The goal of this prospective Phase II clinical trial is to evaluate the efficacy and safety of QL1706-based combination therapy in patients with hepatocellular carcinoma (HCC) who have failed prior targeted-immunotherapy (e.g., anti-PD-1/PD-L1 + antiangiogenic therapy).

The main question is:

Can the combination of localized-regional therapy (e.g., HAIC/TACE) and systemic dual immunotherapy (QL1706) overcome resistance and improve outcomes in second-line HCC treatment?

Participants will:

1. Receive QL1706 (a dual immune checkpoint inhibitor) combined with either:

   Hepatic arterial infusion chemotherapy (HAIC)/transarterial chemoembolization (TACE), or Antiangiogenic targeted therapy.

2. Undergo regular imaging (e.g., MRI/CT) and biomarker assessments for efficacy monitoring.

3. Be evaluated for adverse events (AEs) and quality of life.

This study seeks to establish a novel therapeutic paradigm for HCC patients after targeted-immunotherapy failure, addressing the unmet need for evidence-based second-line strategies.

Inclusion Criteria:

1. Voluntary Participation, Willingly signs the written informed consent form.

2. Aged 18-65 years (inclusive), any gender.

3. Histologically, cytologically, or clinically confirmed hepatocellular carcinoma (HCC) with disease progression after first-line targeted therapy combined with immunotherapy, or intolerable to first-line targeted-immunotherapy combination treatment.

4. No prior exposure to VEGF monoclonal antibodies, CTLA-4 inhibitors, or bispecific antibodies. For arm 1: No prior treatment with oxaliplatin or fluorouracil-based drugs.

5. Liver Function: Child-Pugh class A or class B (score ≤7), with no history of hepatic encephalopathy.

6. Performance Status: ECOG PS score 0 or 1.

7. Life Expectancy ≥12 weeks.

8. Measurable Lesion: ≥1 measurable target lesion per RECIST v1.1 (not previously irradiated/localized; lesions in prior treatment areas are acceptable if progression is confirmed).

9. Preserved organ & bone marrow function (within 7 days before treatment; no blood products/growth factors within 14 days prior):

   • Neutrophil count (ANC) ≥1.5×10⁹/L
   • Platelets ≥75×10⁹/L
   • Hemoglobin ≥90 g/L
   • Albumin ≥28 g/L
   • ALT/AST/Alkaline phosphatase (AKP) ≤3×ULN
   • Total bilirubin (TBIL) ≤2×ULN
   • INR ≤2 or PT prolongation ≤6 sec above ULN
   • Urine protein <2+ (if ≥2+, 24-hour urine protein must be <1.0 g).

10. Viral Hepatitis Management

    • If HBsAg-positive: HBV DNA <2000 IU/mL or 10⁴ copies/mL, with ongoing antiviral therapy (entecavir/tenofovir disoproxil fumarate/tenofovir alafenamide/emtecavir).
    • HCV-infected patients with undetectable HCV RNA are considered HCV-negative.

11. Contraception

    • Fertile participants (male/female) must use reliable contraception (hormonal/barrier/abstinence) during and for ≥180 days post-treatment.
    • Women of childbearing potential must have a negative serum pregnancy test within 7 days before enrollment.

Exclusion Criteria:

1. Histologically/cytologically confirmed fibrolamellar HCC, sarcomatoid HCC, cholangiocarcinoma, or mixed hepatocellular-cholangiocarcinoma.

2. Other active malignancies within 5 years prior to enrollment, except cured localized tumors (e.g., basal cell carcinoma, squamous cell skin cancer, superficial bladder cancer, in situ prostate/cervical/breast cancer).

3. History of or planned liver transplantation.

4. Clinically significant ascites requiring therapeutic paracentesis, uncontrolled pleural/pericardial effusion (asymptomatic minimal ascites on imaging allowed).

5. Known CNS metastases or leptomeningeal disease.

6. Tumor thrombus involving both main portal vein and superior mesenteric vein, or portal vein and inferior vena cava.

7. High-risk variceal bleeding:

   • Esophageal/gastric variceal bleeding within 6 months
   • High-grade varices on endoscopy within 3 months
   • Portal hypertension with bleeding risk (splenomegaly, active ulcers, occult blood+, or endoscopic "red signs").

