Efficacy and Safety Comparison Between PD-1 Inhibitor Combined With Lenvatinib or With Regorafenib For UHCC After Failure of First-line Treatment

The Efficacy and Safety of PD-1 Inhibitor Combined With Lenvatinib or With Regorafenib For Advanced Hepatocellular Carcinoma After Failure of First-line Bevacizumab Plus Sintilimab: A Retrospective Study

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellulcar Carcinoma
• Intervention / Treatment: Drug: Lenvatinib; Drug: PD-1 Inhibitor; Drug: Regorafenib

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Sun Yat-Sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LP Group; Lenvatinib, PD-1 Inhibitor	Drug: Lenvatinib; Lenvatinib, for weight ≤60 kg, 8 mg/d, po, qd; for weight >60 kg, 12 mg/d, po, qd.; Drug: PD-1 Inhibitor; PD-1 inhibitor (Sintilimab, Camrelizumab, Tislelizumab, Toripalimab, Pembrolizumab, Nivolumab), 200mg/dose, iv drip, q3w.
Active Comparator: RP Group; Regorafenib, PD-1 Inhibitor	Drug: PD-1 Inhibitor; PD-1 inhibitor (Sintilimab, Camrelizumab, Tislelizumab, Toripalimab, Pembrolizumab, Nivolumab), 200mg/dose, iv drip, q3w.; Drug: Regorafenib; Regorafenib, 160mg/d, po, qd.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is the length of time from the date of randomization until death from any cause.	6 months
Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression or death due to any cause.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR, as determined based on tumor response according to RECIST 1.1, is defined as the proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR.	6 months
Adverse Events	ORR, as determined based on tumor response according to RECIST 1.1, is defined as the proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR.	30 days

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Actual): August 1, 2025
• Study Completion (Actual): December 25, 2025

Study Registration Dates

• First Submitted: April 12, 2026
• First Submitted That Met QC Criteria: April 12, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Bevacizumab; Lenvatinib; PD-1; Regorafenib; Sintilimab; second-line treatment; ICIs
• Additional Relevant MeSH Terms: Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors; regorafenib; lenvatinib
• Other Study ID Numbers: IM-LENREG

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No