Background
Phase III double-blind RCT, N=565, CLDN18.2-positive (≥75% tumor cells with moderate/strong membranous staining), HER2-negative, previously untreated locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. 215 centers, 20 countries. SPOTLIGHT tested zolbetuximab (anti-CLDN18.2 monoclonal antibody) + mFOLFOX6 vs placebo + mFOLFOX6.
Interventions and follow up
Arm A: Zolbetuximab 800 mg/m² loading dose → 600 mg/m² q3wk + mFOLFOX6 q2wk
Arm B: Placebo + mFOLFOX6 q2wk
Primary endpoint: Progression-free survival (by independent review)
Follow-up: 12.9 mo (PFS analysis)
Arm B: Placebo + mFOLFOX6 q2wk
Primary endpoint: Progression-free survival (by independent review)
Follow-up: 12.9 mo (PFS analysis)
Results
mPFS: 10.61 vs 8.67 mo, HR 0.75, 95% CI 0.60–0.94, P=.0066
mOS: 18.23 vs 15.54 mo, HR 0.75, 95% CI 0.60–0.94, P=.0053
mOS: 18.23 vs 15.54 mo, HR 0.75, 95% CI 0.60–0.94, P=.0053
Adverse events
Grade ≥3 (any): 87% (zolbetuximab) vs 78% (placebo); most common grade ≥3 GI events were nausea, vomiting, decreased appetite (more common with zolbetuximab).
Treatment-related deaths / discontinuation: deaths 5 (2%) vs 4 (1%); discontinuation due to AEs 14% vs 9%.
Treatment-related deaths / discontinuation: deaths 5 (2%) vs 4 (1%); discontinuation due to AEs 14% vs 9%.
Conclusions
Zolbetuximab + mFOLFOX6 significantly improved both PFS and OS vs placebo + mFOLFOX6 in CLDN18.2-positive, HER2-negative gastric/GEJ adenocarcinoma (mOS 18.23 vs 15.54 mo, HR 0.75), establishing CLDN18.2 as the first new targetable biomarker in this disease and adding a new first-line option in biomarker-selected patients.
Key Limitations
Requires CLDN18.2-positive selection (~40% of unselected patients); standardized IHC scoring for CLDN18 is not widely available. GI toxicity (nausea, vomiting) with zolbetuximab is clinically significant. Concurrent immunotherapy was not evaluated; IO + zolbetuximab + chemo combinations are under study. PD-L1 co-expression adds complexity to patient selection.
Clinical Context
FDA approved zolbetuximab + mFOLFOX6 (or CAPOX, based on GLOW) for CLDN18.2-positive, HER2-negative gastric/GEJ adenocarcinoma. Both SPOTLIGHT (mFOLFOX6 backbone) and GLOW (CAPOX backbone) were positive (HR ~0.75 for PFS and OS). CLDN18.2 and PD-L1 can co-express; optimal biomarker sequencing for IO + zolbetuximab is under investigation. ESMO recognizes CLDN18.2 as a validated first-line biomarker.
References