Phase II trial of zanzalintinib (XL-092) in combination with durvalumab and tremelimumab in unresectable hepatocellular carcinoma (ZENOBIA).
Background: Despite the evolving novel treatment options, the prognosis for advanced hepatocellular carcinoma (HCC) remains poor, with a 4-year survival rate of approximately 25%. Immune checkpoint inhibitors (ICIs), including the combination of durvalumab (Durva) & tremelimumab (Treme), represents the current standard-of-care for frontline HCC treatment. However, therapy resistance, either primary or secondary, often arises due to the immunosuppressive tumor microenvironment (TME). VEGFR is a well-established therapeutic target in HCC. Cabozantinib (Cabo), a multi-target tyrosine kinase inhibitor (TKI), is approved for later-line use per the CELESTIAL trial, and it also demonstrated significant TME modulation through antiangiogenic effects. A Phase II study (CHECKMATE 040) reported an impressive objective response rate (ORR) of 29% with the combination of ipilimumab/nivolumab and Cabo but noted high toxicity rates. Zanzalintinib (Zanza) is a novel TKI targeting VEGFR, MET, & TAM kinases (TYRO3, AXL, MER), key mediators of angiogenesis, tumor growth, metastasis, and TME immunosuppression. With a target profile similar to Cabo but an improved pharmacokinetic profile & a shorter half-life (16–22 hours), Zanza has demonstrated potential synergy with ICIs in preclinical and early-phase trials, suggesting enhanced sensitivity by fostering an immune-permissive TME. This phase II study evaluates the safety & efficacy of Zanza combined with Durva and Treme in HCC. Methods: This open-label, non-randomized Phase II trial consists of two parallel cohorts. Eligible patients must have unresectable HCC, be treatment-naïve in the unresectable setting, & have ECOG performance status of 0-1. Exclusion criteria include Child-Pugh score >7, known autoimmune diseases, heightened risk of gastrointestinal perforation or fistula formation, and known gastric or esophageal varices. The study begins with a safety lead-in phase of 9–12 patients to establish the recommended Phase II dose. The two cohorts aim to explore the optimal sequential strategy for combining Zanza with Durva & Treme. Cohort A: Zanza is administered during Cycle 1, followed by Durva + Treme in Cycle 2. Cohort B: Durva + Treme is administered during Cycle 1, followed by Zanza and Durva in Cycle 2. Both cohorts will continue with Zanza and Durva in subsequent cycles. A total of 40 participants (20 per cohort) will be enrolled. The primary endpoint is the ORR assessed by imRECIST 1.1. Secondary endpoints include the conversion rate to resectable or transplant-eligible disease, disease control rate, median PFS and OS, and landmark PFS & OS at 6, 12, 24, and 36 months. Safety and tolerability will also be evaluated. Comprehensive translational analyses include bulk RNA sequencing, spatial transcriptomics of baseline tumor biopsies, & serial ctDNA monitoring. Trial enrollment commenced in December 2024.
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Author Details
Meghana Singh
Department of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Track
Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
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