This is a prospective, single-arm, investigator-initiated clinical study designed to evaluate the safety and efficacy of lenalidomide in combination with targeted therapy and immunotherapy in patients with advanced hepatocellular carcinoma (HCC) who have experienced disease progression after multiple lines of systemic treatment.

Eligible patients must have received at least two prior lines of systemic therapy, including both targeted therapy and immune checkpoint inhibitor (ICI)-based treatment, and must have previously achieved clinical benefit from their most recent treatment regimen before developing disease progression.

Participants will continue their current targeted therapy and immunotherapy regimen and receive lenalidomide as add-on treatment. The study will assess antitumor activity, survival outcomes, and treatment-related adverse events.

The primary objectives are to evaluate 6-month progression-free survival (PFS) and the incidence of grade ≥3 treatment-related adverse events (TRAEs). Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and overall survival (OS).

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide. Although targeted therapy and immune checkpoint inhibitors have significantly improved clinical outcomes, most patients eventually develop disease progression after multiple lines of treatment. Currently, there is no established standard therapy for patients with advanced HCC who have exhausted available targeted and immunotherapeutic options.

Lenalidomide is an immunomodulatory agent with antiangiogenic, immunoregulatory, and antitumor properties. Previous phase II studies have demonstrated modest clinical activity of lenalidomide in patients with advanced HCC who progressed after sorafenib treatment. However, the efficacy of lenalidomide as an add-on strategy in patients with advanced HCC who have previously benefited from targeted therapy and immunotherapy remains unknown.

This prospective, single-arm study aims to evaluate the safety and efficacy of lenalidomide combined with ongoing targeted therapy and immune checkpoint inhibitor treatment in patients with advanced, unresectable, locally advanced, or metastatic HCC who have experienced disease progression after at least two prior lines of systemic therapy.

Eligible patients must have previously achieved clinical benefit, defined as complete response (CR), partial response (PR), or stable disease (SD) lasting at least 4 weeks on their most recent targeted therapy plus immunotherapy regimen before progression. Patients with primary resistance to the most recent regimen will be excluded.

Participants will continue their most recent targeted therapy and immunotherapy regimen and receive lenalidomide until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

The co-primary endpoints are:

1. Progression-free survival (PFS) rate at 6 months after treatment initiation; Incidence of grade ≥3 treatment-related adverse events (TRAEs), assessed according to CTCAE version 5.0.
2. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and additional safety outcomes.

The study is conducted at Peking Union Medical College Hospital and is expected to provide preliminary evidence regarding the potential role of lenalidomide in overcoming acquired resistance to targeted therapy and immunotherapy in advanced HCC.

Inclusion Criteria:

-1. Age ≥18 years and ≤75 years; 2. Clinically or pathologically diagnosed hepatocellular carcinoma (HCC); 3. Unresectable, locally advanced, or metastatic HCC; 4. Prior receipt of at least two lines of systemic antitumor therapy, with previous exposure to both targeted therapy and immune checkpoint inhibitors (ICIs). No restrictions are imposed on the specific targeted agents or ICIs used in combination with lenalidomide; 5. Demonstrated clinical benefit from the most recent line of dual-agent therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) lasting for at least 4 weeks, followed by radiographic progression or clinical treatment failure; 6. At least one measurable lesion according to RECIST version 1.1; 7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1; 8. Adequate organ function, defined as: absolute neutrophil count (ANC) ≥1.0 × 10^9/L, platelet count ≥60 × 10^9/L, hemoglobin ≥80 g/L, creatinine clearance (CrCl) ≥30 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × upper limit of normal (ULN), and total bilirubin ≤3 mg/dL; 9. Virological status, including hepatitis B virus (HBV) and hepatitis C virus (HCV), must be assessed. Patients who are HBsAg-positive or have a history of HBV infection must undergo hepatology evaluation and receive antiviral prophylaxis when indicated.

Exclusion Criteria:

• 1. Primary resistance to the most recent targeted therapy plus ICI regimen, defined as unequivocal disease progression within 6 weeks or 2 treatment cycles without any evidence of prior clinical benefit; 2. Prior exposure to lenalidomide or a history of severe hypersensitivity to lenalidomide or thalidomide; 3. Explosive disease progression, or situations in which continuation of the existing treatment backbone is deemed clinically unreasonable by the investigator; 4. Uncontrolled ascites, hepatic encephalopathy, or active gastrointestinal bleeding; active severe infections, including uncontrolled HBV replication, tuberculosis, severe pulmonary infection, or other serious infections; 5. Persistent treatment-related toxicities of grade ≥2 that have not recovered to baseline or acceptable levels at study entry; 6. Creatinine clearance (CrCl) <30 mL/min; 7. Pregnancy, breastfeeding, or inability/unwillingness to comply with contraceptive requirements.