TPS613 Background: Enhancer of zeste homolog 2 (EZH2) is overexpressed in HCC and correlates with poor prognosis. Preclinical studies demonstrated that EZH2 regulates immune evasion and EZH2 inhibition enhances NK cell–mediated anti-tumor activity in HCC cell lines. EZH2 inhibition combined with anti-PD-L1 blockade leads to increased CD8⁺ T cell trafficking and synergistic anti-tumor effect in HCC murine models. Valemetostat tosylate (DS-3201b) is a dual EZH1/EZH2 inhibitor with potential to restore immune sensitivity and synergize with immune checkpoint inhibitor-based therapy in HCC. Based on this preclinical rationale, we designed a phase Ib/II study to determine the recommended phase II dose (RP2D), evaluate the safety, toxicity profile, preliminary anti-tumor activity, and correlative outcomes of valemetostat, atezolizumab and bevacizumab in patients with treatment-naive advanced HCC. Methods: The phase Ib trial design is a standard 3+3 dose-escalation study. Primary endpoints of phase Ib are RP2D, safety and tolerability. Primary endpoint of phase II (dose expansion) cohort is to estimate objective response rate by RECIST version 1.1 per investigator assessment. Secondary endpoints of the study are overall survival, progression free survival, disease control rate, duration of response, pharmacokinetic profile. Correlative endpoint is to explore immunological biomarkers of treatment response. A Simon’s two stage design will be used for phase II portion of the study (H0: ORR=27.3%; H1: ORR=48%; Type I error=0.1; power=80%). After RP2D is established, 10 patients will be enrolled in the first stage of dose expansion phase (phase II). If three or more objective responses are observed, 17 additional patients will be enrolled in the second stage of phase II (27 total patients). Eleven or more objective responders in 27 patients would be required to be considered positive study. Valemetostat is administered orally (PO) daily in three dose levels of 100 (DL-1, only if ≥2 DLTs observed at DL1), 150 (DL1), 200 (DL2) mg with standard dose of atezolizumab 1200 mg IV on day 1, and bevacizumab 15 mg/kg IV on day 1 of each cycle, in 21-day cycles. Eligible patients must have advanced HCC diagnosis confirmed by histology/cytology or clinically by American Association of Liver Diseases (AASLD) criteria for cirrhotic patients, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST v1.1, adequate organ function, no prior systemic therapy for advanced HCC. Restaging scans will be performed every 9 weeks. Serial peripheral blood samples and optional paired biopsies will be collected for correlative research. This study was activated in July 2025. Clinical trial information: NCT06294548 .
Akce et al. (Sat,) studied this question.