Clinical Efficacy And Related Biomarker Of TACE Combined With Targeted Immunotherapy For Unresectable Hepatocellular Carcinoma

Purpose:To investigate the synergistic anti-tumor effects of transcatheter arterial chemoembolization（TACE）on hepatocellular carcinoma（HCC）based on systemic therapy by comparing the clinical benefit and tolerability of triple therapy of Lenvatinib,programmed death 1（PD-1）inhibitor,and TACE versus dual therapy of Lenvatinib and PD-1 inhibitor in unresectable HCC patients.Methods:This study retrospectively collected clinical data from unresectable HCC patients who received targeted immune combination therapy at the Cancer Hospital of Chinese Academy of Medical Sciences between October 2018 and October 2021.Patients receiving dual therapy of Lenvatinib and PD-1 inhibitor served as the control group and those treated with triple therapy of TACE,Lenvatinib and PD-1 inhibitor served as the study group.The clinical efficacy and safety of the two groups were compared and analyzed.The efficacy was evaluated by survival and therapeutic response,and the tolerability was evaluated by the frequency and severity of key adverse events（AEs）.Results:In total,210 eligible patients with unresectable HCC who received combination therapy were included in this study.Among them,102 patients received triple therapy of TACE,Lenvatinib and PD-1 inhibitor（study group）,and 108 eligible patients received dual therapy of Lenvatinib and PD-1 inhibitor（control group）.Patients who received triple therapy had better overall survival（OS）[median,28.9 vs.23.2 months,P<0.001]and progression-free survival（PFS）[median,16.0 vs.10.6 months,P<0.001]than those who received dual therapy.The objective response rate（ORR,70.6%vs.39.8%,P<0.001）and disease control rate（DCR,90.2%vs.66.7%,P<0.001）in the study group were higher than in the control group,respectively.The incidence and severity of AEs in the study group were comparable to those in the control group（any grade,96.1%vs.94.4%,P=0.817;grade ≥3,33.4%vs.27.8%,P=0.469）,and no adverse events related to death occurred.Conclusion:Compared to Lenvatinib in combination with PD-1 inhibitor,TACE in combination with Lenvatinib and PD-1 inhibitor could significantly prolong PFS and OS in patients with unresectable HCC,could significantly improve ORR and DCR with manageable safety profiles.TACE combined with targeted immunotherapy had the potential to become one of the preferred comprehensive treatment modes for HCC patients.Objective:To investigate the correlation between gut microbiome and treatment response and survival outcome of TACE combined with targeted immunotherapy for unresectable HCC,and to identify specific gut microbiota affecting immunotherapy and provide new therapeutic strategies for modulating the immune anti-tumor response to HCC.Methods:In this study,fresh stool samples were collected prospectively from unresectable HCC patients treated with TACE in combination with Lenvatinib and PD-1 inhibitor at the Cancer Hospital of Chinese Academy of Medical Sciences between January 2020 and October 2021,and patients were divided into treatment responders group（R group）and treatment non-responders group（NR group）based on treatment efficacy.The composition and diversity of gut microbiome were bioinformatically analyzed by using Whole Genome Shotgun strategy,including taxonomic composition analysis,Alpha diversity analysis,Beta diversity analysis,and differential enriched bacterial taxa analysis.Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size（LEfSe）and analyzed for their impact on survival of patient.Results:A total of 45 patients with unresectable HCC treated with TACE in combination with Lenvatinib and PD-1 inhibitor were retrospectively analysed for gut microbiomic data.The gut microbiological composition and Alpha diversity of stool samples were not statistically different,but there was a statistically significant difference in Beta diversity between R and NR groups.（PERMANOVA tests,P=0.006）.There were significantly enriched bacterial taxa between the R and NR groups.The results of survival analysis showed that the abundance of some significantly enriched bacterial taxa were independent related factors of PFS and OS.Compared with patients with low abundance of Collinsella genus and Ruminococcus.AM4211、Ruminococcus.AF25₂8AC,the median PFS and OS of patients with high abundance were significantly longer（P<0.05）.On the contrary,the median PFS and OS of patients with high abundance of Bacteroides.AF20₁3LB and Veillonella_atypica were significantly shorter than those of patients with low abundance（P<0.05）.Conclusion:Significant enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with TACE combined with targeted immunotherapy,and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.Purpose:To investigate the correlation between peripheral blood cell-based inflammatory indexes and treatment response and survival outcome of Lenvatinib and PD-1 inhibitor-based combination therapy in unresectable HCC,and to find potential non-invasive biomarkers and assist clinical decision-making on treatment.Methods:This study collected clinical data and baseline inflammatory indexes from patients with unresectable HCC who received Lenvatinib and PD-1 inhibitor-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between October 2018 and October 2021.The optimal threshold values for PLR,NLR,LMR,SII,SIRI,PNI,APRI,ANRI and C-reactive protein were determined using X-tile.Independent related factors of treatment response were determined by multifactorial logistic regression analysis.Independent prognostic factors for PFS and OS were analyzed by multifactorial COX regression.A risk prediction model for disease progression was constructed based on inflammatory indexes,and the predictive efficacy of the prognostic score model and BCLC staging was compared by the area under the ROC curve.Results:A total of 156 eligible patients with unresectable HCC treated with Lenvatinib and PD-1 inhibitor-based combination therapy were included,with median OS and PFS of 23.8 and 11.5 months,respectively,and ORR of 48.7%.The baseline SIRI was an independent correlate of treatment response,with a significantly higher ORR for patients with a SIRI<0.8 than for patients with a SIRI≥0.8（59.7%vs.41.5%,P=0.03）.Multifactorial COX regression analyses showed that SIRI and PNI were independent prognostic factors of PFS,and SIRI was an independent prognostic factors of OS.The AUC value of nomogram based on baseline SIRI,PNI and tumor distribution in predicting PFS rate of patients at 6,12 and 18 months was significantly higher than that of traditional BCLC stage,and its prediction performance was significantly better than that of BCLC stage system（C-index,0.75 vs 0.54）.Conclusion:The baseline SIRI was an independent factor related to the treatment response and survival outcome in patients with HCC treated with Lenvatinib and PD-1 inhibitor-based combination therapy,and could be used as a potential non-invasive biomarker to predict the efficacy and survival benefit of targeted immune combination therapy for HCC.The nomogram based on inflammation indexes could achieve better prediction performance,which was helpful for clinicians to identify high-risk patients and formulate treatment plans.