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Claudin 18.2 is a tight-junction protein normally hidden inside stomach lining cells that becomes exposed on the surface of many stomach cancers. Zolbetuximab, an antibody against it, added to chemotherapy lengthens survival in tumours that express it strongly, and antibody-drug conjugates and CAR-T cells against the same target are in trials.
Claudin 18.2 is a tight-junction protein confined to the gastric mucosa in normal tissue; during malignant transformation the junctions break down and the protein is exposed on the cell surface, where an antibody can reach it. Expression is tested by immunohistochemistry with the 43-14A antibody, and the trial-defined positive threshold is moderate-to-strong membranous staining in at least 75 percent of tumour cells. Expression is retained in metastases and is as common in diffuse-type as in intestinal-type tumours, so it is the one target that reaches the poor-prognosis diffuse subgroup; HER2 and claudin 18.2 positivity rarely overlap.
Zolbetuximab, a chimeric IgG1 antibody that kills claudin 18.2-positive cells through antibody-dependent cytotoxicity and complement, was tested in two phase 3 trials in HER2-negative, claudin 18.2-positive advanced disease. SPOTLIGHT (Lancet 2023) added it to FOLFOX and extended median progression-free survival from 8.7 to 10.6 months and median overall survival from 15.5 to 18.2 months; GLOW (Nature Medicine 2023) added it to CAPOX and extended survival from 12.2 to 14.4 months. Japan approved zolbetuximab in March 2024, the FDA in October 2024 and Europe later that year; nausea and vomiting in the first cycles, from on-target binding to normal stomach lining, are its characteristic toxicity and are managed with slower infusion and antiemetics.
Because PD-L1 expression is common in the same tumours, the order in which zolbetuximab and PD-1 blockade should be used, or whether they should be combined, is unsettled; trials of zolbetuximab with pembrolizumab or nivolumab and chemotherapy are under way. A second wave of claudin 18.2 agents follows: antibody-drug conjugates such as CMG901 and LM-302, the bispecific ASP2138, and satricabtagene autoleucel, a CAR-T product that produced responses in Chinese patients with heavily pretreated disease.
About four in ten HER2-negative advanced gastric and junctional adenocarcinomas show claudin 18.2 on at least 75 percent of tumour cells, the threshold used in the zolbetuximab trials, making it the most widely shared drug target in stomach cancer.
Squamous cancers sit in the upper and middle oesophagus, adenocarcinomas at the junction and in the stomach; the stomach wall also gives rise to GIST from its pacemaker cells.
Same organ: Gastric & gastro-oesophageal junction cancer, HER2-positive gastric cancer, PD-L1-high gastric cancer, Microsatellite-unstable (MSI-high) gastric cancer, Early gastric cancer, Oesophageal squamous cell carcinoma, Oesophageal and junctional adenocarcinoma, Oesophageal cancer, Gastrointestinal stromal tumour (GIST), KIT exon 11-mutant GIST, PDGFRA D842V-mutant GIST, Imatinib-resistant GIST
Zolbetuximab with FOLFOX (SPOTLIGHT) or CAPOX (GLOW) in HER2-negative, claudin 18.2-positive disease; nivolumab or pembrolizumab with chemotherapy remains an alternative where PD-L1 is high.
Ramucirumab with paclitaxel; claudin 18.2 antibody-drug conjugates and CAR-T in trials.
Antiemetic prophylaxis and slowed infusion for the nausea and vomiting of the first cycles.
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This is the trial behind the first approval of a CAR-T therapy for a solid tumour, in China. The gain in progression-free survival is real but measured in weeks, 15 percent of patients randomised to satri-cel never received it, and nearly every treated patient had cytokine release syndrome, so the trade-off is very different from CAR-T in blood cancers. Overall survival is not reported in the abstract.
Zolbetuximab with either FOLFOX or CAPOX is a first-line standard for claudin 18.2-positive, HER2-negative gastric cancer, making claudin 18.2 testing routine.
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.
Ramucirumab-paclitaxel is the second-line standard for HER2-negative gastric cancer after chemo-immunotherapy, and the comparator for newer agents.
Query for this cancer: (TITLE:"Claudin 18.2-positive gastric cancer" OR ABSTRACT:"Claudin 18.2-positive gastric cancer" OR TITLE:"CLDN18.2-positive gastric cancer" OR ABSTRACT:"CLDN18.2-positive gastric cancer" OR TITLE:"Claudin 18.2-high gastro-oesophageal adenocarcinoma" OR ABSTRACT:"Claudin 18.2-high gastro-oesophageal adenocarcinoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Claudin 18.2-positive gastric cancer, not a curated reading list.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Fever of 38 C or higher is grade 1 CRS; fever with low blood pressure, fast heartbeat, breathlessness or low oxygen is grade 2 or higher. The labels carry a boxed warning and say to report fever immediately.
Temperature of 38 C or higher, or feeling shivery and unwell even without a fever. Antibody-drug conjugates suppress the bone marrow, and several carry a boxed warning for severe neutropenia.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
See all on the product pages:CAPOX (capecitabine, oxaliplatin)FOLFOX (5-FU, leucovorin, oxaliplatin)NivolumabPaclitaxel / nab-paclitaxelPembrolizumabRamucirumabSatricabtagene autoleucelSonesitatug vedotin·Printable cards in the navigator
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