interstitial pneumonia and diabetes mellitus (38%). In concomitant cases of myocarditis and other irAEs, severe cardiac diseases were developed. Conclusion Anti-PD1/PDL1 therapy may cause fatal clinical manifestations when accompanied by multiple irAEs. This study may provide adequate awareness among healthcare providers toward these characteristics.