Adverse Reaction Profile And Predictive Markers Of Anti-PD-1/PD-L1 Immunotherapy

Background and objectiveThe blockade of programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway has ushered in a new era of cancer treatment.Following the success of anti-PD-1/PD-L1 monotherapy,the research focus is shifting to combination therapies,while the toxicities of combination therapies remain unclear.Therefore,we aim to summarize the adverse events(AE)profile of anti-PD-1/PD-L1 combination therapies on the strength of publicly available clinical trials,and statistically pooled the incidence.In addition,some severe AE may terminate the treatment and event lead to death.Therefore,we aim to investigate the predictive biomarkers of immune-related AE,which help identify the high-risk population and indicate close monitoring of these patients.MethodsIn the first part,we searched published clinical trials reporting PD-1/PD-L1 inhibitor-based combination therapies from January 1st,2020 to May 21st,2020.The primary outcomes are the profile and the overall incidence of treatment-related AE.The secondary outcome is the profile of treatment-related deaths.In the second part,we collected cases in FDA Adverse Event Reporting System(FAERS)from July 1st,2014 to September 30th,2020,and cases of 24 tumor types in TCGA.Pearson linear regression was adopted to explore the predictive marker of immune-related pneumonitis.Log-likehood ratio test was utilized for comparing the fitness between different regression models.ResultsIn the first part,161 clinical trials involving 17196 patients were included.In anti-PD-1/PD-L1 plus chemotherapy combination,the all-grade and high-grade overall incidence of TRAE were 97.7%(95%CI,96.4%-98.5%)and 68.3%(95%CI,60.7%-75.0%),respectively;In anti-PD-1/PD-L1 plus targeted therapy combination,the all-grade and high-grade overall incidence of TRAE were 94.5%(90.7%-96.8%)and 47.3%(37.3%-57.5%),respectively;In anti-PD-1/PD-L1 plus immunotherapy combination,the all-grade and high-grade overall incidence of TRAE were 86.8%(80.9%-91.1%)and 35.9%(29.5%-42.9%),respectively;In anti-PD-1/PD-L1 plus radiotherapy combination,the all-grade and high-grade overall incidence of TRAE were 89.4%(69.0%-96.9%)and 12.4%(4.4%-30.6%),respectively.The most common treatment-related death in combination therapies is pneumonitis.In the second part,32772 patients receiving anti-PD-1/PD-L1 therapies from FAERS and 9898 patients from TCGA were included for analysis.The results of linear regression showed that the proportion of tumor infiltrating B cells,tumor PD-L1 mRNA expression and tumor PD-1 mRNA expression were significantly associated with the risk of immune-related pneumonitis,indicating that these factors might be the predictive biomarkers of immune-related pneumonitis.ConclusionsA high proportion of patients experienced treatment-related AE in anti-PD-1/PD-L1 combination therapies,especially in the chemotherapy combination group.The most common fatal treatment-related AE was pneumonitis.Tumor infiltrating B cells,tumor PD-L1 mRNA expression and tumor PD-1 mRNA expression might be the predictive biomarkers of immune-related pneumonitis.Prospective cohorts are required to validate our results.