A phase Ib/II study of zanzalintinib (XL092) in second line and beyond for the treatment of advanced hepatocellular carcinoma.

TPS615 Background: Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver cancers and is responsible for approximately 7.8% of all cancer-related deaths, ranking third among causes of cancer mortality worldwide. Most patients are diagnosed with advanced-stage disease. Following recent randomized controlled trials, immune checkpoint inhibitor (ICI)-based regimens have replaced tyrosine kinase inhibitors as the standard first-line treatment. However, evidence guiding treatment after progression on first-line systemic therapy remains limited, and no approved second-line options exist for patients with advanced HCC. Zanzalintinib (XL092) is a novel, potent, orally bioavailable small-molecule inhibitor that targets multiple receptor kinases, including MET, VEGFR2, AXL, and MER. It is currently under investigation in early-phase and phase III trials across several malignancies, such as colorectal cancer, non–clear cell renal cell carcinoma, head and neck squamous cell carcinoma, and advanced neuroendocrine tumors. Safety data to date suggest that XL092 is well tolerated at a 100 mg daily dose, and preliminary exposure–response analyses indicate no significant difference in efficacy between the 60 mg and 100 mg dose levels. Methods: Eligible patients must have advanced HCC with objective radiographic progression on or after first- or second-line systemic therapy. Key inclusion criteria include measurable disease by RECIST v1.1, Child-Pugh Class A or B (B7–B8) cirrhosis, ECOG performance status 0–1, and adequate organ and marrow function. Prior cabozantinib exposure is an exclusion criterion. Patients will be stratified into two cohorts by liver function: Cohort 1 (Child-Pugh A) and Cohort 2 (Child-Pugh B7–B8). Phase Ib will assess safety, tolerability, and dose-limiting toxicities (DLTs) of Zanzalintinib, and define the recommended phase II dose (RP2D) using a standard 3+3 design at 40 mg and 60 mg daily. Up to 30 patients may be enrolled in the safety lead-in. In Phase II, Cohort 1 (historical median PFS 3.5 months, target 6 months; 80% power, 1-sided α=0.1) will enroll 20 evaluable patients. Cohort 2 (median PFS 1.8 months, target 3.6 months; 80% power, 1-sided α=0.1) will enroll 13 evaluable patients. Efficacy analyses will use a one-sample log-rank test, assuming an exponential survival distribution. Clinical trial information: NCT07042919 .