Phase 2 ILUSTRO trial of 1L zolbetuximab plus mFOLFOX6 and nivolumab in patients with CLDN18.2+ locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

Abstract

LBA284 Background: The anti-CLDN18.2 antibody zolbetuximab plus chemotherapy has shown efficacy in patients with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. Here, we describe the efficacy analysis from cohort 4 of the phase 2 ILUSTRO (NCT03505320) for the 1L combination of zolbetuximab + mFOLFOX6 and nivolumab. Methods: Cohort 4 of ILUSTRO enrolled patients with HER2−, LA unresectable or mG/GEJ adenocarcinoma with CLDN18.2 expression (moderate to strong membranous CLDN18 staining by IHC in ≥50– < 75% [intermediate] or ≥75% [high] of tumor cells). Prior anticancer therapy for advanced disease was not allowed. Cohort 4B planned to enroll 65 patients overall to have 50 with high CLDN18.2 expression, providing 70–76% power to detect a PFS improvement (median 12 vs 8.5 months) compared with historical zolbetuximab + chemotherapy (1-sided α = 0.15). Cohort 4A (safety) determined the tolerable dose for the combination, which was used in cohort 4B (expansion): patients received a loading dose of zolbetuximab 800 mg/m 2 + nivolumab 240 mg and mFOLFOX6 on C1D1, followed by zolbetuximab 400 mg/m 2 + nivolumab 240 mg and mFOLFOX6 Q2W (D15, D29; 42-day cycles). Endpoints included PFS, ORR (both RECIST v1.1 by investigator), and safety. Results: At data cutoff (Sep 2, 2025), 22 (28.6%) of 77 patients enrolled in cohorts 4A+4B remained on zolbetuximab. Median PFS was 12.9 months (95% CI 10.8–23.6) in all patients and 14.8 months (11.0–NE) in those with high CLDN18.2 expression (n = 65), with median follow-up of 12.7 months. In cohort 4B, median PFS was 14.8 (8.3–NE) in all patients (n = 71) and 18.0 months (11.1–NE) in patients with high CLDN18.2 expression (n = 59). Among patients with measurable disease, ORR was 62.9% (95% CI 49.7–74.8) in all patients (n = 62) and 68.6% (54.1–80.9) in patients with high CLDN18.2 expression (n = 51). In patients with measurable disease in 4B, ORR was 62.1% (48.4–74.5) in all patients (n = 58) and 68.1% (52.9–80.9) in patients with high CLDN18.2 expression (n = 47). Adverse events (AEs) related to any treatment (TRAEs) occurred in 98.7% of patients; serious TRAEs occurred in 23.4%. TRAEs led to zolbetuximab discontinuation in 4 patients (5.2%). The most common AEs were nausea (80.5%), decreased appetite (72.7%), peripheral sensory neuropathy (45.5%), and neutrophil count decreased (45.5%). Conclusions: Zolbetuximab + mFOLFOX6 and nivolumab showed promising activity in patients with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma, particularly in those with high CLDN18.2 expression. AEs were consistent with the safety profile of zolbetuximab + chemotherapy. The ongoing phase 3 LUCERNA trial (NCT06901531) is assessing 1L zolbetuximab + pembrolizumab and chemotherapy in patients with HER2−, LA unresectable or mG/GEJ adenocarcinoma with CLDN18.2+ and PD-L1+ tumors. Clinical trial information: NCT03505320 .