ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2–Positive Gastric or Gastroesophageal Junction Adenocarcinoma

Abstract Purpose: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients and Methods: This phase II study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n = 30), with mFOLFOX6 in first-line (Cohort 2, n = 21), or with pembrolizumab in third/later-line (Cohort 3A, n = 3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). Results: ORR was 0% in Cohorts 1A and 3A, and 71.4% [95% confidence interval (CI), 47.82–88.72] in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31–2.56) in Cohort 1A, 2.96 months (95% CI, 1.48–4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05–25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27–11.53). Gastrointestinal adverse events occurred across cohorts [nausea, 63%–90% (grade ≥ 3, 4.8%–6.7%) and vomiting, 33%–67% (grade ≥ 3, 6.7%–9.5%)]. Conclusions: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2-positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.