First-Line Disitamab Vedotin, Tislelizumab, and S-1 in HER2-Overexpressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Arm, Phase II Trial

PURPOSE: Clinical data for first-line combination of antibody-drug conjugates (ADC) and immune checkpoint inhibitors in human epidermal growth factor receptor 2 (HER2)-overexpressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma remain limited. We evaluated the efficacy and safety of disitamab vedotin (a HER2-directed ADC) combined with tislelizumab (a PD-1 inhibitor) and oral fluoropyrimidine S-1 as first-line therapy for patients with advanced HER2-overexpressing (immunohistochemistry [IHC] 3+ or 2+, regardless of in situ hybridization [ISH] status) G/GEJ adenocarcinoma. METHODS: In this single-arm, multicenter, phase II trial, patients received disitamab vedotin (2.5 mg/kg, once on day 1), tislelizumab (200 mg, once on day 1), and S-1 (40-60 mg, twice daily, days 1-14) in 21-day cycles. The primary end point was confirmed objective response rate (ORR) by independent central review (RECIST v1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. RESULTS: Fifty-seven patients (median age 65; IHC 3+ 71.9%, IHC 2+/ISH+ 17.5%, IHC 2+/ISH- 10.5%; PD-L1 combined positive score [CPS] <1 54.4%) were enrolled. The confirmed ORR was 89.5% (95% CI, 78.5 to 96.0). At a median follow-up of 28.2 months, the median PFS (mPFS) was 13.8 months (95% CI, 10.3 to 24.0), the median OS (mOS) reached 31.9 months (95% CI, 22.1 to not reached), and the median DoR was 13.3 months (95% CI, 9.6 to not reached). Patients with CPS ≥1 achieved an ORR of 92.3%, mPFS of 16.7 months, and mOS of 31.9 months; in the CPS <1 subgroup, the ORR was 87.1% with an mPFS of 10.0 months, and mOS of 25.4 months. Grade ≥3 treatment-related adverse events occurred in 64.9% of patients, primarily hematologic and peripheral neuropathy. CONCLUSION: First-line disitamab vedotin with tislelizumab and S-1 demonstrated remarkable antitumor activity and a manageable safety profile in HER2-overexpressing advanced G/GEJ adenocarcinoma, warranting validation in randomized controlled trials.