The Study On Application Of TKIs Combined With PD-1 Inhibitors In Conversion Resection And Postoperative Adjuvant Therapy For Hepatocellular Carcinoma

Objective: To investigate the application value of tyrosine kinase inhibitors(TKIs)combined with programmed cell death protein-1(PD-1)inhibitors in conversion resection and postoperative adjuvant therapy(PAT)for hepatocellular carcinoma(HCC).Methods: The first part retrospectively enrolled HCC patients with intermediate and advanced stage who received either TKIs plus PD-1 inhibitors combined with transcatheter arterial chemoembolization(TPT)or TKIs plus PD-1 inhibitors combined with hepatic arterial infusion chemotherapy(TPH),then compared the overall efficacy of these two treatment options in conversion therapy for HCC.In the second part,HCC patients who underwent radical hepatectomy were retrospectively enrolled,and those with high-risk recurrent factors(HRRFs)were divided into the PAT group(adjuvant TKIs combined with PD-1 inhibitors after surgery)and non-PAT group(without adjuvant therapy after surgery).Recurrence-free survival(RFS)and overall survival(OS)were compared between the two cohorts.In the third part,the genomic sequencing and clinicopathological data of HCC patients with adjuvant TKIs and PD-1 inhibitors after hepatectomy were retrospectively collected,mainly including microsatellite instability(MSI),total number of somatic mutations(TSM),tumor mutation burden(TMB),gene mutations associated with targeted and immunotherapy,and programmed cell death protein ligand-1(PD-L1)expression levels.The predictive value of the above indicators for the early efficacy of PAT was analyzed.Results: The results of the first part indicated that the overall response rate(ORR),disease control rate(DCR),and conversion surgical resection rate(CSR)of patients in the TPH group were significantly improved,and the progression-free survival(PFS)and OS were relatively prolonged.The results of the second part demonstrated that the RFS and OS of patients in the PAT group were significantly prolonged.PAT was an independent factor for improving RFS and OS of HCC patients with HRRFs.The results of the third part showed that the patients with low TMB levels(TMB ≤ 2.63 Muts/Mb)achieved obviously lower early recurrence rate,and significantly longer RFS.The accuracy of TMB in predicting early RFS was relatively high.Conclusions: Compared with TPT,TPH was more likely to improve the overall efficacy of conversion therapy for HCC with intermediate and advanced stage.Adjuvant with TKIs and PD-1 inhibitors after radical resection could effectively improve the survival outcomes of HCC patients with HRRFs.TMB possessed potential predictive value for early RFS in HCC patients treated with adjuvant TKIs combined with PD-1 inhibitors after hepatectomy.Part Ⅰ: Comparison of the Efficacy of TKIs and PD-1 Inhibitors Combined with TACE or HAIC in Conversion Therapy for Hepatocellular CarcinomaObjective: To compare the overall efficacy of TPT and TPH in conversion therapy for HCC.Methods: Patients with HCC who received TPT or TPH as first-line therapy at the Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology between June 2019 and February 2022 were retrospectively enrolled.Tumor therapeutic response was assessed by the modified response evaluation criteria in solid tumors.The ORR,DCR,CSR,PFS,and OS were compared between the two groups.Multivariate logistic regression analysis was used to identify independent influencing factors associated with patients’ successful conversion to surgical resection,and multivariate Cox regression analysis was used to determine independent prognostic factors for OS.Results: A total of 133 HCC patients with intermediate and advanced stage were enrolled,with a median follow-up period of 11.1 months [interquartile range(IQR): 8.1-15.0 months].Of them,30 patients(22.6%)met the criteria for conversion surgery and underwent hepatectomy.The ORR,DCR,and CSR of patients in the TPT and TPH groups were 31.0% vs.63.0%(P = 0.001),72.4% vs.91.3%(P = 0.020),and 16.1% vs.34.8%(P= 0.025),respectively.Compared with patients in the TPT group,the PFS of patients in the TPH group was relatively prolonged(P = 0.061),and the OS was significantly longer(P = 0.033).TPH was an independent influencing factor associated with successful conversion to surgical resection in HCC patients with intermediate and advanced stage [odds ratio: 3.03,95% confidence interval(CI): 1.29-7.27,P = 0.012].Patients with successful conversion surgery obtained significantly longer OS than those without successful conversion(P = 0.015),and successful conversion surgery was an independent prognostic factor in improving OS [hazard ratio(HR): 0.09,95% CI: 0.01-0.77,P = 0.028].Conclusions: Compared with TPT,TPH was more likely to improve the overall efficacy of conversion therapy for HCC with intermediate and advanced stage.Part