Tegavivint, a downstream Wnt/β-catenin inhibitor: Dose-finding results from a phase 1/2 trial in advanced hepatocellular carcinoma (aHCC).

4015 Background: Wnt/β-catenin pathway activation is a hallmark of many cancers, with Wnt pathway mutations (WPMs) present in ~40% of advanced HCC (aHCC). Tegavivint is a first-in-class small-molecule inhibitor of TBL1, a transcriptional co-factor required for nuclear β-catenin–dependent oncogenic gene expression. Binding of TBL1 by tegavivint disrupts the TBL1/β-catenin complex, resulting in selective degradation of nuclear β-catenin while preserving cytoplasmic and membrane-bound β-catenin functions associated with normal tissue homeostasis. This mechanism inhibits Wnt-driven oncogenicity while avoiding toxicities observed with upstream Wnt inhibitors. Here, we report dose-finding results from an ongoing phase 1/2 study of tegavivint in aHCC (NCT05797805). Methods: This multicenter, open-label phase 1/2 study employs a 3+3 dose-escalation design with backfill, followed by dose optimization. Eligible patients (pts) had aHCC previously treated with ≥1 systemic therapy, BCLC stage C or B disease not amenable to locoregional therapy, and Child-Pugh class A or B (score ≤ 7). WPM status was assessed by liquid biopsy. Tegavivint was administered intravenously once weekly. Primary objectives were safety and tolerability; secondary objectives included preliminary efficacy and PK/PD. Results: As of 21 Jan 2026, 39 pts were enrolled (median age 68 years [range 34–84]); 28 had WPMs, and the median number of prior systemic therapies was 2 (range 1–6). Pts were treated across four dose levels (3–8 mg/kg), demonstrating dose-proportional increases in exposure. At 8 mg/kg, 2 of 5 pts experienced Grade 3 anemia within the DLT window, establishing 3–6.5 mg/kg as the recommended dose range (RDR). Across all doses, the most common (all grade/grade ≥ 3; n/n) TRAEs were fatigue (9/0), hyperbilirubinemia (7/4; isolated, asymptomatic and reversible), anemia (5/5; reversible), myalgia (4/0), and decreased appetite (4/0). Among WPM pts evaluable for efficacy within the RDR (n = 18), those with ≤ 3 previous lines of therapy (n = 9) achieved an overall response rate (ORR) of 22%, disease control rate (DCR) of 89%, and median progression-free survival (mPFS) of 8 mo, compared with 0% ORR, 56% DCR, and 4 mo mPFS in pts treated in later lines (n = 9). No significant clinical benefit was observed in pts without WPMs. Pts remaining on treatment for ≥ 4 months (n = 9) demonstrated concordant improvements in liver enzymes, alpha-fetoprotein, platelet counts, and/or ctDNA variant allele frequency. Conclusions: Tegavivint is the first Wnt/β-catenin inhibitor to demonstrate monotherapy clinical activity and a manageable safety profile in heavily pretreated aHCC pts with WPMs. Observed partial responses, durable disease control, and on-target PD effects in 2L and 3L pts support further development of tegavivint as a monotherapy or in combination with other treatments for this population. Clinical trial information: NCT05797805 .