Background
Phase III double-blind RCT, N=507, CLDN18.2-positive (≥75% tumor cells with moderate/strong membranous CLDN18 staining), HER2-negative, previously untreated locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Global trial. GLOW tested zolbetuximab (anti-CLDN18.2 mAb) + CAPOX vs placebo + CAPOX, complementing SPOTLIGHT which used mFOLFOX6.
Interventions and follow up
Arm A: Zolbetuximab 800 mg/m² loading dose → 600 mg/m² q3wk + capecitabine 1000 mg/m² bid d1–14 + oxaliplatin 130 mg/m² d1 q3wk (CAPOX)
Arm B: Placebo + CAPOX (same schedule)
Primary endpoint: Progression-free survival
Follow-up: ~12 mo (PFS)
Arm B: Placebo + CAPOX (same schedule)
Primary endpoint: Progression-free survival
Follow-up: ~12 mo (PFS)
Results
mPFS: 8.21 vs 6.80 mo, HR 0.687, 95% CI 0.544–0.866, P=.0007
mOS: 14.39 vs 12.16 mo, HR 0.771, 95% CI 0.615–0.965, P=.0118
mOS: 14.39 vs 12.16 mo, HR 0.771, 95% CI 0.615–0.965, P=.0118
Adverse events
Grade ≥3 (any): 72.8% (zolbetuximab) vs 69.9% (placebo); most common grade ≥3 GI events were nausea and vomiting (more frequent with zolbetuximab).
Treatment-related deaths / discontinuation: deaths 2% vs 1%; discontinuation due to AEs 13% vs 9%.
Treatment-related deaths / discontinuation: deaths 2% vs 1%; discontinuation due to AEs 13% vs 9%.
Conclusions
Zolbetuximab + CAPOX significantly improved both PFS and OS vs placebo + CAPOX in CLDN18.2-positive, HER2-negative gastric/GEJ adenocarcinoma (mOS 14.39 vs 12.16 mo, HR 0.77). Together with SPOTLIGHT, GLOW confirms zolbetuximab's activity across two chemotherapy backbones.
Key Limitations
CLDN18.2 positivity (~40% of unselected patients) requires IHC screening not universally available. GI toxicity (nausea/vomiting) is clinically significant. No pembrolizumab or nivolumab in control arm, which is now standard; CLDN18.2 + IO + chemo triplet combinations are under investigation. OS difference is modest (~2 mo); CLDN18.2 may overlap with MSI-H or PD-L1 populations.
Clinical Context
FDA approved zolbetuximab + CAPOX (GLOW) or mFOLFOX6 (SPOTLIGHT) for CLDN18.2-positive, HER2-negative gastric/GEJ cancer. CLDN18.2 joins PD-L1 CPS and HER2 as clinically relevant biomarkers in gastric cancer. Optimal IO combination with zolbetuximab is under study; MSI-H patients may benefit more from IO alone. ESMO recognizes CLDN18.2 as a validated first-line target.
References