ZOLBETUXIMAB FOR
CLDN18.2-POSITIVE GASTRIC CANCER
The first-in-class CLDN18.2-targeted antibody that has redefined first-line treatment for a major subgroup of gastric cancer patients β what the SPOTLIGHT and GLOW trials showed, who qualifies, and how to access zolbetuximab at specialist centres in China.
analyticsAt a Glance
- check_circleClaudin 18.2 (CLDN18.2) is expressed in ~38β40% of gastric cancers β the largest novel targetable subgroup since HER2
- check_circleSPOTLIGHT and GLOW Phase III trials: zolbetuximab + chemotherapy significantly improved OS and PFS vs chemotherapy alone
- check_circleZolbetuximab received NMPA approval in China in 2024 β available at specialist centres before many Western markets
- check_circleCancerFax coordinates CLDN18.2 testing adequacy assessment and zolbetuximab access at Chinese centres
What Is CLDN18.2 and Why Does It Matter in Gastric Cancer?
Claudin 18.2 (CLDN18.2) is a tight junction protein normally expressed exclusively in the gastric mucosa β a highly restricted normal tissue distribution that makes it an ideal cancer target. When gastric cells become malignant, CLDN18.2 expression is aberrantly maintained on the tumour cell surface, providing a tumour-selective target that minimises on-target off-tumour toxicity.
βCLDN18.2 is arguably the most important new gastric cancer target since HER2 β with a targetable population nearly twice as large.β
How Common Is CLDN18.2 Positivity?
Approximately 38β40% of advanced gastric and GEJ cancers express CLDN18.2 at the 'high' level required for zolbetuximab eligibility β defined as β₯75% of tumour cells with moderate-to-strong (2+/3+) membranous IHC staining. This makes CLDN18.2 the largest novel biomarker-defined gastric cancer subgroup identified since HER2.
How Is CLDN18.2 Tested?
CLDN18.2 expression is assessed by immunohistochemistry (IHC) on tumour tissue β either from the primary resection specimen or from a biopsy. The validated scoring threshold for zolbetuximab eligibility is β₯75% of tumour cells staining 2+ or 3+ for CLDN18.2. Standardised IHC scoring is essential β not all laboratories perform CLDN18.2 IHC, and scoring variability can affect eligibility determination.
CLDN18.2 and HER2 Co-Positivity
Approximately 8β10% of gastric cancers are both CLDN18.2-high and HER2-positive. The pivotal SPOTLIGHT and GLOW trials excluded HER2-positive patients β so zolbetuximab's approved indication is specifically CLDN18.2 high, HER2-negative. Treatment of the co-positive subgroup is an area of active clinical investigation.
How Zolbetuximab Works
Zolbetuximab (IMAB362) is a chimeric monoclonal antibody that binds to the second extracellular loop of CLDN18.2 on the tumour cell surface. Binding triggers tumour cell killing through two mechanisms: antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells, and complement-dependent cytotoxicity (CDC). No intracellular signalling pathway inhibition is involved.
SPOTLIGHT and GLOW Phase III Trials β Key Results
Two independent Phase III trials of zolbetuximab + chemotherapy vs chemotherapy alone in CLDN18.2-high, HER2-negative advanced gastric cancer β both demonstrating significant OS and PFS benefit.
SPOTLIGHT: Zolbetuximab + mFOLFOX6 vs mFOLFOX6
CLDN18.2 high (β₯75% cells, IHC 2+/3+), HER2-negative advanced gastric/GEJ cancer. Source: Shitara et al., Lancet 2023.
- Median PFS: zolbetuximab + mFOLFOX610.61 months
- Median PFS: mFOLFOX6 alone8.67 months
- Median OS: zolbetuximab + mFOLFOX618.23 months
- Median OS: mFOLFOX6 alone15.54 months
GLOW: Zolbetuximab + CAPOX vs CAPOX
Same CLDN18.2 eligibility criteria, different chemotherapy backbone (CAPOX). Source: Shah et al., Nature Medicine 2023.
- Median PFS: zolbetuximab + CAPOX8.21 months
- Median PFS: CAPOX alone6.80 months
- Median OS: zolbetuximab + CAPOX14.39 months
- Median OS: CAPOX alone12.16 months
CLDN18.2 Eligibility Checklist for Zolbetuximab
A structured reference of the criteria that must be met for a patient to be eligible for zolbetuximab in the approved first-line setting.
| Criterion | Required Value / Status | Why It Matters |
|---|---|---|
| CLDN18.2 IHC | β₯75% of tumour cells with 2+/3+ membranous staining | The validated threshold from SPOTLIGHT/GLOW eligibility criteria |
| HER2 status | HER2-negative (IHC 0/1+ or IHC 2+/ISH non-amplified) | Zolbetuximab approval excludes HER2+ patients β separate treatment pathway |
| Disease stage | Advanced / metastatic (Stage IV) or unresectable | Zolbetuximab approved for first-line advanced/metastatic setting only |
| Prior treatment | Treatment-naΓ―ve for palliative systemic therapy | First-line indication β prior adjuvant chemotherapy completed >6 months prior acceptable |
| ECOG PS | 0β2 | Performance status threshold used in SPOTLIGHT/GLOW eligibility |
| Organ function | Adequate hepatic, renal, haematological function | Standard chemotherapy eligibility criteria apply β oxaliplatin or capecitabine backbone |
Zolbetuximab Safety Profile β What to Expect
The addition of zolbetuximab to FOLFOX or CAPOX introduces a specific additional side effect β nausea and vomiting during infusion β that requires active management.
