Immune-related Adverse Events Caused By PD-1/PD-L1 Inhibitor Therapy Predict Efficacy Of Patients With Advanced Cancer

Objective Immunotherapy has opened up a new landscape in the treatment of malignant tumors.To date,the most widely used immunotherapy drugs are immune checkpoint inhibitors（ICIs）.In patients treated with ICIs,tumor response rates was 15 to 30%.Among them,ICIs targeting programmed cell death protein 1/ligand1（PD-1/PD-L1）are increasingly used in the treatment of many malignant tumors.However,with the increased clinical application of these drugs,reports of immune-related adverse events（ir AEs）have increased accordingly.Ir AEs are the result of ICIs-mediated activation of the immune system.Unlike traditional chemotherapy and targeted therapy,ir AEs usually occur late and last for a long time,and can occur in any organ system.There is rising evidence of a correlation of the occurrence of ir AEs and clinical benefifits regarding tumour control and survival rates under immune checkpoint inhibitors.The presence of ir AEs has the potential to be an predictive biomarker of efficacy in anti-PD-1/PD-L1 therapy of certain tumors（such as non-small cell lung cancer and malignant melanoma）.However,further large sample studies are necessary to confirm our findings.Therefore,the purpose of this study is to explore the relationship between ir AEs and efficacy in patients with advanced malignant solid tumors during anti-PD-1/PD-L1 therapy through real-world clinical studies,so as to provide clinical evidence for clarifying the correlation between them.Methods The clinical data of 367 patients with advanced solid tumors admitted to the First Affiliated Hospital of Anhui Medical University from November 2018 to September 2021 were collected.The patients were treated by anti-PD-1 therapy alone or in combination with other antitumor therapy.Treatment response and ir AEs were recorded.Results In a cohort of 367 patients（median age,62 years;261 men,106 women）,46 patients received p D-1 /PD-L1 inhibitor monotherapy and 321 patients received combination therapy.355 patients were evaluable for efficacy,and all patients were evaluable for adverse reactions.In total,203 patients experienced 289 ir AEs,35 patients experienced 40 ir AEs of grade≥3.The common ir AEs were skin reaction in 111 cases,hypothyroidism in 46 cases,hepatitis in 20 cases,and pancreatitis in 20 cases.Severe immune-related adverse events mainly included hepatitis in 14 cases and myocarditis in 7 cases.The ORR and DCR were higher of patients with ir AEs were higher than those without ir AEs（ORR:40.3% vs 15.9%,P < 0.001;DCR:83.8% vs 42.7%,P <0.001）.According to the ir AEs site,patients with cutaneous ir AEs and endocrine ir AEs had improved ORR compared to patients without ir AEs（cutaneous ir AEs:47.7% vs21.0% P<0.001;endocrine ir AEs:45.8% vs 25.7% P=0.002）,while the ORR of patients with digestive ir AEs was not significantly improved compared with patients without digestive ir AEs（32.5% vs 28.6%,P=0.606）.The median PFS and OS after the initiation of immunotherapy were significantly longer in patients with ir AEs than in those without ir AEs（PFS:10.5 vs 4.2 months,P < 0.001;OS:19.7 vs 8.4 months,P <0.001）.In 6-week landmark analysis,median OS was 25.7 months and 14.9months（P=0.012）for patients with or without ir AEs.On multivariate analysis ir AEs remained independent predictors of OS（HR=0.36,95% CI:0.26-0.50,P < 0.001）in advanced patients with immunotherapy,while age,sex,brain metastases and combined therapy had no significant effect on OS.Conclusion In this study,monotherapy or combination of PD-1/PD-L1 inhibitors showed great efficacy and safety in patients with advanced solid tumors.The effective rate was improved and the survival time was significantly prolonged of ir AEs group than those of without ir AEs group.There is a correlation between the development of ir AEs and the efficacy and prognosis of immunotherapy in patients with advanced solid tumors,which is a possible marker to predict the efficacy.