Combination treatment with antiangiogenic agents and anti-programmed cell death protein 1 (PD-1) antibodies have shown high anti-tumor efficacy for patients with unresectable or advanced hepatocellular carcinoma (uHCC). In this single-center cohort study, we are aiming to (1) evaluate the clinical effectiveness in real-world patients, especially for Chinese patients, most of whom were with hepatitis B virus infection; (2) predict clinical effectiveness with clinicopathological features; (3) predict clinical effectiveness with histologic features and blood samples.

Combination treatment with antiangiogenic agents and anti-programmed cell death protein 1 (PD-1) antibodies have shown high anti-tumor efficacy for patients with unresectable or advanced hepatocellular carcinoma (uHCC). In this single-center cohort study, we are aiming to:

1. To evaluate the clinical effectiveness in real-world patients, especially for Chinese patients most of whom were with hepatitis B virus infection.
2. To predict clinical effectiveness with clinicopathological features, such as lab examinations (at baseline and dynamic changes), radiological features (radiomics study at the baseline);
3. To predict clinical effectiveness with histologic features, such as PD-L1 expression, ctDNA, and peripheral immune cell subtypes.
4. To evaluate the clinical effectiveness of second- or third-line therapies, including TACE, HAIC, and interferon, for those who lost clinical benefit or who were intolerant to the combination therapy.

Inclusion Criteria:

1. Documented diagnosis of HCC confirmed by histology/cytology or clinical diagnosis of HCC by Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2019 edition) criteria.
2. Unresectable or advanced disease at the investigator's discretion. The advanced stage was BCLC C stage or China Liver Cancer Stage IIIa or IIIb.
3. Child-Pugh class A or B7.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Subjects received combination therapy with an anti-angiogenic agent and an anti-PD-1/PD-L1 antibody, received at least one imaging evaluation, and signed an Informed Consent Form. Anti-angiogenic agents include sorafenib, lenvatinib, apatinib, and bevacizumab; anti-PD-1/PD-L1 antibodies include pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, tislelizumab, and atezolizumab.
6. Adequate hematologic and end-organ function.

Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
2. History of malignancy other than HCC within 5 years prior to the therapy, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or papillary thyroid carcinoma.
3. History of organ transplantation or hepatic encephalopathy.
4. Allergic to anti-angiogenic agents or anti-PD-1/PD-L1 agents.
5. History of gastrointestinal perforation and/or fistula within the 6 months, a history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection, Crohn's disease, ulcerative colitis, or chronic diarrhea within 6 months.
6. Active autoimmune disease requiring systemic therapy within 2 years prior to the first dose, allowing the use of alternative therapies (e.g., thyroxine, insulin, or physiologic corticosteroids for adrenal or pituitary insufficiency); history of primary immunodeficiency; presence of only autoimmune antibody-positive subjects. The presence of autoimmune disease needs to be confirmed at the investigator's discretion.
7. Uncontrollable hypertension, SBP >140 mmHg or DBP >90 mmHg after optimal medical therapy, hypertensive crisis, or history of hypertensive encephalopathy.
8. Subjects had a bleeding event in the past 6 months due to esophageal or gastric fundus varices induced by portal venous hypertension; subjects have undergone a gastrointestinal endoscopy within 3 months prior to the first dose to diagnose the presence of severe (G3) varices; subjects had a high risk of bleeding as assessed by the investigator.
9. Subject requests withdrawal of informed consent.
10. Other conditions that the investigator deems inappropriate for participation in this study.

Unresectable or advanced HCC patients who received the combination therapy with an anti-angiogeic agent and an anti-PD-1/PD-L1 agent.