Common With Zolbetuximab Addition
- Nausea and vomiting (most common)In SPOTLIGHT/GLOW, nausea (79%) and vomiting (67%) were the most common adverse events with zolbetuximab β predominantly occurring during or shortly after infusion and manageable with antiemetic prophylaxis.
- Decreased appetiteAppetite reduction was reported more frequently in zolbetuximab arms than control β linked to the GI tolerability profile of the agent.
- Infusion-related reactionsInfusion-related reactions (chills, fever, flushing) were reported in a minority of patients β managed by slowing infusion rate and antihistamine pre-medication.
Rare or Not Observed
- No immune-related adverse eventsUnlike checkpoint inhibitors, zolbetuximab does not cause autoimmune colitis, pneumonitis, thyroiditis, or other irAEs.
- No significant haematological toxicity beyond chemotherapyZolbetuximab does not add meaningful myelosuppression beyond the oxaliplatin/capecitabine backbone.
- No serious cardiac toxicityCardiac safety was not compromised by zolbetuximab addition in either Phase III trial β unlike trastuzumab, which carries cardiotoxicity risk.
CLDN18.2 and Zolbetuximab β Key Numbers
The most important quantitative reference points for patients and clinicians considering zolbetuximab for gastric cancer.
- ~38β40%Proportion of gastric cancers with CLDN18.2 high expressionThe largest novel biomarker-defined gastric cancer subgroup β nearly twice the HER2-positive population.
- HR 0.75OS hazard ratio: zolbetuximab + mFOLFOX6 vs mFOLFOX6 (SPOTLIGHT)A ~25% reduction in mortality risk β consistent across both SPOTLIGHT and GLOW, confirming robustness of the OS benefit.
- 2024Year of NMPA approval for zolbetuximab in ChinaChina was among the first markets to approve zolbetuximab β giving Chinese patients and international patients in China early access.
More from the Gastric Cancer Resource Library
Continue exploring gastric cancer treatment β from HER2-targeted therapy and immunotherapy to advanced options in China.
Frequently Asked Questions About Zolbetuximab and CLDN18.2
My biopsy was done 18 months ago. Can it still be used for CLDN18.2 testing?
Yes β CLDN18.2 IHC can be performed on archival formalin-fixed paraffin-embedded (FFPE) tumour tissue, including older biopsy specimens, provided adequate tumour material is present in the block and the tissue has been stored appropriately. Most pathology laboratories that perform CLDN18.2 testing can work from FFPE blocks or unstained slides sent from the original hospital. CancerFax coordinates CLDN18.2 testing on archival tissue as part of the pre-treatment assessment for patients who have not been previously tested.
I am CLDN18.2-positive AND HER2-positive. Which treatment do I receive?
The approved indication for zolbetuximab specifically excludes HER2-positive patients β the pivotal trials enrolled only HER2-negative patients. For co-positive patients, the current standard is trastuzumab-based first-line treatment (trastuzumab + FOLFOX/CAPOX Β± PD-1 inhibitor), as for all HER2+ gastric cancer. The question of whether co-positive patients might benefit from adding zolbetuximab to trastuzumab-containing regimens is under active investigation. CancerFax can identify clinical trials specifically designed for CLDN18.2+/HER2+ co-positive gastric cancer patients.
Is zolbetuximab available in China for international patients?
Yes. Zolbetuximab received NMPA approval in China in 2024 and is available at major academic cancer centres treating gastric cancer β including in Beijing, Shanghai, and Guangzhou. For international patients who cannot access zolbetuximab in their home country, treatment in China is a concrete option. CancerFax confirms CLDN18.2 testing adequacy from your existing pathology, identifies centres with confirmed zolbetuximab availability and gastric cancer expertise, and coordinates the full access process including treatment cost estimates and logistics.
What happens if my cancer progresses on zolbetuximab?
Post-zolbetuximab progression management is an area of active clinical development with no currently established standard. Options include second-line ramucirumab + paclitaxel (standard regardless of prior first-line regimen), CLDN18.2-directed CAR-T therapy (available in clinical trials at Chinese centres), and novel CLDN18.2-targeting agents in development. CancerFax reviews post-zolbetuximab progression cases and identifies the most appropriate clinical trial or second-line treatment options at Chinese centres.
How CancerFax Helps
CancerFax is a specialist cancer access and patient-navigation platform. We help patients and families understand their options, organise medical records, coordinate hospital communication, and support cross-border treatment planning where appropriate.
We help collect and organise reports, scans, pathology, biomarker results, and treatment history for structured case review.
We communicate with hospitals or trial teams to assess whether a case may be suitable for further screening.
We support appointment coordination, document submission, translation, and direct communication with international departments.
For international patients, we help with practical coordination β travel planning, hospital admission guidance, and local support.
If this option is not suitable, we help explore other relevant treatments, clinical trials, or advanced care pathways.
From inquiry through to follow-up, our coordinators provide a single point of contact for the family.
CancerFax does not guarantee treatment access, eligibility, or clinical outcome. Our role is to help patients access accurate information, structured review, and appropriate specialist pathways.
Has Your Gastric Cancer Been Tested for CLDN18.2 Expression?
CancerFax reviews your pathology reports to confirm CLDN18.2 testing adequacy, and if positive, coordinates access to zolbetuximab + chemotherapy at specialist Chinese gastric cancer centres where it is clinically available.
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified oncologist before making treatment decisions.