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

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Journal: Nature medicine

Phase 2 ILUSTRO Cohort 4 Overview

Phase 2 ILUSTRO cohort 4 evaluated adding zolbetuximab (anti‑CLDN18.2) and nivolumab to mFOLFOX6 as first‑line therapy for metastatic gastric/gastroesophageal junction adenocarcinoma that was HER2‑negative and CLDN18.2‑positive, with an emphasis on CLDN18.2‑high tumors.

Study Design and Population

  • Global, open‑label, phase 2 trial; cohorts 4A (safety lead‑in) and 4B (expansion).
  • 77 patients total; 85.5% had CLDN18.2‑high tumors.
  • Main efficacy endpoint for this cohort: investigator‑assessed PFS (RECIST v1.1).

Efficacy (Cohort 4B)

  • Median follow‑up: 11.5 months.
  • Overall (n = 71):
    • Median PFS: 14.8 months (95% CI 8.3 – not estimable).
    • ORR (measurable disease, n = 58): 62.1% (95% CI 48.4–74.5).
  • CLDN18.2‑high subgroup (n = 59):
    • Median PFS: 18.0 months (95% CI 11.1 – not estimable).
    • ORR (measurable disease, n = 47): 68.1% (95% CI 52.9–80.9).

Safety

  • Most common treatment‑emergent adverse events (cohorts 4A + 4B):
    • Nausea: 80.5%
    • Decreased appetite: 72.7%
  • Safety profile was considered acceptable for combination chemoimmunotherapy plus zolbetuximab.

Clinical Implications

  • The triplet regimen (zolbetuximab + mFOLFOX6 + nivolumab) showed promising PFS and response rates, particularly in CLDN18.2‑high disease, with manageable toxicity.
  • Findings support ongoing randomized phase 3 evaluation in CLDN18.2‑positive, PD‑L1‑positive metastatic gastric/GEJ adenocarcinoma (LUCERNA study; NCT03505320).

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