Efficacy and safety of tecotabart vedotin plus toripalimab with or without chemotherapy as first-line treatment for CLDN18.2-positive advanced gastric or gastroesophageal junction adenocarcinoma: Phase II study results.

4045 Background: Tecotabart vedotin (TV; LM-302) is a novel and potent MMAE-based ADC targeting CLDN18.2. Previous data (ASCO 2025, abstract#4039) demonstrated promising efficacy and manageable safety profile of TV plus PD-1 inhibitor in patients (pts) with systemic therapy-naive advanced gastric or gastroesophageal junction (G/GEJ) cancer. Updated phase II results of TV plus toripalimab (T) with or without chemotherapy in this first-line setting are presented. Methods: Eligible pts had histologically confirmed, no prior systemic therapy, HER2-negative G/GEJ adenocarcinoma with CLDN18.2 positivity (IHC 2+/3+ in ≥1% of tumor cells). Pts received TV (1.8 mg/kg Q2W) plus T (3 mg/kg Q2W), with or without capecitabine or S-1. The primary endpoint was PFS per RECIST v1.1. Secondary endpoints were efficacy, safety, PK, and biomarker analysis. Data cutoff: November 25, 2025. Results: A total of 71 pts with G/GEJ adenocarcinoma were enrolled: 39 in the TV+T cohort and 32 in the TV+T+Chemo cohort. Baseline CLDN18.2 high expression (≥25%) was presented in 82.1% of pts in the TV+T cohort and 84.4% in the TV+T+Chemo cohort. PD-L1 CPS ≥1 was observed in 61.5% and 81.3% of pts, respectively. Median follow-up was 16.16 months in the TV+T cohort and 14.82 months in the TV+T+Chem cohort. The median PFS (95% CI) was 10.68 months (6.28, NE) and 12.55 months (6.80, NE), respectively. Among pts with CLDN18.2 ≥25%, the median PFS (95% CI) was 12.22 months (6.87, NE) and NE (8.44, NE), the median DOR (95% CI) was 13.86 months (9.36, NE) and NE (7.10, NE), ORR was 64.5% and 69.2%, and DCR was 96.8% and 96.2%, respectively. Median OS was not reached in either cohort. In pts with CLDN18.2 <25%, TV+T (N=7) and TV+T+Chemo (N=5) showed a median PFS (95% CI) of 5.72 (1.15, NE) and 6.80 (5.55, NE) months, ORR of 14.3% and 40.0%, DCR of 71.4% and 100%, and OS (95% CI) of 10.78 (2.56, NE) months and NE (8.25, NE), respectively. TRAEs occurred in all pts. Grade ≥3 TRAEs occurred in 66.7% of pts in the TV+T cohort and 81.3% of pts in the TV+T+Chemo cohort. The most common Grade ≥3 TRAEs (incidence ≥20%) were decreased neutrophil count in the TV+T cohort, and decreased neutrophil count and decreased white blood cell count in the TV+T+Chemo cohort. TEAEs leading to dose reduction occurred in 17.9% (Grade ≥3: 12.8%) and 43.8% (Grade ≥3: 18.8%) of pts, respectively. TEAEs led to treatment discontinuation occurred in 15.4% (Grade ≥3: 7.7%) and 31.3% (Grade ≥3: 28.1%), respectively. No treatment-related deaths were reported. Conclusions: TV+T, with or without chemotherapy, demonstrated encouraging anti-tumor activity and manageable safety as first-line treatment for CLDN18.2-positive advanced G/GEJ cancer. The doublet shows comparable efficacy to the triplet with enhanced tolerability, supporting further large-scale clinical investigation. Clinical trial information: NCT05934331 .