Epigenetic therapeutics to overcome resistance against immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC): a proof-of-concept clinical trial
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: Background For hepatocellular carcinoma (HCC), durable responses and improved survivals have been reported in clinical trials on immune checkpoint inhibitor (ICI)-based treatment. However, resistance to ICI is increasingly encountered in clinical practice in HCC patients. Various approaches are currently evaluated in clinical setting to tackle acquired resistance during treatment of ICIs in HCC. Based on single-cell sequencing data of serial biopsy of tumor in an earlier phase II clinical trial on pembrolizumab in HCC (NCT03419481), we demonstrated upregulation of class 1 HDAC in patients with acquired resistance to pembrolizumab. Combination with Zabadinostat (Zaba), a potent selective class I HDAC inhibitor, with anti-PD(L)-1 in orthotopic immunocompetent HCC mouse model resistant to anti-PD(L)-1 treatment and demonstrated that the combination regimen reversed resistance and significantly improved survival 1 . Aim Could Zaba restore sensitivity to patients with advanced HCC who had progressed despite first line therapy with an ICI? Methods We initiated a randomized phase II clinical trial in patients with HCC who developed progressive disease to prior regimen containing anti-PD(L)-1. Patients were randomized 1:1 to two study arms: the experimental arm: Zaba 20mg twice daily Day 1-5 and an anti-PD1, geptanolimab at 3mg/kg Day 1 every 21 days; control arm: investigators' choice of lenvatinib or sorafenib. The primary endpoint is progression-free survival. Tumor biopsies are collected at baseline and 6-weeks post-treatment to explore predictive biomarkers. This preliminary report describes the safety profile of combination therapy in this fragile patient group. Findings 20 patients have been recruited as of 1 st October, 2024, data for the entire trial cohort, will be updated at the time of presentation. Safety – the Zaba/Geptanolimab combination is well tolerated (grade 2 CTC toxicity) and 2 SAEs were reported for Sorafenib arm. Efficacy - No PR/CR were observed. The disease control rate is 55%. The corresponding 95% CI is 33.2%-76.8%. The median PFS and 95% CI is 2.98 months (1.92-4.56) months. The median OS and 95% CI is 8.16 months (6.76 – NR) months. Interpretation These preliminary safety data are consistent with our previous study in which we combined Zaba with the ICI Nivolumab in 4 th line treatment of patients with advanced colorectal cancer. 55 patients were treated with Zaba and nivolumab 2 . The combination therapy was well tolerated with the most frequent grade 3 adverse events being neutropenia [18%]) and anaemia [7%]). Immune-related adverse reactions commonly ascribed to check-point inhibitors were rare. The combination of Zaba with an ICI has a strong scientific rationale, is well tolerated in HCC patients who have progressed through or were resistant to first line therapy with ICIs and efficacy data will be updated at the time of presentation.
Institutions: Chinese University of Hong Kong, University of Oxford
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,250
OpenAlex ID: W4407631485