There is no definitive evidence regarding the therapeutic efficacy of PD-1 inhibitors combined with tyrosine kinase inhibitors (TKIs) after disease progression following first-line treatment with bevacizumab plus sintilimab for unresectable hepatocellular carcinoma (HCC). There is insufficient evidence to support which TKI should be combined with PD-1 inhibitors as the optimal second-line treatment option after first-line therapy failure. Data on the application of lenvatinib as a second-line treatment are limited, whereas the efficacy and safety of regorafenib combined with PD-1 inhibitors have been preliminarily validated [9]. Therefore, this study aims to compare the efficacy and safety of PD-1 inhibitors combined with either lenvatinib or regorafenib after disease progression following first-line bevacizumab plus sintilimab treatment for unresectable HCC, providing evidence-based guidance for the selection of second-line treatment regimens in clinical practice.

Inclusion Criteria:

1. Diagnosed with hepatocellular carcinoma (HCC) based on histological or clinical diagnostic criteria;
2. Classified as unresectable HCC following multidisciplinary assessment;
3. Presence of at least one tumor lesion measurable according to EASL criteria;
4. Patients aged ≥18 years and ≤75 years receiving first-line treatment;
5. Child-Pugh liver function class A/B, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0-2;
6. Disease progression confirmed by CT/MRI and evaluated according to modified RECIST (mRECIST)/RECIST v1.1 criteria after ≥2 cycles of first-line therapy with bevacizumab (15 mg/kg intravenous infusion, once every 3 weeks) combined with sintilimab (200 mg intravenous infusion, once every 3 weeks);
7. Received ≥2 cycles of post-progression treatment with bevacizumab plus sintilimab, lenvatinib, or regorafenib combined with PD-1 inhibitors;
8. Laboratory parameters: hemoglobin(Hb) ≥8.5 g/dL, white blood cell (WBC) count >2000/mm³, platelet (PLT) count ≥75,000/mm³, absolute neutrophil count (ANC) >1500/mm³, total bilirubin ≤30 μmol/L, serum albumin ≥30 g/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN), serum creatinine ≤1.5 times ULN, international normalized ratio (INR) ≤1.5, prothrombin time (PT) ≤18 seconds;
9. Availability of complete baseline data, treatment records, and follow-up data (including imaging assessments, laboratory tests, and clinical documentation).

Exclusion Criteria:

1. Life expectancy ≤2 months;
2. Presence of intrahepatic cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, or other non-HCC malignancies;
3. Active concurrent malignancy or severe comorbid conditions;
4. First-line treatment with other anticancer therapies (chemotherapy, radiotherapy, surgery, or other interventions) concurrently;
5. Known hypersensitivity to study drugs.