First-line zolbetuximab plus mFOLFOX6 and nivolumab in unresectable CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: a phase 2 trial
Year: 2026
Type: article
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 .
Source: Nature Medicine
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
Institutions: National Cancer Center Hospital East, National Cancer Center Hospital, European Institute of Oncology, Istituto Oncologico Veneto, Seoul National University, Seoul National University Bundang Hospital, China Medical University, China Medical University Hospital, The Cancer Institute Hospital, Japanese Foundation For Cancer Research, University of Pisa, Azienda Ospedaliera Universitaria Pisana, Centre Hospitalier Universitaire de Bordeaux, Seoul National University Hospital, Astellas Pharma (United States), Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Massachusetts General Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funder: Astellas Pharma
OpenAlex ID: W7137018602