Perioperative chemotherapy plus disitamab vedotin (RC48) and toripalimab in HER2-overexpressed locally advanced gastric or gastroesophageal junction cancer (PERISCOPE-02): An open-label, single-arm, phase 2 trial.

4080 Background: The use of Disitamab vedotin (RC48) and programmed death-1 (PD-1) inhibitor is effective in patients with HER2-expressing advanced gastric or gastroesophageal junction (G/GEJ) cancer. However, their use has not been investigated in patients with localized disease. This trial evaluated the safety and anti-tumor activity of perioperative chemotherapy combined with RC48 and toripalimab in the treatment of locally advanced HER2-overexpressed (defined as IHC 2+ or 3+) G/GEJ cancer. Methods: This study was an investigator-initiated, open-label, single-arm, phase 2 trial was conducted at Sun Yat-sen University Cancer Center. Eligible patients with HER2-overexpressed locally advanced G/GEJ cancer received 3-4 cycles of neoadjuvant XELOX plus RC48 and toripalimab, followed by surgery. The primary endpoint was TRG 0/1 after neoadjuvant treatment. This study is registered at Chinese Clinical Trial Registry (ChiCTR2400081677). Results: Between July 11, 2024, and July 11, 2025, of 26 patients screened for eligibility, 25 patients were enrolled, all patients had no distant metastasis confirmed by laparoscopic exploration and ascitic fluid cytology, 20 (80%) patients had clinical stage III disease and 5(20%) with stage II. Of these 25 patients, the median age was 58 (IQR, 37-74) years. Tumors were located in the stomach in 21(84%) patients and in the gastroesophageal junction in 4 (16%) patients. The patients with HER2 IHC expression of 2+ and 3+ was 21 (84%) and 4 (16%) respectively. 15 (60%) patients had the PD-L1 CPS of 1 or more, 24 (96%) patients were pMMR. The primary endpoint of TRG 0/1 was met in 16 (64%) patients, 9 (36%) patients achieved pCR (ypT0N0), and 24 (96%) were ypN0. 10 (40%) patients experienced grade 3 treatment-related adverse events, the most common treatment-related adverse events were increased ALT or AST (5 [20%] patients) and neutropenia (3 [12%] patients), no grade 4 treatment-related adverse events. Surgical morbidity (Clavien-Dindo II/III) occurred in 2 of 25 (8%) patients, with no 30-day surgical mortality. Conclusions: Our findings suggested that perioperative chemotherapy plus RC48 and toripalimab had controllable safety and showed encouraging efficacy in patients with HER2-overexpressed G/GEJ cancer. Clinical trial information: ChiCTR2400081677.