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Publications

Journal Article Ahead of print

PubMed: 41840238 DOI: 10.1038/s41591-026-04306-9

First-line zolbetuximab plus mFOLFOX6 and nivolumab in unresectable CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: a phase 2 trial.

Nat Med

Authors: Kohei Shitara, Hirokazu Shoji, Nicola Fazio, Sara Lonardi, Keun-Wook Lee, Li-Yuan Bai, Kensei Yamaguchi, Jean-Philippe Metges, Gianluca Masi, Denis Smith, Tae-Yong Kim, Maria Matsangou, Archita Shrivastava, Miaomai Zhou, Jason Hill, Abraham Guerrero, Xuewei Wang, Aziz Zaanan, Samuel J Klempner

Affiliations

  • Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan.
  • Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
  • Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
  • Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
  • Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and College of Medicine, China Medical University, Taichung, Taiwan.
  • Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of JFCR, Tokyo, Japan.
  • Institut de Cancerologie et d'Hematologie, ARPEGO Network CHU Morvan, Brest, France.
  • Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa and Division of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
  • Department of Digestive Oncology, CHU Bordeaux, Pessac, France.
  • Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Astellas Pharma Global Development, Inc. Northbrook, IL, USA.
  • Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, University of Paris Cité, Paris, France.
  • Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital Center, Boston, MA, USA.

Abstract

There is an unmet need for effective and safe treatments for patients with metastatic gastric/gastroesophageal junction (mG/GEJ) adenocarcinoma. Targeting claudin 18 isoform 2 (CLDN18.2) and programmed death ligand 1 (PD-L1), represents a promising strategy. Zolbetuximab, a CLDN18.2-targeting antibody, plus chemotherapy improved survival outcomes in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative mG/GEJ adenocarcinoma. Cohort 4 of the global, open-label, phase 2 ILUSTRO study examined first-line zolbetuximab plus mFOLFOX6 and nivolumab (a PD-L1 inhibitor). Here we report results from cohorts 4A (safety lead-in phase) and 4B (expansion phase). The primary endpoint of ILUSTRO was specific to cohort 1 and was previously published; the main efficacy endpoint of interest for cohort 4 was progression-free survival (PFS), as assessed by the investigators per Response Evaluation Criteria in Solid Tumors version 1.1. At data cutoff (2 September 2025) for this final analysis, 77 patients were enrolled in 4A + 4B (85.5% with CLDN18.2-high tumors). Cohort 4B median follow-up was 11.5 months, and median PFS (95% confidence interval (CI)) was 14.8 months (8.3-not estimable) overall (n = 71) and 18.0 months (11.1-not estimable) in patients with CLDN18.2-high tumors (n = 59). Objective response rate (measurable disease; 95% CI) was 62.1% (48.4-74.5) in 4B overall (n = 58) and 68.1% (52.9-80.9) in CLDN18.2-high (n = 47). In 4A + 4B, the most common treatment-emergent adverse events were nausea (80.5%) and decreased appetite (72.7%). Efficacy and safety data support randomized evaluation of zolbetuximab plus chemoimmunotherapy in patients with CLDN18.2-positive and PD-L1-positive mG/GEJ adenocarcinoma in the ongoing phase 3 LUCERNA study. ClinicalTrials.gov: NCT03505320 .

MeSH

Safety, Esophagogastric Junction, Neoplasms, Adenocarcinoma, Nivolumab, Therapeutics