Icaritin Soft Capsule Versus Huachansu Tablet in the First-line Treatment of Unresectable Hepatocellular Carcinoma With Poor Conditions and Biomarker Enrichment (Biomarker Enrichment Study of Poor Prognosis HCC Patients, BESTPOP)

Inclusion Criteria: 1. Male or female, 18 years and older; 2. HCC patients who meet the clinical diagnostic criteria of the Chinese Diagnosis and Treatment Guideline of Primary Liver Cancer (2022 edition), and/or with diagnosis confirmed histopathologically/cytologically; 3. Unresectable HCC patients; 4. Patients with a peripheral blood composite biomarker Score ≥ 2 points, 1 point each for AFP ≥ 400 ng/mL, TNF-α \< 2.5 pg/mL, and IFN-γ ≥ 7.0 pg/mL ; 5. No prior first-line systemic treatment for HCC, including sorafenib, lenvatinib, donafenib, atezolizumab plus bevacizumab, sintilimab plus a bevacizumab biosimilar, camrelizumab plus apatinib, and durvalumab plus tremelimumab, oxaliplatin-based systemic chemotherapy (FOLFOX4) , icaritin, huachansu, and other anti-cancer drugs such as targeted agents, immune checkpoint inhibitors, and systemic chemotherapy; 6. Child-Pugh score ≤ 7; 7. Vital organ functions should meet the following requirements: ① Hematopoietic function: platelet ≥ 40×10\^9/L, hemoglobin ≥ 80 g/L, white blood cell ≥ 2.0×10\^9/L; ② Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN) , alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) ≤ 5×ULN; albumin ≥ 28 g/L; ③ Renal function: Serum Creatinine ≤ 1.5×ULN, or creatinine clearance rate ≥ 50 mL/min; 8. If HBV-DNA ≥ 10\^4 copies/mL (2000 IU/mL), antiviral and liver protection therapy must be used before enrollment, until HBV-DNA \< 10\^4 copies/mL (2000 IU/mL). In which case, the antiviral drugs should be administered continuously and liver function and hepatitis B virus load will be monitored during the study period; 9. Patients who meet one of two conditions: (A) are not or less appropriate candidates for first-line standard treatments recommended by the guidelines; (B) are not willing to receive first-line standard treatments recommended by the guidelines. 10. Surgical resection ended \> 3 months, local ablation, hepatic artery intervention or radiotherapy ended \> 4 weeks before randomization (implantation of radioactive particles ended \> 3 months) and relevant adverse reactions having recovered. Patients without extrahepatic spread must have radiographic evidence of disease progression after local treatment; 11. Patients who had previously received adjuvant systemic therapy after surgical resection experienced the first radiographic disease progression more than 6 months after withdrawal of adjuvant therapy will be eligible for enrollment; 12. Within 2 weeks prior to randomization, no treatment with modern Chinese traditional medicine preparations with anti-tumor indications (refer to the 11th inclusion criterion when huaier granule was used as systemic adjuvant therapy), immunomodulators such as interferon-α and thymalfasin, tumor vaccines and cellular immunotherapy; 13. No blood transfusion or infusion of blood products, no use of hematopoietic growth factors (such as granulocyte colony-stimulating factor G-CSF), and no albumin infusion within 2 weeks prior to randomization; 14. ≥1 measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.1), defined as a non-lymphoid lesion with the longest diameter ≥ 10 mm or a lymph node lesion with the short axis ≥ 15 mm; a lesion after previous radiotherapy or other loco-regional therapy which has been demonstrated progression confirmed per RECIST v1.1 with the longest diameter ≥ 10 mm scanned by dynamic-enhanced CT/ dynamic-enhanced MRI is to be deemed as a measurable lesion. 15. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1; 16. Expected survival of ≥ 12 weeks; 17. Female patients of childbearing age with a negative blood pregnancy within the first 7 days prior to randomization will be eligible; Female patients of childbearing age or male patients with female sexual partners of childbearing age should take effective contraceptive measures throughout treatment and within 3 months after the last dose; 18. Voluntary agreement to sign informed consent and the willingness and ability to comply with protocol schedules and testing; 19. No treatment with any other investigational drugs or medical devices within 4 weeks prior to randomization. Exclusion Criteria: 1. Tumor occupancy ≥ 70% of liver, or tumor thrombus occupancy ≥ 50% of the main trunk of portal vein, or mesenteric vein or inferior vena cava tumor thrombus; 2. Moderate-to-severe ascites, i.e., the score of the indicator is \> 2; Moderate-to-severe, or symptomatic pleural effusion and pericardial effusion requiring drainage; 3. Receipt of major surgery (craniotomy, thoracotomy, laparotomy, hip replacement, etc.) within 28 days prior to randomization or planned to receive major surgery during the study; 4. Other types of primary liver cancer, such as intrahepatic cholangiocarcinoma, mixed HCC and cholangiocarcinoma, fibrolamellar HCC, etc. Other malignancies within 5 years prior to signing the informed consent form or at present, excluding radically treated basal cell carcinoma of skin, squamous cell carcinoma of skin and/or radically resected carcinoma in situ; 5. Pregnant or lactating women; 6. Grade 2 or above myocardial ischemia or myocardial infarction (NCI-CTCAE v5.0), poorly-controlled arrhythmia, and/or New York Heart Association (NYHA) class III or IV cardiac insufficiency; 7. Patients who previously received allogeneic transplantation including liver transplantation, or plan to undergo liver transplantation during the study; 8. History of hepatic encephalopathy and/or hepatic nephropathy within 6 months prior to signing informed consent ; 9. HCV-RNA positive, ALT and/or AST \> 2×ULN; 10. Human immunodeficiency virus (HIV) antibody positive; 11. Severe infection (≥ Grade 3 of NCI-CTCAE v5.0 criteria) at randomization; 12. Unable to swallow, chronic diarrhea or intestinal obstruction, which will significantly affect oral administration and absorption of the study drug; 13. History of gastrointestinal hemorrhage within 6 months before signing informed consent, or with clear tendency for gastrointestinal hemorrhage at present, such as: local active ulcers, stool occult blood ≥ 2+ or positive at two consecutive tests (attention should be paid to exclude the influence of food, drugs and other diseases); 14. Active autoimmune diseases requiring systemic treatment (e.g., NSAIDs, immunosuppressants, biologics, corticosteroids, etc.) except for patients receiving replacement therapy (e.g., hypothyroidism treated with thyroxine, type 1 diabetes mellitus treated with insulin, adrenal or pituitary insufficiency treated with physiologic corticosteroids, etc.); 15. Known central nervous system (CNS) metastasis; patients suspected of CNS metastasis need to undergo cerebral MRI/CT for exclusion; 16. Significant coagulation function abnormalities: international standardized ratio (INR) \> 1.5 or prothrombin time (PT) \> 16 s; 17. History of schizophrenia or psychiatric drug abuse; 18. Known allergy or intolerance to any ingredients of icaritin or huachansu preparations; 19. Other conditions that the investigator considers inappropriate for participation in this study.