Lenvatinib Plus Tislelizumab With or Without Gefitinib for Advanced Liver Cancer

This is a prospective, randomized, open-label, phase II clinical trial evaluating lenvatinib plus tislelizumab with or without gefitinib as first-line treatment for unresectable or advanced hepatocellular carcinoma.

Eligible participants will be adults with unresectable or advanced hepatocellular carcinoma who have not received prior systemic anticancer therapy for hepatocellular carcinoma. Participants will be randomly assigned in a 1:1 ratio to receive either lenvatinib plus tislelizumab and gefitinib, or lenvatinib plus tislelizumab. Randomization will be performed centrally. Because gefitinib is administered only in the experimental arm and treatment management differs between groups, the study will be open-label. To reduce assessment bias, radiographic tumor assessments will be evaluated by a blinded independent imaging review committee.

The primary outcome measures are progression-free survival and the number of participants with adverse events of special interest. Progression-free survival will be assessed according to RECIST version 1.1. Adverse events of special interest include protocol-defined events requiring close monitoring, such as selected immune-related, hepatic, gastrointestinal, pulmonary, bleeding, thrombotic, dermatologic, renal, endocrine, and infusion-related events.

Secondary outcomes include overall survival, objective response rate, disease control rate, duration of response, treatment-emergent adverse events, serious adverse events, alpha-fetoprotein response, and conversion to curative-intent local therapy when applicable.

Study treatment will continue until radiographic disease progression, unacceptable toxicity, withdrawal of consent, initiation of new anticancer therapy, death, or other protocol-defined discontinuation criteria. Tumor assessments will be performed at protocol-defined intervals using CT or MRI. Safety will be monitored through adverse event reporting and protocol-defined clinical and laboratory assessments.

Exploratory analyses may include evaluation of epidermal growth factor receptor-related biomarkers, tumor immune microenvironment, circulating tumor DNA, tumor mutation profiles, alpha-fetoprotein dynamics, and other candidate biomarkers to explore potential associations with treatment response, disease progression, resistance, and safety.

• Lenvatinib (Drug), also known as LEN: Lenvatinib will be administered orally once daily. The dose will be based on baseline body weight: 8 mg once daily for participants weighing less than 60 kg and 12 mg once daily for participants weighing 60 kg or more. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, death, or other protocol-defined discontinuation criteria.
• Tislelizumab (Drug), also known as TIS: Tislelizumab will be administered by intravenous infusion at a dose of 200 mg on Day 1 of each 21-day cycle. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, death, or other protocol-defined discontinuation criteria.
• Gefitinib (Drug), also known as GEF: Gefitinib will be administered orally at a dose of 250 mg once daily in the experimental arm. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, death, or other protocol-defined discontinuation criteria.

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events [From the first dose of study treatment through 90 days after the last dose of study treatment]: Treatment-emergent adverse events are defined as adverse events that occur or worsen after the start of study treatment. Adverse events will be coded and graded according to NCI CTCAE version 5.0. This outcome measure will report the number of participants who experience at least one treatment-emergent adverse event during the study.
• Progression-Free Survival [From randomization until disease progression or death from any cause, assessed up to 36 months]: Progression-free survival is defined as the time from randomization to the first documented radiographic disease progression or death from any cause, whichever occurs first. Disease progression will be assessed by a blinded independent imaging review committee according to RECIST version 1.1.

Secondary outcomes

• Overall Survival [From randomization until death from any cause, assessed up to 36 months]: Overall survival is defined as the time from randomization to death from any cause.
• Objective Response Rate [From randomization until disease progression, start of new anticancer therapy, or study completion, assessed up to 24 months]: Objective response rate is defined as the proportion of participants with a best overall response of complete response or partial response, as assessed according to RECIST version 1.1.
• Disease Control Rate [From randomization until disease progression, start of new anticancer therapy, or study completion, assessed up to 24 months]: Disease control rate is defined as the proportion of participants with a best overall response of complete response, partial response, or stable disease, as assessed according to RECIST version 1.1.
• Duration of Response [From first documented objective response until disease progression or death from any cause, assessed up to 24 months]: Duration of response is defined for participants who achieve complete response or partial response as the time from the first documented objective response to the first documented disease progression or death from any cause, whichever occurs first.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria：

* Age 18 to 75 years, male or female.
* Histologically or clinically/radiologically confirmed hepatocellular carcinoma.
* Unresectable or advanced hepatocellular carcinoma requiring systemic therapy.
* No prior systemic anticancer therapy for hepatocellular carcinoma.
* At least one measurable lesion according to RECIST version 1.1.
* Eastern Cooperative Oncology Group performance status of 0 to 1.
* Child-Pugh class A liver function.
* Life expectancy of at least 12 weeks.
* Adequate hematologic, hepatic, renal, and coagulation function as defined in the protocol.
* For participants with hepatitis B virus infection, antiviral therapy must be given according to local practice, and hepatitis B virus DNA must meet protocol-defined requirements.
* Participants of childbearing potential must agree to use effective contraception during the study and for the protocol-defined period after the last dose of study treatment.
* Ability to understand and willingness to sign written informed consent.

Exclusion Criteria：

* Prior systemic anticancer therapy for hepatocellular carcinoma.
* Known fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, mixed hepatocellular-cholangiocarcinoma, or other non-hepatocellular carcinoma histology.
* Prior treatment with an epidermal growth factor receptor inhibitor.
* Uncontrolled hypertension, clinically significant cardiovascular disease, or serious bleeding or thrombotic events within the protocol-defined period.
* Active or high-risk gastrointestinal bleeding, untreated or inadequately treated esophageal or gastric varices, or clinically significant coagulation disorder.
* History of interstitial lung disease, drug-induced pneumonitis, radiation pneumonitis requiring steroid treatment, or active pneumonitis.
* Active autoimmune disease or history of autoimmune disease requiring systemic treatment, except as allowed by the protocol.
* Active uncontrolled infection, including uncontrolled hepatitis B virus infection or hepatitis C virus infection requiring treatment but not adequately controlled.
* Known human immunodeficiency virus infection with uncontrolled disease, if applicable according to local regulations.
* Clinically significant ascites, hepatic encephalopathy, or other evidence of hepatic decompensation.
* Untreated or symptomatic central nervous system metastases.
* Major surgery, locoregional therapy, radiotherapy, or other anticancer therapy within the protocol-defined washout period before randomization.
* Inability to swallow oral medication or any condition that may significantly affect absorption of oral study drugs.
* Known allergy or hypersensitivity to lenvatinib, tislelizumab, gefitinib, or any of their excipients.
* Pregnancy or breastfeeding.
* Any other condition that, in the investigator's judgment, would make the participant unsuitable for the study or interfere with study treatment, safety evaluation, or protocol compliance.