Efficacy and safety of disitamab vedotin (DV) combined with trastuzumab, and tislelizumab versus chemotherapy (CAPOX) combined with trastuzumab ± pembrolizumab for patients with first-line HER2-high advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJA): A randomized controlled phase 3 trial.

TPS4245 Background: Patients (pts) with HER2-high (defined as IHC 3+, or IHC 2+/FISH+ according to Chinese Society of Clinical Oncology Gastric Cancer Guidelines) advanced G/GEJA continue to face a poor prognosis. Although adding pembrolizumab to trastuzumab and chemotherapy significantly improved overall survival in this pts population with a PD-L1 combined positive score (CPS) ≥1 in the first-line (1L) setting, there remains an unmet need for more effective treatment options. DV (anti-HER2 antibody-drug conjugate) is approved as monotherapy for the treatment of pts with HER2 IHC 2+/3+ advanced G/GEJA in China. In the randomized phase 2 part of the RC48-C027 trial, DV + trastuzumab + an anti-PD-1 agent showed a promising objective response rate (ORR) in 1L HER2-high advanced G/GEJA compared with the control (82.4% vs. 68.8%) (Shen et al. J Clin Oncol. 2025). Building on these results, the open-label randomized phase 3 RC48-C040 trial is designed to assess the efficacy and safety of DV + trastuzumab + tislelizumab versus chemotherapy + trastuzumab ± pembrolizumab in pts with previously untreated, HER2-high, advanced G/GEJA (NCT07315750). Methods: The key eligibility criteria are pts aged 18-75 years with histologically confirmed unresectable locally advanced or metastatic G/GEJA; central lab-confirmed high HER2 expression; no previous systemic treatment for locally advanced or metastatic gastric cancer; and at least one assessable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Pts with central nervous system metastasis and/or carcinomatous meningitis are ineligible. The planned sample size is 555. Pts will be randomized (2:1) to receive DV (2.5 mg/kg, intravenously IV, Q2W) + trastuzumab (staring dose of 8 mg/kg followed by 6 mg/kg, IV, Q3W) + tislelizumab (200 mg, IV, Q3W) or to receive CAPOX (oxaliplatin: 130 mg/m², IV, Q3W for up to 6 doses; capecitabine: 1000 mg/m², orally, BID, days 1-14 every 3 weeks) + trastuzumab ± pembrolizumab (200 mg/kg, IV, Q3W) until occurrence of disease progression, intolerable toxicity, or initiation of new anti-tumor treatment. Randomization will be stratified by HER2 expression (IHC 2+/FISH+ or IHC 3+), PD-L1 expression (CPS < 1 or 1≤CPS < 10 or CPS≥10), and liver metastasis (presence or absence). The primary endpoint is progression-free survival (PFS) assessed by the Blinded Independent Review Committee as per RECIST v1.1. The secondary endpoints include overall survival, investigator-assessed PFS, ORR, disease control rate, duration of response, patient-reported outcomes, adverse events, pharmacokinetic parameters, and immunogenicity. This study started in January 2026; enrollment is ongoing in China. Clinical trial information: NCT07315750 .