Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial

  • Nat Med. 2023 Aug;29(8):2133-2141. doi: 10.1038/s41591-023-02465-7.
Manish A Shah  1 ,  Kohei Shitara  2 ,  Jaffer A Ajani  3 ,  Yung-Jue Bang  4 ,  Peter Enzinger  5 ,  David Ilson  6 ,  Florian Lordick  7 ,  Eric Van Cutsem  8 ,  Javier Gallego Plazas  9 ,  Jing Huang  10 ,  Lin Shen  11 ,  Sang Cheul Oh  12 ,  Patrapim Sunpaweravong  13 ,  Hwoei Fen Soo Hoo  14 ,  Haci Mehmet Turk  15 ,  Mok Oh  16 ,  Jung Wook Park  16 ,  Diarmuid Moran  16 ,  Pranob Bhattacharya  16 ,  Ahsan Arozullah  16 ,  Rui-Hua Xu  17
Affiliations
  • 1. Weill Cornell Medical College, New York City, NY, USA.
  • 2. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan.
  • 3. The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 5. Center for Esophageal and Gastric Cancer, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6. Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
  • 7. Department of Medicine and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany.
  • 8. Digestive Oncology, University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium.
  • 9. Department of Medical Oncology, Hospital General Universitario de Elche, Elche, Spain.
  • 10. Department of Medical Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 11. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
  • 12. Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
  • 13. Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.
  • 14. Department of Oncology and Radiotherapy, Penang Hospital, Penang, Malaysia.
  • 15. Department of Medical Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey.
  • 16. Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
  • 17. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. [email protected].
PMID: 37524953 DOI: 10.1038/s41591-023-02465-7
Abstract

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .