Dual TIGIT and PD-1 blockade with domvanalimab plus zimberelimab in hepatocellular carcinoma refractory to anti-PD-1 therapies: the phase 2 LIVERTI trial

David Hsiehchen (), Radhika Kainthla, Heather Kline, Ellen Siglinsky, Chul Ahn and Hao Zhu
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David Hsiehchen: University of Texas Southwestern Medical Center
Radhika Kainthla: University of Texas Southwestern Medical Center
Heather Kline: University of Texas Southwestern Medical Center
Ellen Siglinsky: University of Texas Southwestern Medical Center
Chul Ahn: University of Texas Southwestern Medical Center
Hao Zhu: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-7

Abstract: Abstract T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes and NK cells, and is a candidate compensatory immune checkpoint that may mediate anti-PD-1/L1 resistance in hepatocellular carcinoma (HCC). We conducted the phase 2 LIVERTI trial testing domvanalimab, a monoclonal Fc-silent anti-TIGIT antibody, plus zimberelimab, an anti-PD-1 antibody, in immunotherapy refractory HCC. Here, we report an analysis of the primary endpoint, the confirmed overall response rate (ORR). Secondary endpoints included rates of adverse events, progression-free survival (PFS), 6-month PFS survival, overall survival, and duration of response, of which the latter two endpoints were excluded from this analysis due to the immaturity of long-term survival data. Among the 29 patients enrolled, the confirmed ORR was 17.2% (95% CI 5.8%-35.8%) and the median PFS was 4.4 months (95% CI, 4.1–4.6 months). Treatment-related adverse events occurred in 16 patients (55.2%). Analysis of circulating tumor DNA (ctDNA) demonstrated that ctDNA dynamics may serve as pharmacodynamic markers of response to domvanalimab plus zimberelimab. Despite the primary endpoint failing to meet the protocol-specified threshold, these results indicate that targeting TIGIT in anti-PD-1/L1 therapy refractory HCC is well-tolerated, associated with anti-tumor effects, and may be guided by ctDNA assessment. ClinicalTrials.gov registration: NCT05724563.

Date: 2025
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DOI: 10.1038/s41467-025-60757-7

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