Phase I trial of efficacy and safety of IMC002, a VHH-based anti-CLDN18.2 CAR-T therapy, for gastroesophageal cancers.

Abstract

398 Background: Advanced gastric and gastroesophageal junction (GC/GEJ) cancers are highly aggressive with limited late-line treatment options. Novel strategies are therefore urgently needed. Preclinical studies demonstrated that IMC002, a VHH-based anti-CLDN18.2 CAR-T, exhibited lower toxicity and reduced T-cell exhaustion compared with scFv-based constructs. In an IIT study, 1 of 6 GC patients achieved CR, which persisted for >2 years post-infusion. Methods: IMC002-RT01 is a single-arm, open-label, multi-center study evaluating the safety and efficacy of IMC002 in late-line CLDN18.2+ (≥2+ in ≥40%) GC/GEJ or pancreatic cancer (PC) patients. Three dose levels (1.0×10⁸, 2.5×10⁸, and 5.0×10⁸ CAR-T cells) were evaluated using a 3+3 design. Primary endpoint was safety while secondary endpoint was mainly efficacy. Here we report results from the GC/GEJ cohort. Data cutoff: August 8, 2025. Results: Between August 2023 and April 2025, 16 GC/GEJ patients received IMC002 (2.5×10⁸, n=11; 5.0×10⁸, n=5). Median follow-up was 7.0 months (range: 5.5–10.4). Baseline characteristics of all 16 patients: 50.0% ≥3 prior lines, 37.5% liver metastases, all PD-1/PD-L1 exposed. No DLTs, treatment-related deaths, ICANS or grade ≥3 liver toxicity occurred. Grade ≥3 TRAEs were mainly hematologic and lymphodepletion-related. All patients experienced CRS, with 75% grade 1 and 25% grade 2. In 15 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 66.7% and 93.3%. The CR rate was 6.7%. PFS and OS data were not mature with the current median PFS of 7.0 months (95% CI: 3.9–NR) and OS of 10.3 (95% CI: 6.1–NR) months. Notably, this represents a significantly improved PFS (7.0 months) in late-line GC, compared to historical benchmarks. One patient with liver metastases achieved a deep and durable response, converting from PR to CR and maintained through 48 weeks, while another patient maintained a PR for 60 weeks without progression, demonstrating durable anti-tumor activity. These results align with preclinical and IIT study data indicating sustained activity and low CAR-T cell exhaustion. Conclusions: IMC002 exhibited favorable tolerability and durable anti-tumor efficacy in GC/GEJ patients of the Phase I trial (n=16), including one durable CR. When combined with the IIT (n=6) data, the overall CR rate reached 9.1% (2/22) in late-line GC patients. IMC002 has the potential to be evaluated in earlier-line settings and achieve higher CR rates. Based on these findings, a phase III RCT of IMC002 in late-line GC/GEJ patients has been initiated. Clinical trial information: NCT05946226 .