First-in-human phase I/II study of MRG006A, a first-in-class Glypican-3 (GPC3)–targeted antibody-drug conjugate (ADC), in patients (pts) with advanced hepatocellular carcinoma (HCC).

Abstract

3028 Background: Pts with advanced HCC face limited treatment options beyond immunotherapy and anti-angiogenic agents. GPC3, a surface antigen overexpressed in HCC and associated with poor prognosis, represents a promising therapeutic target due to its tumor-specific expression. MRG006A, a potential first-in-class GPC3-targeted ADC, demonstrated potent pre-clinical anti-tumor activity. Here we report the preliminary safety and efficacy of MRG006A in advanced HCC with intermediate/high GPC3 expression from a phase I/II trial. Methods: MRG006A-001 (NCT07093970) is an ongoing first-in-human, open-label, multi-center phase I/II study. The phase I study comprises dose escalation (Ia) and dose optimization/expansion (Ib) stages. The dose-escalation employed an accelerated titration plus 3+3 design. Eligible pts who had failed standard treatment received MRG006A intravenously at 1.6-6.4 mg/kg every three weeks (Q3W). GPC3 expression was only required for dose expansion cohorts. The primary endpoints were safety and tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), etc. Results: As of Dec 19, 2025, the maximum administered dose was established as 6.4 mg/kg Q3W, with ≥ G3 treatment-related adverse event (TRAE) of platelet count decreased reported in all six pts at this dose level and dose-limiting toxicity (G4 platelet count decreased) observed in one patient. During dose escalation, tumor response was observed at 3.2 mg/kg and 4.8 mg/kg. Accordingly, dose optimization in phase Ib proceeded with three levels (3.2, 4.0, and 4.8 mg/kg Q3W). Twenty-six HCC pts with intermediate or high GPC3 expression were enrolled across three cohorts; 61.5% had BCLC stage C disease; median 2 (range 1-4) prior lines of therapy, and 25 (96.2%) had received immune checkpoint inhibitors and anti-angiogenic agents. Among 25 efficacy evaluable pts, ORR, DCR and CBR were 23.1%, 68.0% and 32.0%, respectively. In pts with high GPC3 expression (n=12), ORR, DCR and CBR increased to 33.3%, 75.0% and 50.0%, respectively; median PFS and DOR were 7.0 and 4.2 months (median follow-up 5.7 months). Most pts (24 [92.3%]) experienced TRAE of any Grade. TRAEs of ≥ G3 were reported in 11 (42.3%) pts . The most common TRAEs were platelet count decreased (88.5%), blood bilirubin increased (50.0%), AST increased (46.2%), white blood cell count decreased (38.5%), and nausea (30.8%). No treatment-related permanent discontinuations or deaths occurred. Conclusions: MRG006A demonstrated manageable safety and promising anti-tumor activity in heavily pretreated pts with GPC3-expressing advanced HCC. Our findings support the therapeutic potential of GPC3-directed ADC and merits further clinical investigations. Clinical trial information: NCT07093970 .