The Adverse Events Of Anti-HER2 Treatments:A Study Of The FDA Adverse Event Reporting System (FAERS)

Research background and objective:A variety of drugs targeting human epidermal growth factor receptor 2(HER-2)are being developed to treat patients with solid tumors,including HER-2 positive(HER2+)breast cancer.And the clinical benefit is remarkable.However,Adverse drug events(ADEs)are an important factor causing treatment interruption,tumor progression and lower quality of life in patients.Therefore,how to effectively evaluate the potential ADEs risk induced by anti-HER-2 therapy has become an important consideration in clinical treatment selection.Based on big database,this study attempted to analyze the type and frequency of ADEs occurrence in each system and organ of a variety induced by anti-HER-2 drugs.In the context of an increasing number of molecular-targeted drugs with improved blood-brain barrier permeability and the ongoing global pandemic of COVID-19,we have further focused on ADEs related to neurological,psychiatric and respiratory diseases.It provides guidance value for rational and safe use of HER-2 inhibitors in clinic.Methods:The US Food and Drug Administration Adverse Event Reporting System(FAERS)data from January 2004 through March 2022 was cleaned and analyzed by us to summarize characteristics of reported ADEs of anti-HER-2 drugs.Disproportionality analyses including PRR、Chi_squared、ROR 和 IC and other indicators was used to detect ADEs signals.Results:A total of 78624 adverse event reports were obtained for eight HER-2 inhibitors(Trastuzumab,Pertuzumab,Lapatinib,Pyrotinib,Tucatinib,Neratinib,T-DXd,and TDM-1).A total of 6211 HER-2 inhibitor combinations were screened.Compared with Trastuzumab,Pertuzumab,and Trastuzumab emtansine(TDM-1),the cardiotoxicity of Trastuzumab deruxtecan(T-DXd)was relatively weak.Among them,breast cancer and 45-64 years old patients accounted for the highest proportion of all drugs.Almost system organ class(SOC)were included in the analysis.Trastuzumab occurred most frequently in ADEs(class 862).Trastuzumab and Pertuzumab have a higher risk of inducing cardiotoxicity relative to ADC drugs and small moleculetargeted drugs,with heart failure being the ADEs with the highest frequency,but TDXd has relatively weak cardiotoxicity.The risk of gastrointestinal system-related ADEs is more pronounced for molecularly targeted drugs,and the risk of nutritional and metabolic disease-related ADEs is also higher for such drugs.Second,Lapatinib and TDM-1 had a significant tendency to hepatotoxicity,and Lapatinib combination increased the risk of hepatotoxicity(OR=4.96,95%CI:3.31～7.68,P<0.001).In addition,Tucatinib was associated with the highest risk of neurologic disease(OR=1.54,95%CI:1.35～1.76,P<0.001)and psychiatric disease(OR=15.08,95%CI:9.13～25.33,P<0.001),memory impairment was a specific ADEs of Tucatinib,and Tucatinib combined with Trastuzumab increased the risk of neurologic toxicity.T-DXd had the highest risk of respiratory disease ADEs(OR=2.56,95%CI:2.09～3.16,P<0.001),with interstitial pneumonia being the most frequent ADEs.Also,anti-HER-2 treatments in patients younger than 18 years induces a high probability of interstitial lung disease.Finally,drug combinations increased the risk of multiple ADEs compared to single agents.Conclusions:ADEs may be induced by different anti-HER-2 drugs in various SOCs,and TDM-1 and T-DXd have great differences in hematological system,respiratory system,cardiotoxicity,hepatotoxicity and other aspects.In addition,Tucatinib is more likely to induce neurological and psychiatric ADEs.Finally,anti-HER-2 combinations may increase the risk of ADEs.