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

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 .