Safety Evaluation Of Clinical Application Of Programmed Cell Death-1 Inhibitors

Background:Immunotherapy includes cellular immunotherapy and immune checkpoint inhibitor therapy.Immune checkpoint inhibitors have been marketed into various products The pharmacological explanation of immune checkpoint inhibitors for anti-tumor therapy is:by inhibiting the activity of immune checkpoints,re-stimulating T lymphocytes to launch an immune attack against the tumor,thereby achieving anti-tumor effects.Immune checkpoint inhibitors include cytotoxic T lymphocyte associated antigen-4(CTLA-4)inhibitors and programmed cell death-1(PD-1)inhibitors and programmed cell death ligand-1(PD-L1)inhibitors.While PD-1 inhibitors have been extensively used clinically,immune-related adverse events caused by PD-1 inhibitors have attracted the attention of researchers.Safety evaluation is a key content in the field of clinical pharmacy,which can provide reference to clinical use of drugsObjective:By collecting,processing and statistical analysis of retrospective and prospective data on PD-1 inhibitors’ adverse events,the safety of such drugs and the influencing factors of adverse events were explored.This study is intended to provide a certain preference for the safe and reasonable use of PD-1 inhibitors for anti-tumor therapy.Methods:This research included 4 parts(1)Bibliometric analysis.A bibliometric analysis of researches on immune-related adverse reactions of PD-1 inhibitors was conducted including annual publications,domestic and foreign gaps,and future research directions(2)Network Meta-analysis.Data from international multi-centered randomized controlled trials(RCT)were collected to explore the safety differences between PD-1 inhibitors,PD-1 inhibitors combined with other drugs,and other anti-tumor therapies such as chemotherapy.Subgroup analysis of patients with melanoma,digestive system tumors,non small cell lung cancer and head and neck cancer was conducted(3)Signal mining of the adverse reaction of imported PD-1 inhibitor-nivolumab and pembrolizumab.Based on the FAERS database,using the reporting odds ratio(ROR)method and the proportional reporting ratio(Proportional reporting ratio,PRR)method,the signals of adverse reactions of these two drugs was explored and the association between adverse reactions and the use of such drugs(4)A prospective study on the influencing factors of adverse events of domestic marketed PD-1 inhibitor camrelizumab.Following-up by telephone,we prospectively collected the adverse events of patients who used camrelizumab for anti-tumor therapy in Yantai and Weihai,collecting baseline characteristics,tumor types,the frequency of administration,combination therapies,to explore the statistical correlation between adverse events and probable influencing factors.Results:(1)After screening by exclusion criteria,a total of 64 articles were found from CNKI.881 related articles were found from Web of Science.Domestic researches has barely studies in more detailed fields such as drug dosage and combination medication.And these kinds of researches should be conducted in the future.The next direction of researches abroad may be on monitoring and prevention,so it will be important to further explore the relationship between adverse events and probable influencing factors.Combined with emerging real-world research in recent years,it is possible to carry out patient registration research on immune-related adverse reactions of PD-1 inhibitors(2)57 qualified studies were picked out of 8048 studies,including 11 interventions,and 27,379 patients.The results of the network meta-analysis of serious adverse events(SAE,grade 3-5 adverse events)indicators show that the placebo group has the lowest probability of SAE,followed by the PD-1 inhibitor monotherapy group,and the combination therapy of PD-1 inhibitors and targeted drugs has the highest probability.For adverse events(grade 1-2 adverse reactions,AE),the placebo group,still,showed the lowest probability,also followed by PD-1 inhibitors monotherapy,and the epidermal growth factor receptor(EGFR)inhibitor combined with chemotherapy group had the highest incidence.It was proved that one intervention had different safety outcomes in patients with different types of tumors(3)After mining in the FAERS database and deleting the duplicates,a total of 70,930 adverse event reports with pembrolizumab as the main suspected drug were obtained,and 532 repetitive signals of the ROR and PRR methods were included,and a total of 23 systems/organs were obtained.Abdominal pain showed the strongest signal;A total of 166,687 adverse events with nivolumab as the main suspected drug was included in 954 repetitive signals of ROR and PRR methods,and a total of 23 systems/organs were included.Paraneoplastic dermatosis showed the strongest signal(4)A total of 97 patients using camrelizumab were collected.The association of adverse events with probable influencing factors was studied.The incidence of reactive cutaneous capillary endothelial proliferation(RCCEP)and fatigue is not statistically significant with gender and frequency of administration(P>0.05).Fatigue may be statistically significant with age(P<0.05).Sweating,aversion to hotness,diplopia,hematuria might have an association with gender;cough,headache might have an association with the frequency of administration(P<0.05)Conclusion:When PD-1 inhibitors are combined with other drugs for anti-tumor therapy,the incidence of adverse events increases.PD-1 inhibitor mono-therapy has a lower incidence of adverse events on the basis of its efficacy.Adverse events of nivolumab were mainly infections,followed by adverse events of the gastrointestinal system and nervous system.Adverse events of pembrolizumab were mainly immune system diseases,followed by adverse events of the gastrointestinal system.Occurrence of these adverse events should be noted that they may be related to the use of such drugs.Age,gender,the frequency of administration,etc.may have a certain impact on the occurrence of camrelizumab’s adverse eventsInnovation(1)Safety evaluation conducted from multiple angles with a complete content.This study started with a summary of existing research,conducted retrospective research on comparative advantage drug regimens,mined the adverse reaction signals of imported PD-1 inhibitors,and conducted research on the influencing factors of adverse events of domestic products.(2)A complete network meta-analysis of including interventions.Meta-analysis of PD-1 inhibitors is mostly based on simple Meta,and there are few network Meta-analysis.At present,the English-language meta-analysis was mostly researches about efficacy,and mostly limited drugs to nivolumab and pembrolizumab.This study included not only these two imported drugs,but also domestic drugs such as camrelizumab and sintilimab(3)Study on the adverse events of camrelizumab bought and used out-of-hospital.The self-reported data of patients is still far from enough.This has led to that adverse events of many patients who purchase drugs in social pharmacies are hard to collect,and the risk of patients’social drug use is difficult to be measured and monitored.In this study,insufficient data was supplemented by collecting data of adverse events of patients who purchased drugs for self-use in specialty pharmacies outside medical institutions.