First-Line Disitamab Vedotin, Tislelizumab, and S-1 in HER2-Overexpressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Arm, Phase II Trial
Mené sur 57 patients atteints d'un adénocarcinome HER2+ avancé de l'estomac ou de la jonction oesogastrique, cet essai multicentrique de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement de première ligne combinant disitamab védotin, tislélizumab et S-1
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.
Journal of Clinical Oncology , article en libre accès, 2026