| Purpose:In recent years,immune checkpoint inhibitors(ICIs)have been strongly recommended for the treatment of various cancers and have shown significant efficacy.However,only about 20%of cancer patients can benefit from ICIs treatment.Therefore,it is necessary to explore some reliable and effective biomarkers to screen the most appropriate cancer patients.Tumor mutation burden(TMB)as a potential biomarker has been drawing more and more attention and shown to be related to the efficacy of ICIs.However,as TMB remains a controversial biomarker for the patient selection and screening for the treatments of ICIs and the cost-effectiveness of TMB detection on tumor immune precision medicine is unknown,this study comprehensively evaluates the clinical value of tumor precision medicine based on TMB detection,which aims to promote the rational use of clinical drugs and provide a reference for policy makers on medical insurance department.Methods:(1)Searching the literature related to the efficacy of TMB and ICIs treated with tumors from Pub Med,Embase,Cochrane-Library and CNKI database up to December 2020.The primary endpoints were the progression-free survival(PFS)and the overall survival(OS)in patients with high TMB or low TMB.The pooled hazard ratios(HR)for PFS and OS in Meta-analysis were performed by STATA 14.0.(2)Based on the clinical data of the Check Mate 227 trial,the utility value and direct medical cost gathered from the published studies,a three-state Markov model was carried out using Tree Age Pro 2017 to compare the total cost,quality-adjusted life years(QALYs)and incremental cost-effectiveness ratios(ICER)of three treatment strategies in the first-line treatment for non-small-cell lung cancer(NSCLC):(Ⅰ)all patients treated with chemotherapy without tumor sample tested for TMB;(Ⅱ)all patients treated with Nivolumab plus Ipilimumab without tumor sample tested for TMB;(Ⅲ)patients treated according to their TMB status:patients with high TMB were treated with Nivolumab plus Ipilimumab,and patients with low TMB treated with chemotherapy.Result:The main results have two aspects: meta-analysis and cost-effectiveness analysis.1.Meta-analysis(1)A total of 42 studies were included in this study,including 17 controlled trials and 25single-arm trials,with a total of 13,289 patients;The qualities of included studies were high.(2)Efficacy comparison for ICIs versus chemotherapy according to the level of TMB: For the patients with high TMB,patients treated with ICIs had significant benefits on PFS(HR=0.61,95%CI: 0.55-0.68,P<0.001)and OS(HR=0.62,95%CI: 0.57-0.68,P<0.001)compared to those treated with chemotherapy.For the patients with low TMB,patients treated with ICIs had no significant benefits on PFS(HR=1.15,95%CI: 0.99-1.34,P=0.075)and OS(HR=0.94,95%CI: 0.85-1.04,P=0.230)compared to those treated with chemotherapy.(3)Efficacy comparison for ICIs in patients with high TMB versus patients with low TMB:Patients with high TMB had significant benefits on PFS(HR=0.52,95%CI: 0.45-0.60,P<0.001)and OS(HR=0.57,95%CI: 0.47-0.70,P <0.001)compared to patients with low TMB when they were treated with ICIs.Overall,it showed that ICIs could significantly prolong the PFS and OS of cancer patients with high TMB.(4)Subgroup analysis: Patients with high TMB treated with ICIs could obtain longer PFS and OS for NSCLC,while patients with high TMB for triple-negative breast cancer,urothelial carcinoma,HNSCC and gastric cancer could not have significant benefits on PFS or OS when they were treated with ICIs.2.Cost-effectiveness analysis(1)Base-case analysis: The Markov model was used to estimate the 10-year survival status of NSCLC patients from the US payer perspective.The results show that the ICER of Nivolumab plus Ipilimumab without TMB testing strategy and using TMB test for patient selection strategy compared with chemotherapy were $212,753/QALY and $228,949/QALY,respectively.It indicated that e at a willingness-to-pay(WTP)threshold of $150,000/QALY,neither of these two strategies were not considered to be cost-effective.(2)Sensitivity analysis: The patient’s weight and the utility for progressed disease stage were more sensitive to the results,but the conclusion cannot be reversed.From the US payer perspective,when the price of Nivolumab was reduced to 20%($5.708/mg),the ICERs of Nivolumab plus Ipilimumab without TMB testing strategy and using TMB test for patient selection strategy could reduce below a WTP of $150,000/QALY,and the acceptable probabilities of cost-effectiveness of these two strategies were 90.8% and 100%,respectively.(3)China perspective: When the price of Ipilimumab was 0 RMB and the price of Nivolumab remained at 9,250 RMB/bottle(100mg/100ml)or the price of Nivolumab droped to 0RMB and the price of Ipilimumab was 25,478 RMB/bottle(50mg/10ml)from China payer perspective,the ICERs of Nivolumab plus Ipilimumab without TMB testing strategy and using TMB test for patient selection strategy were far greater than Chinese WTP(triple per capita Gross Domestic Product,217,341 RMB).Only when the price of Nivolumab plus Ipilimumab was less than 5,970.28 RMB/week,the ICER of these two strategies compared with chemotherapy could below the WTP,and the acceptable probabilities of cost-effectiveness of these two strategies were 99.9% and 59.6%,respectively.Conclusion:Patients with high TMB,especially for NSCLC patients,could have significant benefits on PFS and OS when they were treated with ICIs,which showed that TMB may be a preferable biomarker for NSCLC patients to screen the most appropriate patients treated with ICIs.However,the ability to predict the efficacy of ICIs for other tumors such as triple-negative breast cancer,urothelial cancer,HNSCC and gastric cancer needs to be verified by large-sample studies in the later stage.Due to the high price of ICIs,using TMB testingto achieve precision medicine for cancer patients was both not cost-effective from the US and China payer perspective.It is shown that TMB testing could guide clinicians to accurately select tumor treatment options.Therefore,it is still necessary to support TMB testing for its clinical application based on the not cost-effectiveness conclusion of economic evaluation.Meanwhile,it is recommended to reduce the price of innovative high-value tumor immune drugs and include them in medical insurance through negotiation and other methods to benefit more patients. |
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