Overview

The aim of this study is to the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of transarterial chemoembolization (TACE), Anti-VEGF antibodies or pan-target anti-angiogenic drugs, and anti-PD-1/ PD-L1 antibody for advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years old
2. Diagnosis of HCC is according to the American Association for the Study of Liver Diseases or European Association for the Study of the Liver guidelines of HCC management;
3. at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or mRESIST criteria.
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
5. Hepatocellular carcinoma (HCC) was assessed as not suitable for radical resection, liver transplant, or ablation treatment after the assessment of a multidisciplinary team because either: (1) R0 resection was not feasible; (2) remnant liver volume was less than 30% in patients who did not have cirrhosis or 40% in patients with cirrhosis, or the results of an indocyanine green test were higher than 15%; (3) patients had Barcelona Clinic Liver Cancer (BCLC) stage B or BCLC stage C.
6. portal vein involvement (Chen's groups A, or Cheng's type I-II) is allowed: Chen's group A1 or Cheng's type I, tumor thrombus is involved in segmental or sectoral branches of the portal vein or above; Chen's group A2 or Cheng's type II, involvement of the first branch of portal vein.
7. hepatic vein invasion (VV1 to VV2) were allowed.
8. Patients with extrahepatic oligometastasis is allowed: extrahepatic oligometastasis was defined as up to three metastatic lesions in up to two organs with the largest diameter of 3 cm
9. Child-Pugh liver function class A-B7
10. No prior transplantation, TACE, or radioembolization to the liver was allowed. Prior locoregional therapies, such as surgical resection, radiotherapy, radiofrequency ablation, percutaneous ethanol injection or cryoablation, are allowed if the disease have progressed since prior treatment. Local therapy must have been completed at least 4 weeks prior to the baseline scan.
11. Adequate organ and marrow function, as defined below:

        (1) Hemoglobin ≥80 g/L (2) Absolute neutrophil count ≥1.5 ×109/L (3) Platelet count ≥50
        ×109/L (4) Total bilirubin < 51 μmol/L (5) Alanine transaminase (ALT) and aminotransferase
        (AST)≤5×ULN (6) Albumin ≥28 g/L (7) INR ≤1.6 (8) Serum creatinine < 110 μmol/L 12. Time
        interval between TACE and systemic therapy within 7 days.
        Exclusion Criteria:
        1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as
        cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the
        skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured 2.
        Severe, active and uncontrolled co-morbidity including but not limited to:
          1. Persistent or activity (except the HBV and HCV) infection;
          2. symptoms of congestive heart failure and uncontrolled diabetes;
          3. uncontrolled hypertension, systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100
             mmHg despite anti-hypertension medications ≤ 28 days before randomization or first
             dose of drug.
          4. unstable angina,
          5. uncontrolled arrhythmias,
          6. active ILD,
          7. severe chronic GI disease accompanied by diarrhea,
          8. compliance with requirements may limit the research, resulted in significant increase
             risk of AE or influence Subjects provided psychiatric/social problem status on their
             ability to provide written informed consent.
          9. A history of active primary immunodeficiency or human immunodeficiency virus; (10)
             Active or previous records of autoimmune disease or inflammatory diseases, including
             inflammatory bowel disease (e.g., colitis or Crohn's disease], diverticulitis, except
             [diverticulosis], systemic lupus erythematosus (SLE), sarcoidosis syndrome or Wegener
             syndrome (e.g., granulomatous vasculitis, gray's disease, rheumatoid arthritis, the
             pituitary gland inflammation and uveitis]).
        (11) A history of hepatic decompensation, including refractory ascites, gastrointestinal
        bleeding, or hepatic encephalopathy; 3. Known to produce allergic or hypersensitive
        reactions to any study drug or any excipient thereof; 4. Significant clinical
        gastrointestinal bleeding or a potential risk of bleeding was identified by the
        investigator during the 30 days prior to study entry.
        5. Tumors of the central nervous system, including metastatic brain tumors; 6. Pregnant
        women or breast-feeding patients; 7. Has received anti-tumor system therapy for HCC.
        Non-anti-tumor purpose combined hormone therapy (e.g., hormone replacement therapy) is
        excluded.
        8. Is currently using, or has used an immunosuppressive drug within 14 days prior to the
        first dose of the investigational drug. This standard has the following exceptions: (1)
        intranasal, inhaled, topical or topical steroids. (e.g., intraarticular) (2) Systemic
        corticosteroid therapy not exceeding 10 mg/ day of prednisone; (3) prophylactic use of
        steroids for hypersensitivity. (e.g., CT scan pretherapy medication) 9. A live attenuated
        vaccine was administered within 30 days prior to the first administration of the study
        drug. Note: If enrolled, patients shall not receive live attenuated vaccine within 30 days
        of receiving study drug therapy and after the last administration of study drug.
        10. Extrahepatic vascular involvement or thrombosis: main trunk of portal vein and superior
        mesenteric vein (Cheng's type III and IV) or inferior vena cava (IVC) (VV3).