SBRT Plus QL1706 as Second-Line Therapy for Hepatocellular Carcinoma

A Prospective, Single-Arm, Single-Center Exploratory Clinical Study of Stereotactic Body Radiation Therapy Combined With QL1706 in the Second-Line Treatment of Hepatocellular Carcinoma

This is a prospective, single-arm, single-center exploratory clinical study designed to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) combined with QL1706 in patients with hepatocellular carcinoma who have received one prior line of systemic therapy and experienced radiographic disease progression or intolerance.

Eligible patients will receive SBRT to all evaluable intrahepatic lesions at a total dose of 25-50 Gy delivered in 5 fractions. Within 7-14 days after completion of SBRT, patients will receive QL1706 at 7.5 mg/kg by intravenous infusion every 3 weeks. Treatment with QL1706 will continue until confirmed disease progression, intolerable toxicity, patient request to withdraw, withdrawal of informed consent, or other protocol-defined treatment discontinuation criteria, whichever occurs first.

The primary endpoint is objective response rate assessed by the investigator according to modified RECIST criteria. Secondary endpoints include local control rate of SBRT target lesions, progression-free survival, overall survival, disease control rate, and the incidence of adverse events and serious adverse events. Exploratory endpoints include dynamic changes in serum tumor biomarkers and immune-related indicators, as well as their association with clinical outcomes. A total of 36 patients are planned for enrollment.

This is a prospective, single-arm, single-center exploratory clinical study designed to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) followed by QL1706 in patients with hepatocellular carcinoma who require second-line treatment after one prior line of systemic therapy.

Patients with hepatocellular carcinoma who have received one prior line of systemic therapy and have experienced radiographic disease progression or intolerance may be enrolled if they meet all eligibility criteria. Eligible participants must have at least one measurable lesion according to modified RECIST, and all intrahepatic tumor lesions must be considered suitable for SBRT by the investigator. Patients with extrahepatic metastasis are not eligible.

All enrolled participants will receive SBRT to intrahepatic tumor lesions. SBRT will be delivered at a total dose of 25-50 Gy in 5 fractions, with 5-10 Gy per fraction. Radiation treatment planning will ensure that at least 700 cc of normal liver volume is preserved, with a mean radiation dose to this volume of no more than 15 Gy.

Within 7-14 days after completion of SBRT, participants will receive QL1706 at 7.5 mg/kg by intravenous infusion once every 3 weeks. QL1706 treatment will continue until confirmed disease progression, intolerable toxicity, patient request to withdraw, withdrawal of informed consent, initiation of new anticancer therapy, or other protocol-defined discontinuation criteria, whichever occurs first. Dose interruption or permanent discontinuation may be required based on individual safety and tolerability. Dose escalation or dose reduction is not recommended.

Tumor assessments will be performed at baseline, after completion of SBRT and before the first cycle of QL1706, and every 2 treatment cycles thereafter during study treatment. After treatment discontinuation, follow-up assessments, including survival follow-up, will be performed every 3 months where applicable.

The primary outcome measure is objective response rate assessed by the investigator according to modified RECIST. Secondary outcome measures include local control rate of SBRT target lesions, progression-free survival, overall survival, disease control rate, and the incidence of adverse events and serious adverse events. Exploratory outcome measures include dynamic changes in serum tumor biomarkers and immune-related indicators, and their association with clinical outcomes.

Approximately 36 participants are planned to be enrolled.

Inclusion Criteria:

• Male or female patients aged 18 to 75 years, inclusive.

• Eastern Cooperative Oncology Group performance status score of 0 or 1.

• Pathologically confirmed hepatocellular carcinoma, based on at least one lesion or previous biopsy confirming hepatocellular carcinoma.

• Child-Pugh class A, score 5 to 6, or Child-Pugh class B, score 7 only.

• Barcelona Clinic Liver Cancer stage C or earlier.

• Not suitable for curative treatment such as surgical resection or liver transplantation, or refusal of curative treatment such as surgical resection or liver transplantation after first-line therapy.

• At least one measurable lesion confirmed by the investigator according to modified RECIST.

• All intrahepatic tumor lesions must be considered suitable for stereotactic body radiation therapy by the investigator.

• At least 700 cc of normal liver volume must be preserved, with a mean radiation dose to this volume of no more than 15 Gy.

• Received one prior line of systemic therapy and experienced radiographic disease progression or intolerance.

• Prior local treatment, such as transarterial chemoembolization, hepatic arterial infusion chemotherapy, or radiofrequency ablation, is allowed if the interval between the prior local treatment and initiation of study treatment is at least 28 days.

• Adequate organ and bone marrow function, defined as all of the following:

  • Hemoglobin at least 9.0 g/dL.
  • Absolute neutrophil count at least 1.5 × 10^9/L or greater than 1500/mm^3.
  • Platelet count at least 75 × 10^9/L or greater than 75,000/mm^3.
  • Serum bilirubin no more than 1.5 times the institutional upper limit of normal.
  • Aspartate aminotransferase and alanine aminotransferase no more than 2.5 times the institutional upper limit of normal.
  • Creatinine clearance greater than 45 mL/min, measured directly, calculated by the Cockcroft-Gault formula, or measured by 24-hour urine collection.

• Female patients of childbearing potential must have a negative urine or serum pregnancy test before the first dose of study treatment.

• Male or female patients of reproductive potential must agree to use adequate contraception from the first dose of study treatment until 180 days after the last dose of study treatment.

• Life expectancy of more than 6 months, as assessed by the investigator.

• Able to understand and comply with study requirements and voluntarily sign the informed consent form.

Exclusion Criteria:

• Histologically confirmed combined hepatocellular-cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, or other non-hepatocellular primary liver malignancy.
• Prior yttrium-90 radioembolization.
• Hepatitis B viral load greater than 2000 IU/mL despite effective antiviral therapy.
• More than 3 discrete hepatic nodules.
• Presence of extrahepatic metastasis or M1 disease.
• Current participation in another study with investigational treatment, or participation in an investigational drug or device study within 4 weeks before the first dose of study treatment.
• Immunodeficiency disease, or use of systemic corticosteroids at a daily dose greater than 10 mg prednisone or equivalent on the day of the first dose of study treatment or within 14 days before the first dose of study treatment.
• Active tuberculosis, or inadequately treated latent tuberculosis infection with a high risk of recurrence in the investigator's judgment.
• Hypersensitivity to recombinant humanized anti-PD-1 or anti-PD-L1 monoclonal antibodies, recombinant humanized anti-CTLA-4 monoclonal antibodies, or any of their components.
• Receipt of anticancer therapy within 4 weeks before Day 1 of study treatment, or failure of toxicities from prior therapy to recover to Grade 1 or lower or to baseline level.
• Other progressive malignancy requiring active treatment.
• Autoimmune disease requiring systemic treatment within the past 2 years, including immunomodulators, corticosteroids, or immunosuppressants. Replacement therapy such as thyroxine, insulin, or physiologic hormone replacement for adrenal or pituitary insufficiency is not considered systemic treatment. Prior organ transplantation, including liver transplantation.
• History or evidence of active non-infectious pneumonitis.
• Active infection requiring systemic therapy.
• Psychiatric illness or history of substance abuse that may interfere with study compliance.
• Receipt of a live vaccine within 30 days before the planned initiation of study treatment.
• Planned pregnancy or breastfeeding.
• Any medical history, treatment, or laboratory abnormality that, in the investigator's judgment, may interfere with study results, affect full participation in the study, or not be in the patient's best interest.