Phase 2 study of zolbetuximab plus mFOLFOX6 in claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ): ILUSTRO cohort 2

e16063 Background: One accepted treatment for patients (pts) with advanced HER2-negative G/GEJ is mFOLFOX6 (5-FU, folinic acid, oxaliplatin). Despite treatment options, 5-year survival is poor, and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a tight junction protein normally confined to gastric mucosa of healthy tissue, is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Nonclinical results showed that cytotoxic chemotherapy increased CLDN18.2 expression, improving ADCC/CDC activity of zolbetuximab. Phase 2 results (NCT01630083, FAST) showed prolonged survival with zolbetuximab+EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. This study assessed antitumor activity and safety/tolerability of first-line zolbetuximab+mFOLFOX6 (Cohort 2 in NCT03505320) in G/GEJ with high CLDN18.2 expression. Methods: Cohort 2 of this multicohort study enrolled adult pts with metastatic or locally advanced unresectable G/GEJ. Patients had measurable disease (RECIST v1.1), HER2-negative disease, and high CLDN18.2 expression (≥75% of tumor cells demonstrating moderate-to-strong membranous staining by central IHC testing). Patients received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 3 then 600 mg/m2 Q3W. Zolbetuximab and mFOLFOX (Q2W from Cycle 1 Day 1) were administered in 42-day cycles. Key endpoints were safety/tolerability and objective response rate by independent central review (ORRICR RECIST v1.1). Results: As of Jan 26, 2021, Cohort 2 had enrolled 21 pts; median age was 63 years (range, 36-74), 57% were male, 43% were Asian, and 38% were white. Of 19 evaluable pts, 12 had confirmed partial responses; ORRICR was 63.2% (95% CI: 38.4-83.7) (Table). Median PFS was 13.7 months (95% CI: 7.4-not estimable); 12-month PFS rate was 58%. Common adverse events (AEs) were nausea (90.5%; grade 3, 4.8%) and vomiting (61.9%; grade 3, 9.5%). Common grade 3/4 AEs were decreased neutrophil count (33.3%) and neutropenia (28.6%). There were no fatal AEs. Conclusions: Results suggest promising antitumor activity with zolbetuximab+mFOLFOX6 in metastatic or locally advanced G/GEJ. The safety profile was manageable and no new safety signals were identified. Clinical trial information: NCT03505320. [Table: see text]