Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial

Abstract Objective To evaluate the safety and preliminary efficacy of IMC001, an epithelial cell adhesion molecule (EpCAM)-targeted CAR-T cell therapy, in patients with advanced gastric cancer (GC). Design This was a phase I, open-label, single or multiple infusion, dose escalation study utilizing a classic 3+3 design that included adults (aged ≥18 years) with locally advanced or metastatic GC with positive EpCAM histological staining of a biopsy tumor tissue sample who had failed at least two lines of treatment and were ineligible for a standard treatment. Eligible patients received IMC001 at doses of 3×105 (low), 1×106 (middle) or 3×106 (high) CAR-T cells/kg after lymphodepletion. The primary objective was evaluation of the safety and tolerability of IMC001. Secondary objectives included determination of the recommended phase II dose (RP2D) based on dose-limiting toxicity (DLT), preliminary evaluation of efficacy and characterization of pharmacokinetics and pharmacodynamics. Results From August 18, 2021 to May 8, 2023, 11 patients with advanced GC received IMC001, the median age was 53 (36-70) years and 63.6% (7/11) were male. Most patients 91.9% (10/11) had failed ≥2 lines of chemotherapy and 27.3% (3/11) had received prior immunotherapy. By the cutoff date (March 31st, 2024), low- and middle-dose IMC001 infusion was associated with a favorable safety profile. The disease control rate was 90% in 10 evaluable patients; 1 patient in the low-dose group (1/3, 33.3%) and 2 in the middle-dose group (2/5, 40%) achieved a partial response (PR). The median PFS was 18.1 weeks (95% CI 7.97, --) and the OS was 55.1 weeks (95% CI 23.78, --) for the middle dose group; 3/5 patients in the middle dose group had survived more than 10 months. One patient in the middle-dose group achieved a confirmed PR by Week 24, culminating in a radical gastrectomy at Week 27 and had survived for more than 22 months by the cutoff date. Tumor immune microenvironment analysis suggested that an inflamed tumor environment may enhance the anti-tumor effects of IMC001. The 1×106 CAR-T cells/kg dose was selected as the recommended dose for future study. Conclusion In this phase I dose-escalation trial, IMC001 demonstrated a favorable safety profile and encouraging efficacy in patients with advanced, pre-treated GC. Further investigation is warranted to further evaluate the use of IMC001 for patients with advanced GC.