DAWN trial: a prospective, multicenter, single-arm phase II study of neoadjuvant disitamab vedotin (RC48) in combination with adebrelimab, apatinib, and S-1 for locally advanced HER2-positive gastric cancer.

[BACKGROUND] Gastric cancer is the fifth most common malignancy worldwide and a major cause of cancer-related mortality, with over 750,000 deaths annually. Neoadjuvant chemotherapy remains the standard treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, but recent evidence suggests that incorporating immunotherapy could offer synergistic effects. However, clinical benefits are limited in patients with low HER2 expression or programmed death-ligand 1 (PD-L1) levels due to primary or acquired resistance. To address this, we are conducting a prospective study to evaluate the efficacy and safety of a four-drug neoadjuvant regimen combining RC48 [a HER2-targeted antibody-drug conjugate (ADC)], adebrelimab (a PD-L1 inhibitor), apatinib (a VEGFR2 inhibitor), and S-1 (an oral fluoropyrimidine) in patients with locally advanced HER2-positive gastric cancer.

[METHODS] The DAWN trial is a prospective, open-label, phase II clinical trial designed to enroll 32 treatment-naïve patients with resectable, locally advanced HER2-positive gastric adenocarcinoma. Eligible patients will receive 3-4 cycles of neoadjuvant therapy, with each cycle lasting 21 days. The treatment regimen includes: RC48: 2.5 mg/kg, intravenous (iv), day 1, every 3 weeks (q3w). Adebrelimab: 1,200 mg, iv, day 1, q3w. S-1: For patients with a body surface area (BSA) ≤1.5 m, 50 mg orally, twice daily (bid), days 1-14, q3w; for BSA >1.5 m, 60 mg orally, bid, days 1-14, q3w. Apatinib: 250 mg orally, once daily (qd), q3w. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, disease-free survival (DFS), overall survival (OS), and safety. All patients must provide written informed consent before enrollment. The study protocol was approved by the independent ethics committee at each participating institution.

[DISCUSSION] Previous preclinical and clinical studies have demonstrated the synergistic effects among chemotherapy, immunotherapy, anti-angiogenic therapy, and anti-HER2 antibody-drug conjugates (ADCs). We hypothesize that the combination of these four therapeutic strategies could significantly enhance treatment efficacy in HER2-positive gastric cancer, particularly in combined positive score (CPS) PD-L1-negative patients.

[TRIAL REGISTRATION] This study was registered at ClinicalTrials.gov (Identifier: NCT06385873).