# Claudin 18.2-positive gastric cancer

Source: https://onco.cc/cancers/gastric-cldn18-2-positive/  
OnCo record `gastric-cldn18-2-positive` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: CLDN18.2-positive gastric cancer; Claudin 18.2-high gastro-oesophageal adenocarcinoma
- Tags: subtype-page
- Group: gastrointestinal
- Burden: 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.
- Subtypes: Claudin 18.2-positive (75 percent or more of cells, moderate to strong), HER2-negative; Claudin 18.2-positive diffuse-type gastric cancer; Claudin 18.2-positive with PD-L1 CPS 5 or above (sequencing question); Claudin 18.2-low (candidates for antibody-drug conjugates)
- Biomarkers: Claudin 18.2 by immunohistochemistry (VENTANA 43-14A; 75 percent threshold); HER2 (must be negative for zolbetuximab); PD-L1 combined positive score; Claudin 18.2 expression in metastases and after prior therapy

## Standard of care

- Advanced, first line: 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. ([SPOTLIGHT & GLOW](https://onco.cc/trials/spotlight-glow/), [Zolbetuximab](https://onco.cc/drugs/zolbetuximab/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [Claudin 18.2](https://onco.cc/targets/cldn18-2/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/))
- Second line: Ramucirumab with paclitaxel; claudin 18.2 antibody-drug conjugates and CAR-T in trials. ([Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Sonesitatug vedotin](https://onco.cc/drugs/cmg901/), [Satricabtagene autoleucel](https://onco.cc/drugs/satricabtagene-autoleucel/), [CLDN18.2 antibody first line → CLDN18.2 ADC or CAR-T on progression](https://onco.cc/pairings/cldn18-antibody-then-adc/))
- Toxicity management: Antiemetic prophylaxis and slowed infusion for the nausea and vomiting of the first cycles. ([Zolbetuximab](https://onco.cc/drugs/zolbetuximab/))

## State of the art

- Zolbetuximab is the first drug approved on a target other than HER2 or PD-L1 in stomach cancer and the first to reach the diffuse subtype.
- Two positive phase 3 trials with different chemotherapy backbones give the result unusual robustness.
- Antibody-drug conjugates and CAR-T against claudin 18.2 aim to treat tumours with lower expression and later lines.

## Open problems

- Whether zolbetuximab or PD-1 blockade should come first when both PD-L1 and claudin 18.2 are positive.
- Tumours below the 75 percent threshold have no approved claudin 18.2 therapy.
- Nausea and vomiting lead some patients to stop early.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Zolbetuximab
- SPOTLIGHT (Lancet 2023): https://pubmed.ncbi.nlm.nih.gov/37068504/
- GLOW (Nature Medicine 2023): https://pubmed.ncbi.nlm.nih.gov/37524953/
- Wikipedia: https://en.wikipedia.org/wiki/Zolbetuximab

## Connected records

- trials: [SPOTLIGHT & GLOW](https://onco.cc/trials/spotlight-glow/)
- drugs: [ASP2138](https://onco.cc/drugs/asp2138/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [LM-302](https://onco.cc/drugs/lm-302/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Satricabtagene autoleucel](https://onco.cc/drugs/satricabtagene-autoleucel/), [Sonesitatug vedotin](https://onco.cc/drugs/cmg901/), [Zolbetuximab](https://onco.cc/drugs/zolbetuximab/)
- pairings: [CLDN18.2 antibody first line → CLDN18.2 ADC or CAR-T on progression](https://onco.cc/pairings/cldn18-antibody-then-adc/)
- ideas: [Biomarker-directed first-line quadruplets in gastric cancer](https://onco.cc/ideas/idea-biomarker-quadruplet-gastric/)
- targets: [Claudin 18.2](https://onco.cc/targets/cldn18-2/)
- cancers: [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/)

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