Regorafenib After Treatment Failure of First Line Immune Checkpoint Inhibitor Treatment in Advanced Hepatocellular Carcinoma Patients (RECOMEND)

Regorafenib After Failure of First-Line Immune Checkpoint Inhibitor-Based Combination Therapy in Child-Pugh B Patients With HCC: A Phase 2 RECOMEND Trial

Immune checkpoint inhibitor (ICI)-based regimens (atezolizumab+bevacizumab, durvalumab+tremelimumab, nivolumab+ipilimumab) are now a first-line standard for advanced hepatocellular carcinoma (HCC). For Child-Pugh (CP) A patients, regorafenib, cabozantinib, and ramucirumab are approved second-line agents, but there is no approved second-line systemic therapy for CP-B. In CP-B historical controls treated with best supportive care, median progression free survival (PFS) was ~1.4 months in a REACH trial subgroup analysis and ~1.9 months in a CELESTIAL trial subgroup analysis. Regorafenib demonstrated benefit as a post-sorafenib second-line therapy in CP-A patients in the RESORCE trial, but prospective evidence in CP-B is lacking. A multicenter retrospective study of CP-B patients receiving second-line regorafenib after sorafenib reported a median PFS of 1.8 months, and prospective data after ICI-based first-line therapy are not available.

This study will evaluate the efficacy and safety of regorafenib as second-line therapy in CP-B patients with disease progression after first-line ICI-based treatment. The primary objective is to demonstrate superiority over historical controls, with PFS as the primary endpoint.

After written informed consent, all participants will receive regorafenib. Regorafenib will be administered at 120 mg orally once daily at the same time each day, after a meal with water, for 3 consecutive weeks followed by 1 week off (4-week cycle). Treatment must start within 3 days after screening and will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. After treatment discontinuation, patients will be followed every 12 week (+/-7 days) for survival status and subsequent anticancer therapies, and survival follow-up will continue for at least 12 months after enrollment of the last participant.

Study Overview

• Status: Not yet recruiting
• Conditions: Disease Progression; Carcinoma, Hepatocellular; Treatment Failure; Hepatic Insufficien
• Intervention / Treatment: Drug: Regorafenib (BAY 73-4506)

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ju Hyun Shim, MD PhD; Phone Number: 82230103190; Email: s5854@amc.seoul.kr

Study Locations

• South Korea
  • Seoul, South Korea, 05505
    • Asan Medical Center
    • Contact: Ju Hyun Shim, MD PhD; Phone Number: 82-2-03103190; Email: s5854@amc.seoul.kr
    • Contact: Sung Won Chung, MD; Phone Number: 82-2-3010-1105; Email: schungaa@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Voluntarily signed written informed consent form.
2. Age ≥19 years at the time of signing the informed consent form.
3. Histologically or clinically diagnosed hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines.
4. Disease progression or treatment discontinuation due to toxicity during first-line immune checkpoint inhibitor-based combination therapy (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, or nivolumab plus ipilimumab).
5. At least one measurable target lesion according to RECIST v1.1.
6. Child-Pugh score B (7-8).Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. Adequate hematologic and end-organ function defined by the following laboratory results obtained within 14 days prior to the test (or enrollment):

   • Hemoglobin ≥ 8.5 g/dL
   • Absolute Neutrophil Count (ANC) ≥1,200/mm³
   • Platelet count ≥60,000/µL
   • Total bilirubin < 3.5 mg/dL
   • Serum albumin ≥2.5 g/dL
   • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤7 times upper limit of normal (ULN)
   • Prothrombin time (INR ≤1.8 times ULN)
   • Serum creatinine ≤2.0 times ULN or calculated creatinine clearance ≥40 mL/min (using the Cockcroft-Gault equation)

10) Virologic status of hepatitis confirmed and documented by HBV and HCV screening tests.Patients with HBV or HCV infection must receive antiviral therapy according to institutional guidelines.

11) Women of childbearing potential must agree to remain abstinent or use effective contraception (with an annual failure rate of < 1%) from the time of signing informed consent until at least 6 months after the last dose of the study drug.Male participants must agree to remain abstinent or use effective contraception (with an annual failure rate of < 1%) and refrain from sperm donation from the time of signing informed consent until at least 6 months after the last dose of the study drug.

Exclusion Criteria:

1. ALBI (Albumin-Bilirubin) grade 3.
2. Fibrolamellar carcinoma or sarcomatoid carcinoma.
3. Prior treatment with regorafenib.
4. Within 2 weeks since the last administration of an immune checkpoint inhibitor.
5. Receipt of any other systemic or locoregional therapy after the failure of first-line immune checkpoint inhibitor-based therapy.
6. History of allogeneic stem cell transplantation or solid organ transplantation.
7. Active brain metastases or leptomeningeal metastases.
8. History of malignancy other than hepatocellular carcinoma (HCC) within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year survival rate > 90%).
9. Severe cardiovascular disease within 3 months prior to the start of study therapy (e.g., New York Heart Association [NYHA] Class II or higher heart disease, myocardial infarction, or cerebrovascular accident); unstable arrhythmia or unstable angina; history of gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months prior to the start of study therapy; active gastrointestinal disease with a high risk of bleeding or perforation (e.g., peptic ulcer, inflammatory bowel disease, diverticulitis, cholecystitis, acute pancreatitis); untreated high-risk varices or recent history of variceal bleeding (enrollment is permitted only if at least 28 days have passed since stabilization with standard treatment); prolonged QTc interval (> 450 ms for males, > 470 ms for females); systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical therapy; or other significant medical conditions or abnormal findings that, in the opinion of the investigator, may increase the risk associated with study participation.
10. Female participants who are pregnant or breastfeeding, or male or female participants of reproductive potential who are unwilling to use effective contraception from screening until 6 months after the last dose of the study drug.
11. Participants deemed by the investigator to be unlikely to comply with study procedures, restrictions, and requirements.
12. Patients who have received locoregional therapy (e.g., radiofrequency ablation [RFA], microwave ablation [MWA], transarterial chemoembolization [TACE], transarterial radioembolization [TARE], transarterial embolization [TAE], radiation therapy, etc.) after the discontinuation of immune checkpoint inhibitor-based combination therapy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regorafenib	Drug: Regorafenib (BAY 73-4506); Oral regorafenib 120 mg once daily, taken at the same time each day after a meal with water. The study drug is administered on a 28-day cycle, consisting of 3 consecutive weeks of daily dosing followed by 1 week off. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival	From treatment initiation until the date of first documented progression or death from any cause, whichever comes first, assessed up to 36 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		From treatment initiation until the date of death from any cause, assessed up to 36 months.
time to progression		From treatment initiation until the date of first documented progression, assessed up to 36 months.
objective response rate		From treatment initiation until first documented progression or start of subsequent systemic anticancer therapy, assessed up to 36 months.
disease control rate		From treatment initiation until first documented progression or start of subsequent systemic anticancer therapy, assessed up to 36 months.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Adverse events will be graded according to the NCI CTCAE version 5.0.	From first dose of study drug until 30 days after last dose, assessed up to 36months.

Collaborators and Investigators

• Sponsor: Ju Hyun Shim
• Collaborators: National Cancer Center, Korea; Samsung Medical Center; Seoul National University Hospital; Seoul National University Bundang Hospital; Boryung Pharmaceutical Co., Ltd; Hanyang University Guri Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 15, 2026
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 30, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Pathological Conditions, Signs and Symptoms; Carcinoma, Hepatocellular; Disease Progression; regorafenib
• Other Study ID Numbers: 2026-0244

Drug and device information, study documents

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