FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma

  • Ann Oncol. 2021 May;32(5):609-619. doi: 10.1016/j.annonc.2021.02.005.
U Sahin  1 ,  Ö Türeci  2 ,  G Manikhas  3 ,  F Lordick  4 ,  A Rusyn  5 ,  I Vynnychenko  6 ,  A Dudov  7 ,  I Bazin  8 ,  I Bondarenko  9 ,  B Melichar  10 ,  K Dhaene  11 ,  K Wiechen  12 ,  C Huber  13 ,  D Maurus  14 ,  A Arozullah  15 ,  J W Park  15 ,  M Schuler  16 ,  S-E Al-Batran  17
Affiliations
  • 1. Department of Experimental and Translational Oncology, TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Department of Oncology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany.
  • 2. Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH.
  • 3. Department of Oncology, City Clinical Oncology Center, St. Petersburg, Russia.
  • 4. Department of Medicine II and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany.
  • 5. Department of Oncology, Transcarpathian Regional Clinical Oncological Center, Uzhhorod, Ukraine.
  • 6. Sumy State University, Sumy Regional Clinical Oncology Center, Oncothoracic Department, Sumy, Ukraine.
  • 7. Department of Oncology, Acibadem City Clinic Mladost, Sofia, Bulgaria.
  • 8. Department of Clinical Pharmacology and Chemotherapy, Russian Oncology Research Center n. a. N.N. Blokhin, Moscow, Russia.
  • 9. Dnipropetrovsk Medical Academy, City Multispecialty Clinical Hospital #4, Department of Chemotherapy, Dnipropetrovsk, Ukraine.
  • 10. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
  • 11. MD Dhaene Pathology Lab BVBA, Destelbergen, Belgium.
  • 12. Department of Pathology, Klinikum Worms GmbH, Institute for Pathology, Worms, Germany.
  • 13. Department of Experimental and Translational Oncology, TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH.
  • 14. Formerly of Ganymed Pharmaceuticals GmbH, Mainz, Germany.
  • 15. Astellas Pharma Global Development, Inc., Northbrook, USA.
  • 16. West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
  • 17. Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, Frankfurt, Germany. Electronic address: [email protected].
PMID: 33610734 DOI: 10.1016/j.annonc.2021.02.005
Abstract

Background: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms.

Patients and methods: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint.

Results: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone).

Conclusions: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Keywords
advanced gastric cancer; advanced gastroesophageal junction adenocarcinoma; advanced oesophageal adenocarcinoma; capecitabine (EOX); claudin 18.2; epirubicin; oxaliplatin; zolbetuximab.