A phase 1 study of SHR-3821, an ADCC-enhanced CLDN18.2/4-1BB bispecific antibody, in patients with advanced solid tumors.

4037 Background: CLDN18.2 is a highly selective tumor-associated antigen overexpressed in gastrointestinal malignancies, and has emerged as a promising therapeutic target. 4-1BB is a co-stimulatory receptor expressed on activated immune cells; its activation enhances antitumor immunity. SHR-3821 is an ADCC-enhanced bispecific antibody that specifically targets CLDN18.2 and activates 4-1BB in a CLDN18.2-dependent manner, enabling tumor-specific killing while minimizing systemic toxicity. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of SHR-3821 in patients with CLDN18.2-positive advanced solid tumors. Methods: Eligible patients had CLDN18.2-positive advanced solid tumors that had progressed on or lacked standard therapies. Patients received SHR-3821 via intravenous infusion every 3 weeks at prespecified dose levels: 0.1, 1, 3, 10, 15, 20 and 30 mg/kg during dose escalation (using a Bayesian optimal interval design), followed by dose expansion and efficacy expansion at 15 and 20 mg/kg. Primary endpoints included safety, maximum tolerated dose, and recommended phase 2 dose. Results: As of November 30, 2025, 40 patients with CLDN18.2-positive advanced solid tumors (23 gastric cancer GC, 17 pancreatic cancer PC) were treated with SHR-3821 at doses ranging from 0.1 to 20 mg/kg. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached across the evaluated dose range. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 15 patients (37.5%), most commonly decreased neutrophil count (20.0%), decreased lymphocyte count (7.5%), and vomiting (5.0%). No TRAEs led to death; one (2.5%) patients discontinued treatment due to TRAEs. Preliminary pharmacokinetic analyses demonstrated dose-proportional increases in systemic exposure following a single 1–20 mg/kg administration, with terminal elimination half-lives ranging from 4.2 to 7.0 days. ORR in GC were 22.2% at 15 mg/kg and 37.5% at 20 mg/kg (Table). Conclusions: SHR-3821 showed tolerable safety and promising antitumor activity in patients with CLDN18.2-positive GC and PC. These data support further clinical development of SHR-3821. Clinical trial information: NCT06618651 . Efficacy in GC and PC. GC PC 15 mg/kg(N=9) 20 mg/kg(N=8) 15 mg/kg(N=4) 20 mg/kg(N=7) Confirmed ORR, % (n/N; 95% CI) 11.1(1/9; 0.28-48.25) 0(0/8; 0.00-36.94) 0(0/4; 0.00-60.24) 0(0/7; 0.00-40.96) Confirmed DCR, %(n/N; 95% CI) 55.6(5/9; 21.20-86.30) 62.5(5/8; 24.49-91.48) 50.0(2/4; 6.76-93.24) 42.9(3/7; 9.90-81.59) Unconfirmed ORR * , % (n/N; 95% CI) 22.2(2/9; 2.80-60.01) 37.5(3/8; 8.52-75.51) 0(0/4; 0.00-60.24) 0(0/7; 0.00-40.96) Unconfirmed DCR, %(n/N; 95% CI) 55.6(5/9; 21.20-86.30) 62.5(5/8; 24.49-91.48) 50.0(2/4; 6.76-93.24) 42.9(3/7; 9.90-81.59) ORR, objective response rate; DCR, disease control rate. *Four patients were pending efficacy confirmation.