What Is Claudin 18.2 (CLDN18.2)? Its Importance in Cancer Treatment, Testing and FDA Approvals
In this article
A comprehensive technical guide to changes in the microscopic bonds between cells during the cancer journey and to targeted smart-drug strategies.
Gastric cancer remains a challenging field in oncology because of high rates of diagnosis at advanced stages and limited treatment options. Targeted treatment options were restricted for many years, particularly in the HER2-negative group, which accounts for approximately 80% of patients. Identification of the Claudin 18.2 (CLDN18.2) biomarker and the clinical success of molecules targeting this protein, such as Zolbetuximab (Vyloy), are filling this substantial treatment gap. This guide examines the biological mechanism and current standards of CLDN18.2, a precise waypoint in personalised oncology.
What is Claudin 18.2? Its role in cell biology
“Tight junctions”, which allow cells to adhere tightly to one another to preserve tissue integrity and prevent substances from leaking, are built by the Claudin protein family. Claudin 18.2is a special subtype of this family that, in healthy individuals, is found only in the gastric mucosal cells lining the stomach.
In healthy tissues, this protein is “hidden” in deep layers at the junctions between cells, beyond the reach of circulating drugs. When cells begin to become cancerous, however, this architecture breaks down. Bonds between cells disintegrate, and the CLDN18.2 protein “migrates” towards the cancer cell surface, becoming a fully exposed, precise target for smart drugs.
Its absence from healthy organs outside the stomach enables treatment to target only the tumour, optimising the side-effect profile.
It is a new gateway to precise treatment that has entered oncology guidelines, particularly for patients with HER2-negative gastric cancer.
In which cancer types is it important?
Claudin 18.2 expression (presence) is observed predominantly in adenocarcinomas of the digestive system:
- Gastric Cancer (Gastric Adenocarcinoma): High levels of CLDN18.2 are detected in approximately 35-38% of cases.
- Gastroesophageal Junction (GEJ) Cancer: It occurs in tumours at the junction of the oesophagus and stomach at rates similar to those in gastric cancer.
- Pancreatic Cancer: It has been detected in 60-80% of pancreatic adenocarcinomas, and research into CAR-T and ADC treatments is ongoing.
- Biliary Tract and Oesophagus: The protein is known to be present in some subtypes, and clinical trials are continuing.
Measurement and testing methods: Criteria for precise diagnosis
Whether a patient will benefit from these targeted treatments is determined by tissue-based Immunohistochemistry (IHC) testing. This test is performed on a tumour biopsy specimen, not on blood (liquid biopsy).
FDA-Approved Positivity Criteria
According to data from the standard companion diagnostic test (Roche/Ventana) approved by the FDA as of October 2024, a patient is considered positive if:
- Staining is seen in at least 75% of tumour cells,
- and this staining is of moderate to strong intensity (≥2+ or 3+) and membranous in nature.
Clinical data and the Zolbetuximab (Vyloy) era
The most important development in gastric cancer management in recent years is the FDA approval granted to the world’s first antibody targeting CLDN18.2, Zolbetuximab (Vyloy). This approval is based on the globally conducted SPOTLIGHT and GLOW phase 3 trials.
Administration and Success Rates
Zolbetuximab is a cytolytic monoclonal antibody administered intravenously (IV). Added to standard chemotherapy regimens (mFOLFOX6 or CAPOX), this agent has demonstrated the following outcomes:
- A marked extension of the time during which disease is held without progression (PFS).
- A reduction in the risk of disease progression or death of approximately 25%.
- A statistically and clinically significant increase in overall survival (OS).
| Side-Effect Profile | Frequency / Characteristics | Clinical Management |
|---|---|---|
| Nausea and Vomiting | Very Common (60-80%) | Managed with strong antiemetic (anti-nausea) protocols. |
| Loss of Appetite | Common | Dietitian support and supportive treatments. |
| Fatigue | Moderately Common | Activity planning and biological restoration. |
Frequently asked questions
Yes. Current oncology guidelines recommend CLDN18.2 testing, alongside HER2 and PD-L1, for every patient diagnosed with metastatic gastric cancer.
In this case, CLDN18.2-targeted drugs are not appropriate; however, your oncologist will determine the most suitable plan for you based on immunotherapy (PD-L1) or other molecular targets.
The drug is a very new agent that received US approval in October 2024. While licensing and reimbursement processes continue in Turkey, “Medicine Procurement from Abroad” pathways through TEB may be considered for eligible patients.
The DROZDOGAN Academy Path
For years, in our struggle against gastric cancer, we focused on “what could be seen”. The philosophy of biological restoration, however, has shown us how cells hold on to one another and how this attachment becomes a precise target during the cancer journey.
Claudin 18.2 is not merely a new drug; it is a victory for our vision of “precise guidance” in oncology. By following our patients with genetic and molecular compasses, we now aim to inflict the sharpest blow on the tumour while causing the least harm to healthy tissues. Healing is built in the light of honest data and a personalised strategy.
Scientific References
- 1. FDA Approves Zolbetuximab-clzb for Claudin 18.2-Positive Gastric Cancer. October 18, 2024.
- 2. Shitara K, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative gastric cancer (SPOTLIGHT). The Lancet, 2023.
- 3. Xu R, et al. Zolbetuximab plus CAPOX in patients with CLDN18.2-positive, HER2-negative gastric cancer (GLOW). Nature Medicine, 2023.
- 4. VENTANA CLDN18 (43-14A) RxDx Assay - Technical Guide for Pathologists (2024).
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