Efficacy and safety of disitamab vedotin (RC48) combined with camrelizumab and S‐1 for neoadjuvant therapy of locally advanced gastric cancer with HER2‐overexpressing: Preliminary results of a prospective, single‐arm, phase II study

PURPOSE: Perioperative treatment of gastric and gastroesophageal junction (G/GEJ) cancer is evolving towards multimodal strategies incorporating HER2-targeted therapy, immunotherapy and chemotherapy. Disitamab vedotin (RC48), an HER2-targeted antibody-drug conjugate, shows promising antitumour activity and potential synergy with immune checkpoint inhibitors. This study evaluated neoadjuvant RC48 combined with camrelizumab and S-1 in resectable HER2-overexpressing locally advanced G/GEJ adenocarcinoma. METHODS: Patients with histologically confirmed HER2-overexpressing (IHC 3+ or 2+) resectable G/GEJ cancer staged as cT3-4aN1-3M0 were enrolled in this prospective single-arm phase II study. Patients received three 3-weekly cycles of RC48, camrelizumab and S-1 before surgery. Pathological complete response (pCR) was defined as the primary endpoint, whereas major pathological response (MPR), objective response rate (ORR), tumour downstaging, disease-free survival (DFS), overall survival (OS) and safety were evaluated as secondary endpoints. Exploratory circulating tumour DNA (ctDNA) methylation profiling (PredicineEPIC) assessed molecular response dynamics and ERBB2 copy number variation. RESULTS: From 18 September 2022 to 12 December 2024, 32 patients were enrolled; 24 proceeded to D2 resection. The ORR after neoadjuvant therapy was 80.0% (24/30). In the surgical cohort, pCR and MPR were achieved in 25.0% (6/24) and 45.8% (11/24) of patients, respectively, with an R0 resection rate of 100%. The median DFS and OS were not reached at the time of analysis. In the ctDNA substudy (n = 14), methylation-derived tumour fraction declined during therapy and ERBB2 plasma copy number gain aligned with tissue HER2 status. Treatment-related adverse events of grade ≥3 were reported in 31.3% of patients. CONCLUSION: Neoadjuvant RC48 combined with camrelizumab and S-1 showed potential antitumour activity with an acceptable safety profile in HER2-overexpressing locally advanced resectable G/GEJ adenocarcinoma. KEY POINTS: Neoadjuvant RC48 plus camrelizumab and S-1 showed encouraging pathological responses in HER2-overexpressing gastric cancer. The regimen achieved a pCR rate of 25% and an MPR rate of 45.8%. The combination therapy demonstrated a manageable safety profile. Exploratory ctDNA methylation analysis suggested potential for dynamic response monitoring.