SPOTLIGHT: zolbetuximab, the first Claudin 18.2 antibody, added to chemotherapy in gastric cancer
In stomach cancers that express the protein Claudin 18.2, adding the antibody zolbetuximab to chemotherapy extended survival by nearly three months, making Claudin 18.2 a new biomarker to test for.
Double-blind phase 3 trial of 565 patients with untreated, HER2-negative, Claudin 18.2-positive (moderate-to-strong staining in 75% or more of tumour cells) locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, randomised to zolbetuximab or placebo plus mFOLFOX6. Primary endpoint was PFS.
Median PFS was 10.6 vs 8.7 months (HR 0.75) and median OS 18.2 vs 15.5 months (HR 0.75). Together with the GLOW trial (zolbetuximab plus CAPOX) it led to approvals in 2024 and made Claudin 18.2 testing routine for HER2-negative gastric cancer, while opening a target now pursued by ADCs and CAR-T cells.
- Median PFS 10.61 vs 8.67 months; HR 0.751 (95% CI 0.598-0.942).
- Median overall survival 18.23 vs 15.54 months; HR 0.750 (95% CI 0.601-0.936).
- About 38% of screened patients were Claudin 18.2-positive by the trial definition.
- Nausea (81% vs 61%) and vomiting (65% vs 35%) were much more common with zolbetuximab, particularly during the first infusions.
- GLOW (Nature Medicine 2023) confirmed the result with CAPOX: PFS 8.2 vs 6.8 months (HR 0.69), OS 14.4 vs 12.2 months (HR 0.77).
Patients with newly diagnosed advanced stomach cancer should now have Claudin 18.2 tested alongside HER2, PD-L1 and mismatch repair, because roughly a third will be eligible for zolbetuximab, which adds about three months of median survival. The main practical problem is nausea and vomiting during infusions, which needs aggressive prophylaxis. How to sequence or combine it with immunotherapy in PD-L1-positive tumours is unresolved.
- The PD-L1-positive population, who would now receive nivolumab or pembrolizumab with chemotherapy, was not addressed; the trials predate that standard.
- Claudin 18.2 immunohistochemistry cut-off (75% of cells at 2+/3+) is stringent and assay standardisation is incomplete.
- Gastrointestinal toxicity leads to infusion interruptions in many patients.
- Modest absolute gains for a costly antibody.
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