Ⅱ: Postoperative Adjuvant TKIs Combined with PD-1 Inhibitors Improves Survival Outcomes for Hepatocellular Carcinoma Patients with High-risk Recurrent FactorsObjective: To investigate whether adjuvant TKIs combined with PD-1 inhibitors after radical resection could improve the survival prognosis of HCC patients with HRRFs.Methods: Patients with HCC who underwent radical resection at the Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology between January 2019 and December 2021 were retrospectively enrolled,and those with HRRFs(tumor diameter > 5 cm,multiple tumors,satellite nodules,or vascular invasion)were divided into PAT group and non-PAT group.Propensity score matching(PSM)was used to balance the baseline characteristics of the two groups of patients.The survival curves for RFS and OS were generated by the Kaplan-Meier method and compared using the log-rank test.Independent prognostic factors for RFS and OS were determined by Cox regression analysis,and subgroup analysis was conducted.Results: A total of 250 HCC patients were enrolled in this study,with a median follow-up time of 22.4 months(IQR: 14.3-34.1 months).Of them,174(69.6%)cases were identified with HRRFs and 76(30.4%)cases were without HRRFs,while the RFS and OS of the latter were significantly longer than those of the former(all P < 0.05).A total of 47 pairs of HCC patients with HRRFs in the PAT group and the non-PAT group were matched through PSM,and there was no statistical difference in the baseline characteristics between the two groups(all P > 0.05).Among the two groups of patients,17(36.2%)and 35(74.5%)cases suffered from recurrence(P < 0.001),while 4(8.5%)and 23(48.9%)cases died(P < 0.001),respectively.The RFS and OS of the patients in PAT group were significantly longer than those in the non-PAT group(all P < 0.05).The 1-and 2-year RFS rates in the two groups were 82.1% vs.40.0%(P < 0.001)and 54.2% vs.25.1%(P = 0.012),respectively.The corresponding 1-and 2-year OS rates were 95.4% vs.69.8%(P = 0.001)and 84.3% vs.55.5%(P = 0.014),respectively.Multivariate Cox regression results indicated that PAT was an independent factor in improving RFS and OS for HCC patients with HRRFs(HR: 0.33,95% CI: 0.18-0.60,P < 0.001;HR: 0.18,95% CI: 0.06-0.54,P = 0.002).Subgroup analysis results demonstrated that PAT could significantly benefit RFS and OS in HCC patients with tumor diameter > 5 cm,satellite nodules,or vascular invasion.Pruritus(44.7%),hypertension(42.6%),dermatitis(34.0%),and proteinuria(31.9%)were common grade 1-3 toxicities,and no grade 4-5 toxicities or serious adverse events were occurred.Conclusions: Adjuvant with TKIs and PD-1 inhibitors after radical resection could effectively improve the survival outcomes of HCC patients with HRRFs.Part Ⅲ: To Explore Predictive Indicators for Early Efficacy of Postoperative Adjuvant TKIs Combined with PD-1 Inhibitors in Hepatocellular CarcinomaObjective: To explore the predictive indicators for early efficacy of postoperative adjuvant TKIs combined with PD-1 inhibitors in HCC.Methods: The genomic sequencing and clinicopathological data of HCC patients treated with adjuvant TKIs and PD-1 inhibitors after hepatectomy at the Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology between January 2019 and December 2021 were retrospectively collected,including TSM,MSI,TMB,gene mutations related to targeted and immunotherapy,PD-L1 expression levels,and peripheral blood neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR).Survival curves were produced by the Kaplan-Meier method and compared by the log-rank test.Time-dependent receiver operating characteristic curve(ROC)and AUC were used to evaluate the predictive value of the above indicators for early RFS.Results: A total of 19 patients with HCC were enrolled in the study,with a median follow-up of 14.4 months(IQR: 10.3-18.2 months).Of whom,6(31.6%)cases experienced recurrence and 2(10.5%)cases died,respectively.Genes with a mutation frequency exceeding 15% included TERT(21.1%)and CTNNB1(15.8%).The RFS and OS were not statistically different among the following subgroups(all P > 0.05),including low NLR group(NLR ≤ 1.35)vs.high NLR group(NLR > 1.35),low PLR group(PLR ≤ 96.21)vs.high PLR group(PLR > 96.21),low TSM group(TSM ≤ 6)vs.high TSM group(TSM > 6),low frequency microsatellite instability group vs.microsatellite stable group,low PD-L1 expression group vs.high PD-L1 expression group,and TERT/CTNNB1 mutation group vs.non-mutation group.The patients with low TMB levels(TMB ≤ 2.63 Muts/Mb)achieved obviously lower early recurrence rate(0 vs.50%,P = 0.044),and significantly longer RFS(P = 0.049)compared to those with high TMB levels(TMB > 2.63 Muts/Mb).The AUC of TMB in predicting 1-year RFS was 0.786(95% CI: 0.597-0.974).Conclusions: TMB possessed potential predictive value for early RFS in HCC patients treated with adjuvant TKIs and PD-1 inhibitors after hepatectomy.