Phase I/II trial of anti-CLDN18.2/PD-L1 recombinant humanized bispecific antibody Q-1802 plus XELOX in treatment-naive CLDN18.2-positive advanced GC/GEJ.

4036 Background: First-line therapy for HER2-negative advanced GC/GEJ remains a huge unmet clinical need. Claudin 18.2 (CLDN18.2), a tight junction protein, is specifically expressed in normal gastric mucosa but aberrantly overexpressed in various cancers, making it a high-value therapeutic target. Q-1802 is a first-in-class humanized bispecific antibody targeting both CLDN18.2 and PD-L1. Q-1802 can bind CLDN18.2 on tumor cells and kill them through Fc mediating antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Meanwhile, it can activate immune system to eliminate tumor cells by blocking PD-1/PD-L1 binding. Methods: Qure-1802-201 was a multicenter, open-label, nonrandomized phase Ⅰ/Ⅱ trial. Eligible pts: CLDN18.2-positive (≥40% tumor cells with 2+/3+ membranous staining), HER2-negative, treatment-naïve, histologically confirmed unresectable locally advanced/metastatic GC/GEJ. Pts received Q-1802 (10 mg/kg or 20 mg/kg Q2W) plus standard XELOX (oxaliplatin IV d1; capecitabine PO d1-14 Q3W). Primary endpoints: DLT/MTD (Phase Ⅰ) and ORR per RECIST v1.1 (Phase Ⅱ). Secondary endpoints: efficacy, safety, pharmacokinetics, pharmacodynamics, immunogenicity. Results: As of Dec 11, 2025, 62 pts were enrolled (45 in 10 mg/kg, 17 in 20 mg/kg). No DLT observed; MTD not reached. All pts had TEAEs and Q-1802-related TEAEs; the latter mainly included nausea (75.8%), AST increase (61.3%), nausea (59.7%), ALT increase (51.6%), fatigue (50.0%). Incidences of ≥3 Grade TEAEs and Q-1802-related ≥3 Grade TEAEs: 74.2% and 43.5%, respectively. Most common Q-1802-related ≥3 Grade TEAE: thrombocytopenia (8.1%), followed by neutropenia (6.5%), anemia, WBC decrease, hypokalemia (4.8% each). Rate of Q-1802 permanent discontinuation due to TEAEs: 6.5%; no treatment-related death. ORR and median progression-free survival (mPFS) in 60 efficacy-evaluable pts were 70.0% (42/60; 95% CI: 56.8%–81.2%) and 11.3 months (95% CI: 8.0–16.8). A correlated trend was observed between efficacy and CLDN18.2 expression. In the 10 mg/kg cohort, ORR and mPFS were 73.0% (27/37; 95% CI: 55.9%–86.2%) and 11.3 months (95% CI: 7.1–16.8) in pts with CLDN18.2 high expression (2+/3+≥70%, N = 37), which were improved to 81.8% (9/11; 95% CI: 48.2%–97.7%) and 12.2 months (95% CI: 2.7–NE) when CLDN18.2 high expression companied with PD-L1 CPS≥5 (N = 11). DCR was nearly complete (non-response in 1 of 60 pts). ORR in the 20 mg/kg cohort (70.6%, 12/17; 95% CI: 44.0%–89.7%) was similar to 10 mg/kg (69.8%, 30/43; 95% CI: 53.9%–82.8%.). Overall survival (OS) in all pts and PFS in the 20 mg/kg cohort are under follow-up. Conclusions: Q-1802 plus XELOX has manageable safety and promising antitumor activity as first-line therapy for CLDN18.2-positive/HER2-negative advanced GC/GEJ, supporting a phase III trial (Q-1802 10 mg/kg as recommended dose). Clinical trial information: NCT05964543 .