Clinical Observation Of Immune Checkpoint Inhibitors Plus Antiangiogenic Drugs In Patients With Advanced Hepatocellular Carcinoma

BackgroundThe incidence and mortality of liver cancer are on the rise all over the world.In2020,the incidence and mortality of liver cancer is 6th in the world and 3rd in the world.The pathological types of primary liver cancer include Hepatocellular Carcinoma（HCC）,Intrahepatic Cholangiocarcinoma and mixed type,HCC accounts for 75%～85% of primary liver cancer and is the most important pathological subtype of primary liver cancer.The onset of HCC is insidious,most patients have no chance of surgery or distant metastasis at the time of diagnosis.Systematic treatment is the main choice for advanced HCC.In recent years,immune checkpoint inhibitors（ICIs）have become an important means of anti-tumor therapy,bringing survival benefits to patients with a variety of malignant tumors.Based on IMbrave150 and ORIENT-32,ICIs combined with antiangiogenic therapy（AT）has been approved by the NMPA for first-line treatment of advanced HCC.It can significantly improve the progression-free survival time（PFS）and overall survival time（OS）of HCC patients.To investigate the efficacy and safety of ICIs combined with AT in the first-line treatment of advanced HCC in the real world,we retrospectively analyzed the efficacy and safety of ICIs combined with AT in the first-line treatment of advanced HCC patients,and analyzed the relationship between the expression of relevant molecules in tumor microenvironment and clinicopathological parameters and the efficacy.It provides more reference for first-line treatment of advanced HCC patients and screening of advantageous population.Objective1.To examine the efficacy and safety of immune checkpoint inhibitors（ICIs）combined with first-line antiangiogenesis drugs（AT）in real-world advanced HCC patients.2.To analyze the efficacy of different immune checkpoint inhibitors（ICIs）combined with antiangiogenesis（AT）in the first-line treatment of advanced HCC patients.3.To explore the factors related to tumor microenvironment and clinicopathological parameters affect the efficacy of immune checkpoint inhibitors（ICIs）combined with antiangiogenesis（AT）first-line therapy for advanced HCC.MethodsA retrospective study was conducted to select 45 patients with advanced HCC who received ICIs combined with AT first-line treatment in our hospital from June2018 to June 2020,including 24 patients with carrelizumab combined with apatinib（Group A）and 21 patients with sindilizumab combined with bevacizumab（Group B）.Clinicopathological data of patients were collected,and the efficacy and adverse events of different groups were evaluated according to RECIST1.1 and CTC AE 4.0criteria,and the relationship between clinicopathological parameters and efficacy was statistically analyzed.In addition,paraffin tissues of patients with tumor tissue samples before treatment were collected and immunohistochemical staining（IHC）was used to detect the expression of PD-L1,VEGFA,CD3,CD4,CD8,CD68,CD163 and FOXP3 in tumor microenvironment to analyze the relationship between the above molecular expressions and efficacy.Research Results1.Among 45 patients,The objective response rate（ORR）and disease control rate（DCR）was 28.89% and 57.78%,respectively.Median progression-free survival（mPFS）was 6.6 months.2.The ORR in group A was 29.17%（7/24）,DCR was 58.33%（14/24）,mPFS was 6.7 months.The ORR in group B was 28.57%（6/21）,DCR was 57.14%（12/21）,mPFS was 6.5 months.3.There were no significant differences in ORR,DCR and mPFS between the groups（P>0.05）.There were no treatment-related deaths and new adverse events among the 45 patients.The incidence of adverse reactions from any cause was97.78%（44/45）,treatment-related adverse events of any grade were 84.44%（38/45）,and the incidence of adverse reactions above grade 3 was 11.11%（5/45）.4.Among the 45 patients,Child A,ECOG 0,BCLC B patients had higher ORR than Child B,ECOG 1,and BCLC C patients（P<0.05）.Patients with ECOG 0 and BCLC B had higher DCR than those with ECOG 1 and BCLC C（P<0.05）.Child A and ECOG 0 had longer mPFS than Child B and ECOG 1（P<0.05）.5.The expressions of VEGFA,CD3,CD4,CD8,CD68,CD163 and FOXP3 in tumor micro-environment were not correlated with the ORR of ICIs combined with AT（P>0.05）.DCR was higher in patients with PD-L1（TPS）positive expression and FOXP3 negative expression（P<0.05）.6.VEGFA,CD3,CD4,CD8,CD68 and CD163 were not associated with mPFS in 45 HCC patients.Patients with positive PD-L1（TPS）expression and negative FOXP3 expression had longer mPFS（P<0.05）.ConclusionImmune checkpoint inhibitors（ICIs）combined with anti-angiogenic therapy（AT）have a positive efficacy and good safety in first-line treatment of advanced liver cancer.The efficacy of different immunocheckpoint inhibitors and antiangiogenic drugs combined is similar.Patients’ p Hysical status score,Child score,stage of BCLC,and expression of PD-L1（TPS）and FOXP3 in the tumor microenvironment are associated with the efficacy of immune checkpoint inhibitors in combination with antiangiogenesis therapy,and may contribute to the screening of dominant populations.