Disitamab vedotin (DV) plus toripalimab (Tor) and chemotherapy (C)/trastuzumab (Tra) as first-line (1L) treatment of patients (pts) with HER2-expressing locally advanced or metastatic (la/m) gastric cancer.

LBA4012 Background: DV+T showed encouraging efficacy with manageable safety for pts with HER2-expressing gastric or gastroesophageal junction (G/GEJ) cancer in the second- and later-line setting in a phase 1 trial (Wang et al, eClinicalMedicine, 2024). Here, we first report the efficacy and safety of 1L DV+Tor+C/Tra in pts with HER2-postive or HER2-low la/m G/GEJ cancer from the randomized phase 2 part of a seamless phase 2/3 trial. Methods: Pts with previously untreated HER2-positive (IHC 3+, or IHC 2+/FISH+) la/m G/GEJ cancer were randomized (1:1:1) to receive DV (2.5 mg/kg, Q2W) + Tor (3.0 mg/kg, Q2W) + CAPOX (oxaliplatin [OX]: 130 mg/m 2 , day 1; capecitabine [CAP]: 1000 mg/m 2 , days 1-14; Q3W) (experimental group [EG] 1), or DV + Tor +Tra (staring dose of 8 mg/kg followed by 6 mg/kg, Q3W) (EG2), or Tor + Tra + CAPOX (control group [CG] 1). For pts with HER2-low (IHC 1+, or IHC 2+/FISH-) la/m G/GEJ cancer, they were initially randomized (1:1) to receive DV (2.5 mg/kg) + Tor + CAPOX (EG1), or Tor + CAPOX (CG1) in stage 1; based on the safety data from stage 1, stage 2 was designed to randomize pts (1:1:1) to receive DV (2.5 mg/kg) + Tor + CAPOX (reduced dose: OX 100 mg/m 2 ; CAP 750 mg/m 2 ) (EG2), or DV (2.0 mg/kg) + Tor + CAPOX (reduced dose) (EG3), or Tor + CAPOX (CG2). The primary endpoint was objective response rate (ORR). Results: By date cutoff (Feb 7, 2025), 51 HER2-positive pts (mostly being HER2 IHC 3+) and 93 HER2-low pts (mostly being HER2 IHC 1+) were enrolled. In HER2-positive pts, superior ORR of 82.4% was observed in EG2. In HER2-low pts, the ORR was 70.8% in EG1 and the hazard ratio (HR) for PFS was 0.67 compared to CG1 in stage 1, which favored the experimental group; the highest ORR was 76.9% in EG2 in stage 2. Main outcomes are listed in the Table. Data will be updated during presentation. Conclusions: In pts with HER2-positive la/m G/GEJ cancer, DV + Tor + Tra demonstrated a superior ORR, offering a potential chemo-free treatment option. In pts with HER2-low la/m G/GEJ cancer, DV + Tor + CAPOX showed superior ORR and PFS with a manageable safety profile; lowering the CAPOX dose improved tolerability of the combination therapy while maintaining high efficacy. Clinical trial information: NCT05980481 . HER2-positive pts HER2-low pts / Stage 1 Stage 2 (dose optimization) EG1 (n=18) EG2 (n=17) CG1 (n=16) EG1 (n=25) CG1 (n=23) EG2 (n=14) EG3 (n=15) CG2 (n=16) Confirmed ORR*, % (95% CI) 66.7(41.0-86.7) 82.4(56.6-96.2) 68.8(41.3-89.0) 70.8(48.9-87.4) 47.8(26.8-69.4) 76.9(46.2-95.0) 60.0(32.3-83.7) 46.7(21.3-73.4) Median PFS follow-up, months 11.2 12.2 12.2 9.7 5.6 Median PFS (95% CI), months Immature 9.7(5.8-NE) 7.2(5.4-11.3) Immature HR / 0.67 / Any-G/G ≥3 TRAEs, % 100/94.4 100/82.4 100/75.0 100/100 100/87.0 100/85.7 100/73.3 100/75.0 *In pts with ≥1 post-baseline tumor assessment. PFS, progression-free survival; NE, not estimable; G, grade; TRAE, treatment-related adverse event.