Fatal adverse events associated with programmed cell death protein 1 or programmed cell death-ligand 1 monotherapy in cancer

BACKGROUND: The introduction of antibodies targeting programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) into clinical practice has had a revolutionary effect on cancer treatment. However, the incidence and risk of fatal adverse events (FAEs) following PD-1/PD-L1 inhibitor administration are controversial. METHODS: We performed a systematic search for randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors (atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab) in Embase, PubMed, the Cochrane database, and abstracts presented at American Society of Clinical Oncology and European Society of Medical Oncology from inception to July 2018. FAEs were extracted from each study and pooled to calculate overall incidence and odds ratios (ORs). RESULTS: In total, 20 RCTs involving 12,398 patients with solid tumors were included in this study. The overall incidence of FAEs with PD-1/PD-L1 inhibitors was 0.43% [95% confidence interval (CI), 0.25–0.66%]. However, the incidences of FAEs varied significantly by tumor type and median follow-up time. Compared with conventional agents, the application of PD-1/PD-L1 inhibitors significantly reduced the risk of FAEs (OR, 0.56; 95% CI, 0.35–0.89; p = 0.015). Moreover, trial sequential analysis confirmed that our results were solid and reliable; further studies were unlikely to alter this conclusion. FAEs occurred dispersed in major organ systems, with the most common mortalities appearing in the respiratory system (46.2%). CONCLUSIONS: Compared with conventional treatment, PD-1/PD-L1 blockade monotherapy is associated with a significantly reduced risk of mortality in patients with solid tumors.