Combination of SBRT, PD-L1 Inhibitor, and Lenvatinib in Hepatocellular Carcinoma (HSBRT2401)

Official title

Efficacy and Safety of Stereotactic Body Radiotherapy Followed by Adebrelimab and Lenvatinib for Hepatocellular Carcinoma With Abdominal Lymph Node Metastases: A Two-arm, Phase II Trial

Overview

Abdominal lymph node metastasis (LNM) is one of the major modes of extrahepatic metastasis in hepatocellular carcinoma (HCC). Immunotherapy targeting the PD-1/PD-L1 checkpoints combined with targeted therapy is the standard treatment for HCC with abdominal LNM, but the outcome remains very poor, with an objective response rate of 5% to 30%. Previous studies have demonstrated that stereotactic body radiotherapy (SBRT) is an effective local treatment for HCC with abdominal LNM, with a high response rate of 60% to 80%. However, intrahepatic dissemination and distant metastasis remains the major recurrence pattern after SBRT in these patients, suggesting radiotherapy should be combined with systematic treatment. Recently, the combination of immunotherapy with SBRT has shown promising activity in HCC. The aim of this study was to investigate the efficacy and safety of SBRT followed by adebrelimab (an anti-PD-L1 antibody) and lenvatinib in HCC patients with portal abdominal LNM.

Detailed description

A total of 60 HCC patients (2 cohorts) with abdominal LNM will be enrolled to receive SBRT followed by adebrelimab (an anti-PD-L1 antibody) and lenvatinib. Arm A included the patients who previously had not received PD-1/PD-L1 antibody, and Arm B included the patients who had progressed after receiving PD-1/PD-L1 antibody.

Patients in both cohorts will receive stereotactic body radiotherapy (SBRT) using volumetric arc therapy. The prescribed dose is 33-48 Gy in 6 fractions over 2 weeks. Then all patients will receive lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight \<60 kg) orally once daily in combination with adebrelimab 1200 mg every 3 weeks for up to 35 cycles. The first course of adebrelimab will be given within 1 week after completion of SBRT.

Interventions

• Radiation Stereotactic body radiotherapy
  Patients in both cohorts will receive stereotactic body radiotherapy (SBRT) using volumetric arc therapy. The prescribed dose is 33-48 Gy in 6 fractions over 2 weeks.
• Drug Adebrelimab
  All patients will reveive adebrelimab 1200 mg every 3 weeks for up to 35 cycles after the completion of SBRT.
• Drug Lenvatinib
  All patients will receive lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight \<60 kg) orally once daily after the completion of SBRT.

Primary outcome measures

• Progression-free survival (PFS) [Time frame: From date of enrollment until the date of death from any cause or the date of first documented disease progression whichever came first, assessed up to 36 months.]

Secondary outcome measures (5)

• Overall survival (OS) [Time frame: From date of enrollment until the date of death from any cause or the date of last follow-up, whichever came first, assessed up to 36 months.]
• Overall response rate (ORR) [Time frame: From date of enrollment to the date of last follow-up, assessed up to 36 months.]
• Disease control rate (DCR) [Time frame: From date of enrollment to the date of last follow-up, assessed up to 36 months.]
• Duration of response (DOR) [Time frame: From date of first CR/PR to the date of first PD according to RECIST criteria, assessed up to 36 months.]
• Treatment-related adverse events [Time frame: From date of enrollment to the date of last follow-up, assessed up to 36 months.]

Eligibility criteria

Inclusion criteria

• Histologically confirmed hepatocellular carcinoma or diagnosed by American Association for the Study of Liver Disease criteria;
• Presence of abdominal metastatic lymph nodes confirmed by CT or MRI, the sum of the maximum diameter of lymph nodes ≤10 cm, and at least one of which is measurable according to the RECIST 1.1 Criteria;
• Previous local treatment for intrahepatic lesion and systemic anti-tumor therapy are allowed; no matter whether the disease progressed or not;
• Less than 3 active intrahepatic lesions with a total diameter of less than 10 cm; Portal vein invasion is allowed; absence of other extrahepatic metastasis disease except abdominal LNM;
• Cohort 1: Patients who never received PD-1/PD-L1 antibody therapy; Cohort 2: patients who had tumor progression after previous PD-1/PD-L1 antibody therapy.
• Age at diagnosis 18 to 75 years;
• Eastern Cooperative Oncology Group performance status ≤ 2
• Child-Pugh class A liver function;
• Normal liver volume greater than 700 ml;
• Estimated life expectancy ≥12 weeks;
• The function of important organs meets the following requirements: a. white blood cell count (WBC) ≥ 3.0×109/L, absolute neutrophil count (ANC) ≥ 1.5×109/L; b. platelets ≥ 50×109/L; c. hemoglobin ≥ 9g/dL; d. serum albumin ≥ 2.8g/dL; e. total bilirubin ≤ 1.5×ULN, ALT, AST and/or AKP ≤ 2.5×ULN; f. serum creatinine ≤ 1.5×ULN or creatinine clearance rate >60 mL/min;
• Ability to understand the study and sign informed consent.

Exclusion criteria

• Diffuse hepatocellular carcinoma;
• Patients who have previously been treated with lenvatinib or PD-1/PD-L1 antibody but could not be tolerated;
• Patients with other extrahepatic metastasis disease except abdominal LNM;
• A history of abdominal radiotherapy;
• Known or suspected allergy or hypersensitivity to monoclonal antibodies;
• Patients who have a preexisting or coexisting bleeding disorder;
• Female patients who are pregnant or lactating;
• Inability to provide informed consent due to psychological, familial, social and other factors;
• A history of malignancies other than hepatocellular carcinoma before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer;
• A history of diabetes for more than 10 years and poorly controlled blood glucose levels;
• Patients who cannot tolerate radiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia;
• Active autoimmune diseases, a history of autoimmune diseases (including but not limited to these diseases or syndromes, such as colitis, hepatitis, hyperthyroidism), a history of immunodeficiency (including a positive HIV test result), or other acquired or congenital immunodeficiency diseases, a history of organ transplantation or allogeneic bone marrow transplantation;
• A history of interstitial lung disease or non-infectious pneumonia;
• A history of active pulmonary tuberculosis infection within 1 year or a history of active pulmonary tuberculosis infection more than 1 year ago but without formal anti-tuberculosis treatment;
• Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (positive for hepatitis C antibody, and HCV-RNA levels higher than the lower limit of the assay);
• Any unstable situation that may endanger the safety and compliance of patients.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Mian Xi — Guangzhou

Publications

• Wang Y, Li Q, Zhang L, Liu S, Zhu J, Yang Y, Liu M, Zhang Y, Xi M. Efficacy and Dose-Response Relationship of Stereotactic Body Radiotherapy for Abdominal Lymph Node Metastases from Hepatocellular Carcinoma. Oncologist. 2023 Jun 2;28(6):e369-e378. doi: 10.1093/oncolo/oyad083. PMID 37011232
• Kim HJ, Park S, Kim KJ, Seong J. Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy. Radiother Oncol. 2018 Oct;129(1):130-135. doi: 10.1016/j.radonc.2017.11.027. Epub 2018 Jan 30. PMID 29366520
• Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, Dai WC, Lam TC, Chen W, Wong NSM, Cheung ALY, Lee VWY, Lau VWH, El Helali A, Man K, Kong FMS, Lo CM, Chan AC. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase PMID 36529152
• Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020 Sep 10;38(26):2960-2970. doi: 10.1200/JCO.20.00808. Epub 2020 Jul 27. PMID 32716739

Identifiers

NCT: NCT06261125 · SL-B2023-718

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