Efficacy and safety of LM-302 (anti-claudin 18.2 ADC) in combination with anti-PD-1 therapy for advanced gastric, gastroesophageal junction cancer and esophageal adenocarcinoma: Early-phase study results.

4039 Background: Claudin 18.2 (CLDN18.2), a tight junction protein highly expressed in gastric and gastroesophageal junction (GEJ) cancers, has emerged as a promising therapeutic target. LM-302 (tecotabart vedotin), a novel and potent MMAE-based ADC targeting CLDN18.2, has shown promising efficacy and safety as monotherapy in heavily pretreated advanced gastric cancer. This pooled analysis evaluates the efficacy and safety of LM-302 in combination with the anti-PD-1 antibody toripalimab as a first-line treatment option for patients with gastric, GEJ, or esophageal adenocarcinoma (EAC). Methods: Eligible patients with histologically confirmed, previously untreated, unresectable, HER2-negative gastric, GEJ, or EAC were included. Patients received LM-302 (1.6 mg/kg Q3W, 2.0 mg/kg Q3W or 1.8 mg/kg Q2W) and toripalimab (240 mg Q3W or 3 mg/kg Q2W). Endpoints included safety, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), OS, and biomarker analysis. Data cutoff: January 7, 2025. Results: A total of 43 gastric, GEJ, or EAC patients (median age: 62.3 years; 65.1% male) from Australia and China were treated. No dose-limiting toxicities (DLT) were observed across all these dose levels. Treatment-related adverse events (TRAEs) related to LM-302 were reported in 39 patients (90.7%), with common events (≥20%) including anemia, decreased white blood cell count, decreased neutrophil count, increased aspartate transaminase (AST), vomiting, loss of appetite, and nausea. Grade ≥3 TRAEs related to LM-302 occurred in 16 patients (37.2%), the most common events (≥5%) were decreased neutrophil count (14.0%), increased alanine transaminase (11.6%), increased AST (9.3%), and anemia (7.0%). Among 41 efficacy-evaluable patients (median follow-up: 6.01 months), ORR was 65.9% (95% CI: 49.4-79.9%), and DCR was 85.4% (95% CI: 70.8- 94.4%). In 32 GC patients with CLDN18.2 expression in ≥25% of tumor cells (IHC 2+/3+), ORR was 71.9% (95% CI: 53.3-86.3%) and DCR was 96.9% (95% CI: 83.8-99.9%). Among these patients, ORR was 63.3% (95% CI: 35.1-87.2%) for patients with PD-L1 CPS < 1 and 77.8% (95% CI: 52.4-93.6%) for patients with PD-L1 CPS ≥1. Median PFS and OS were not reached; one patient with PD-L1 CPS < 1 achieved PR and remained on treatment for 14.70 months. Conclusions: LM-302 combined with toripalimab demonstrated encouraging anti-tumor activity and manageable safety as first-line treatment for patients with CLDN18.2-positive gastric, GEJ, and EAC, including those with low-to-moderate CLDN18.2 expression. These findings support further large-scale clinical trials to confirm efficacy, safety and clinical utility. Clinical trial information: NCT05188664 ; NCT05934331 .