8. Life-threatening hemorrhage within 3 months requiring transfusion/surgery/medical intervention.

9. Significant bleeding risk:

   • Hemoptysis/tumor bleeding within 2 weeks
   • Thromboembolism within 6 months
   • Therapeutic anticoagulation (except prophylactic LMWH) within 2 weeks
   • Antiplatelet therapy (aspirin >325 mg/day, clopidogrel >75 mg/day) within 10 days
   • Tumor invasion of major vessels/airways/mediastinum.

10. Severe cardiovascular disease:

    • Significant arrhythmias (requiring intervention), QTcF ≥450 ms (M)/470 ms (F)
    • ACS/heart failure/stroke/TIA within 6 months
    • NYHA class ≥II or LVEF <50%
    • Uncontrolled hypertension (≥160/100 mmHg despite ≥2 agents).

11. Abdominal fistula/GI perforation/abscess within 6 months.

12. Bowel obstruction/clinical signs of GI obstruction within 6 months.

13. Non-healing wounds, active ulcers, or untreated fractures.

14. Active autoimmune diseases or history of autoimmune diseases with potential recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [patients with hypothyroidism controlled by hormone replacement therapy alone are not excluded]). Note: Patients with non-systemic skin conditions (e.g., vitiligo, psoriasis, alopecia), well-controlled type 1 diabetes on insulin, or childhood asthma with complete remission in adulthood requiring no intervention may be enrolled. Asthma patients requiring bronchodilator therapy are excluded.

15. Immunosuppressants (>10 mg/day prednisone equivalent) within 2 weeks.

16. Severe hypersensitivity to monoclonal antibodies.

17. Hepatic encephalopathy or CNS metastases.

18. Organ transplant history.

19. Symptomatic ascites requiring drainage within 3 months.

20. Uncontrolled hypertension (≥140/90 mmHg despite treatment).

21. Arterial/venous thrombosis within 6 months (stroke, DVT, PE).

22. Bleeding/thrombotic disorders (hemophilia, coagulopathy, thrombocytopenia).

23. Proteinuria ≥++ with 24-h urine protein >1.0 g.

24. Active infection (fever ≥38.5°C within 7 days or WBC >15×10⁹/L).

25. Interstitial lung disease (current or steroid-requiring history).

26. Active tuberculosis (confirmed by imaging/sputum/clinical assessment).

27. Immunodeficiency (HIV/syphilis).

28. Severe infection within 4 weeks (hospitalization required) or antibiotics within 2 weeks (prophylaxis allowed).

29. Recent treatments:

    • Liver surgery/HCC locoregional therapy within 4 weeks
    • Palliative bone radiotherapy within 2 weeks
    • Anti-HCC herbal medicine within 2 weeks
    • Unresolved toxicities (>Grade 1 per CTCAE v5.0, except alopecia).

30. Immunomodulators (interferons, interleukins) within 2 weeks.

31. Other investigational drugs within 4 weeks.

32. Allogeneic stem cell/organ transplant.

33. HBV-HCV coinfection.

34. Hypersensitivity to trial drug components/monoclonal antibodies/antiangiogenic agents.

35. Live vaccines within 4 weeks or planned during study.

36. Major surgery within 4 weeks or planned during study (biopsies/IV catheterization allowed).

37. Other exclusionary factors per investigator judgment (substance abuse, severe comorbidities, psychosocial risks).

Study Protocol, Statistical Analysis Plan (SAP), and Clinical Study Report (CSR)

Beginning 3 months and ending 1 years after the publication of results.

Data will be shared with qualified researchers who:

1. Submit a scientifically valid research proposal with defined objectives and statistical analysis plans

2. Require individual participant data (IPD) to address research questions not covered in the original publication

3. Provide institutional ethics approval for the proposed secondary analysis

4. Sign a Data Use Agreement (DUA) committing to:

   • Protect participant confidentiality
   • Not attempt to re-identify participants
   • Not transfer data to third parties
   • Destroy data after analysis completion