Disitamab vedotin (DV) plus toripalimab (Tor) and chemotherapy (Chemo)/trastuzumab (Tra) for first-line (1L) HER2-expressing locally advanced or metastatic (la/m) gastric cancer (GC): Updated results from the RC48-C027 trial.

LBA4026 Background: For patients (pts) with HER2-high (defined as IHC 3+, or IHC 2+/FISH+ based on Chinese CSCO GC guidelines) GC, current 1L therapy consisting of trastuzumab combined with pembrolizumab and chemotherapy offers limited efficacy. For pts with HER2-intermediate/low (defined as IHC 1+, or IHC 2+/FISH- as per Chinese guidelines) GC, no HER2-targeted precision treatment is available. Previous analysis of the RC48-C027 randomized phase 2 part showed notable objective response rates (ORRs): 82.4% with DV + Tor + Tra in HER2-high GC; 72.0% with DV + Tor + CAPOX (oxaliplatin and capecitabine) in HER2-intermediate/low GC, and lowering the CAPOX dose showed improved safety while maintaining efficacy (ORR: 71.4%) (Shen et al. J Clin Oncol. 2025). We report updated results with extended follow-up, including tumor response, mature progression-free survival (PFS), and overall survival (OS) data. Methods: Pts with HER2-high, untreated, la/m gastric/gastroesophageal junction (G/GEJ) cancer were randomized at a ratio of 1:1:1 to receive DV + Tor + CAPOX (DTC), or DV + Tor +Tra (DTT), or Tor + Tra + CAPOX (TTC). For HER2-intermediate/low, untreated, la/m G/GEJ cancer, pts were randomized at 1:1 to receive DV + Tor + CAPOX (DTC), or Tor + CAPOX (TC) in Stage 1; to enhance the overall tolerability, Stage 2 was initiated and randomized pts at 1:1:1 to receive DV + Tor + dose-reduced CAPOX (DTCr), or dose-reduced DV + Tor + dose-reduced CAPOX (DrTCr), or Tor + CAPOX (TC). The primary endpoint was ORR; secondary endpoints included PFS, duration of response (DoR), OS, and safety. Results: By the data cutoff (Jan 16, 2026), durable responses, a clinically meaningful improvement in PFS, and a favorable trend in OS were observed with DTT and DTCr. No new safety signals emerged. More outcomes are detailed in the Table. Conclusions: With extended follow-up, DTT and DTCr demonstrated sustained and clinically meaningful efficacy as 1L treatments for HER2-high and HER2-intermediate/low G/GEJ cancer, respectively. These findings warrant further confirmation in phase 3 trials. Clinical trial information: NCT05980481 . HER2-high pts HER2-intermediate/low pts / Stage 1 Stage 2 DTC (n=18) DTT (n=17) TTC * (n=16) DTC (n=25) TC * (n=23) DTCr (n=14) DrTCr (n=15) TC * (n=16) OS follow-up (m), median 23.3 21.3 16.6 Confirmed ORR ^ , % (95% CI) 66.7(41.0-86.7) 82.4(56.6-96.2) 68.8(41.3-89.0) 75.0(53.3-90.2) 47.8(26.8-69.4) 76.9(46.2-95.0) 66.7(38.4-88.2) 60.0(32.3-83.7) DoR (m), median NR NR 13.9 12.4 10.0 NR 12.9 10.6 PFS (m), median (95% CI) NR(8.2-NR) 18.0(8.5-NR) 13.8(3.1-19.6) 9.9(5.8- NR) 7.2(5.4-11.3) 9.5(4.8-NR) 12.7(2.4-NR) 9.9(2.8-13.4) HR 0.39 0.58 / 0.58 / 0.59 0.70 / OS (m), median</jat