CXD101 in Immunotherapy-related Liver Cancer

Overview

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. Our group has a track record of studying the role of histone deacetylases (HDACs) in mediating resistance to ICI in HCC. First, based on single-cell sequencing data of serial biopsy of tumor in our phase II clinical trial on pembrolizumab in HCC (NCT03419481), the investigators reveal an upregulation of class 1 HDAC in patients with acquired resistance to pembrolizumab, which was associated with reduced lymphoid/myeloid cellular ratio in the tumor. Further, the investigators showed that HDAC8, a class 1 HDAC, could diminish the efficacy of anti-programmed cell death (ligand)-1 (PD\[L\]-1) by the mechanism of T-cell exclusion from the tumor environment (SciTranl Med. 2021;13:online). Finally, the investigators combine CXD101, a potent selective class I HDAC inhibitor, with anti-PD(L)-1 in orthotopic immunocompetent HCC mouse model with resistance to anti-PD(L)-1 treatment and find that the combination regimen could reverse the resistance phenotype and significantly improve survivals of mice than either CXD101 or anti-PD(L)-1 alone.

To move from bench to clinic, it is crucial to validate the above in HCC patients demonstrating resistance to ICI-based treatment. In this grant, the investigators propose a randomized phase II clinical trial in patients with HCC who developed progressive disease to prior regimen containing anti-PD(L)-1. The investigators have already secured support of study medications from two pharmaceuticals to provide class 1 HDAC inhibitor and anti-PD1, respectively. Patients were randomized 1:1 to two study arms: the experiment arm consists of CXD101 20mg twice daily Day 1-5 every 3 weeks and an anti-PD1, geptanolimab at 3mg/kg Day 1 every 2 weeks. The dose of CXD101 has already been confirmed to be safe to combine with anti-PD1 in phase I/II studies in cancer patients. The control arm consists of investigators' choice of lenvatinib or sorafenib which are both considered standard treatment after failure with first-line atezolizumab-bevacizumab or other anti-PD(L)-1-based treatment. The primary endpoint is progress-free survival. Along the clinical trial, tumor biopsy will also be conducted at baseline and 6-week post-treatment to explore potential predictive biomarkers. Results of the study not only act as proof-of-concept but also potentially develop a novel treatment combination to tackle resistance to anti-PD(L)-1 treatment in HCC.