免疫检查点抑制剂不良事件信号的挖掘与评价OA

Objective To provide reference for the rational clinical use of immune checkpoint inhibitors(ICIs).Methods Adverse drug event(ADE)reports related to ICIs(including ipilimumab,nivolumab,pembrolizumab,durvalumab,and atezolizumab)from the second quarter of 2011 to the second quarter of 2023 were extracted from the U.S.Food and Drug Administration(FDA)Adverse Event Reporting System(FAERS).The reporting odds ratio(ROR)method and the Bayesian confidence propagation neural network(BCPNN)method,both based on disproportionality analysis,were used to mine ADE signals.Positive ADE signals were standardized using the Medical Dictionary for Regulatory Activities(MedDRA)version 26.0.The risk signal intensities of different ICIs were compared and analyzed.Results A total of 56 749 ADE reports were included,accounting for 10 572 for ipilimumab,22 770 for nivolumab,11 784 for pembrolizumab,8 930 for atezolizumab,and 2 693 for durvalumab.ADE patients were predominantly male and aged≥60 years.Reports were mainly submitted from the U.S.,Japan,and France,with hospitalization(including prolonged hospitalization)and death as the primary outcomes.The annual number of reports showed an overall upward trend.In terms of system organ class(SOC)distribution,nivolumab and pembrolizumab covered the widest range(both 23 SOCs),followed by atezolizumab(20 SOCs)and ipilimumab(19 SOCs),with durvalumab covering the fewest(17 SOCs).Gastrointestinal disorders accounted for the highest proportion in ipilimumab(16.96%),while general disorders and administration site conditions were the most common manifestations for nivolumab,pembrolizumab,atezolizumab,and durvalumab,accounting for 17.57%,12.43%,15.07%,and 18.24%,respectively.Among high-frequency ADEs,diarrhea,pyrexia,rash,interstitial lung disease,infectious pneumonia,and hypothyroidism were shared by 4-5 ICIs.In terms of signal intensity,the ADEs with the highest ROR025 values were ipilimumab-associated hypophysitis(ROR025=697.74),nivolumab-associated fulminant type 1 diabetes mellitus(ROR025=327.96),pembrolizumab-associated immune-mediated hypothyroidism(ROR025=571.93),atezolizumab-associated systemic immune activation(ROR025=206.94),and durvalumab-associated radiation pneumonitis(ROR025=2 574.81).Among the top 20 ADEs by ROR value,15 were not listed in the package inserts.For high-intensity signals(IC025≥3),nivolumab detected the most(15 items),with fulminant type 1 diabetes mellitus as the primary signal(IC025=6.52);ipilimumab and pembrolizumab each detected 14 items,with the strongest signals being hypophysitis(IC025=7.54)and immune-mediated adverse reactions(IC025=7.00),respectively;durvalumab and atezolizumab each detected 4 items,with the strongest signals being radiation pneumonitis(IC025=8.06)and immune-mediated hepatitis(IC025=3.92),respectively.A total of four ADEs were not listed in the package inserts.Conclusion The ADEs of five ICIs exhibit significant drug-specific differences,and multiple potential adverse signals not listed in the package inserts were identified.These findings provide a reference for the individualized identification,monitoring,and prevention of ICI-related adverse reactions.