Claudin 18.2-positive gastric cancer

aka CLDN18.2-positive gastric cancer, Claudin 18.2-high gastro-oesophageal adenocarcinoma

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.

Part ofGastric & gastro-oesophageal junction cancer

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.

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.

Red cards

From the labels and guidelines behind the standard of care. Your team's thresholds win.

Emergency services now
Bleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
CAPOX (capecitabine, oxaliplatin)FOLFOX (5-FU, leucovorin, oxaliplatin)Paclitaxel / nab-paclitaxel source
Emergency services now
Hypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Nivolumab Pembrolizumab source
Emergency services now
Bowel perforation
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Ramucirumab source
Emergency services now
Cytokine release syndrome
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.
Satricabtagene autoleucel source
Emergency services now
Skin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
Sonesitatug vedotin source
Check before combining
Food and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Pembrolizumab source

See all on the product pages:CAPOX (capecitabine, oxaliplatin)FOLFOX (5-FU, leucovorin, oxaliplatin)Nivolumab Paclitaxel / nab-paclitaxel Pembrolizumab Ramucirumab Satricabtagene autoleucel Sonesitatug vedotin·Printable cards in the navigator

Anatomy and lymph node drainage

Oesophagus and stomach: subsites and node stations · wireframe schematic, not to scale

Organ atlas →

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.

Subsites

Upper and middle oesophagus (squamous)
Lower oesophagus and junction (adenocarcinoma)
Cardia and fundus
Body (diffuse or intestinal type)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)
Antrum and pylorus
Muscle wall (GIST)

Regional lymph nodes

perigastric (greater and lesser curve)
coeliac and hepatic
mediastinal
cervical (upper oesophagus)

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

Who gets it and what has changed

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.

Group

gastrointestinal

Cases by country

Cases by country · GLOBOCAN 2022

All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Lines of therapy by subgroup →Staging and risk scores →

Decisions you may face

2 with more than one option · full decision page →

One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.

Advanced, first line5 Second line4 Toxicity management

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 & GLOWZolbetuximabFOLFOX (5-FU, leucovorin, oxaliplatin)CAPOX (capecitabine, oxaliplatin)Claudin 18.2NivolumabPembrolizumab

Second line

Ramucirumab with paclitaxel; claudin 18.2 antibody-drug conjugates and CAR-T in trials.

RamucirumabPaclitaxel / nab-paclitaxelSonesitatug vedotinSatricabtagene autoleucelCLDN18.2 antibody first line → CLDN18.2 ADC or CAR-T on progression

Toxicity management

Antiemetic prophylaxis and slowed infusion for the nausea and vomiting of the first cycles.

Zolbetuximab

Subtypes & biomarkers

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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 clinicians test

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

How often this target appears

History

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2008Claudin 18.2 identified as a tumour-exposed target (Sahin and colleagues)
2016FAST phase 2: claudin 18.2 antibody plus chemotherapy improves survival
2023SPOTLIGHT and GLOW: zolbetuximab plus chemotherapy extends survival
SPOTLIGHT & GLOWZolbetuximab
2024Zolbetuximab approved in Japan, the United States and Europe
Zolbetuximab

What changed

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Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.

All 6 changes by month →

FollowWatch this cancer and Saved shows what changed since you last looked.Follow by feed

In development

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What is in development for Claudin 18.2-positive gastric cancer, drawn from the whole corpus: 6 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.

Drugs in phase 3 · 3

Phase 3bispecific antibody

ASP2138

Trials reported · 1

SPOTLIGHT & GLOW · phase 3 · 2023 · positive

Combinations being explored · 1

CLDN18.2 antibody first line → CLDN18.2 ADC or CAR-T on progression

Ideas not yet in a trial · 1

Biomarker-directed first-line quadruplets in gastric cancer

Open problems and what is being done

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.
What is being done about this
Side effects and quality of life
and how the field plans to fix it →
Available now
ZolbetuximabApproved
In trials
Nothing recorded yet.
Ideas and roadmaps
Nothing recorded yet.
Also on OnCo: Side effects by symptom · Immune-related side effects · Toxicity compare · Survivorship planner.

Trials

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Trials recruiting now

Recruiting trials near you · live from ClinicalTrials.gov

Claudin 18.2-positive gastric cancer

condition: Claudin 18.2-positive gastric cancer

Open on ClinicalTrials.gov →

within

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Landmark trials

SPOTLIGHT & GLOW

Expert centres

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Where the expertise is

Expert centres

16 centres in 8 countries · 0 with a trial for this cancer on record · second-opinion finder →

Choose a region from the globe in the header to mark centres near you.

16 centres


Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center Baltimore · cancer center	United States	NCI comprehensive	2,955	41,449	Multi-cancer early detection (MCED)Liquid biopsy (ctDNA)Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems +2	#10
Peking University Cancer Hospital Beijing · cancer center Programme: Gastric and oesophageal cancer	China	none recorded	1,344	18,195	CAR-T cell therapy Immune checkpoint inhibitors Antibody-drug conjugate (ADC)	-
Istituto Nazionale Tumori IRCCS Fondazione G. Pascale Naples · cancer center	Italy	none recorded	961	15,028	Immune checkpoint inhibitors Liquid biopsy (ctDNA)Companion diagnostics	-
Lausanne University Hospital (CHUV) / Ludwig Institute Lausanne Lausanne · hospital	Switzerland	none recorded	509	9,176	TIL therapy TCR-T cell therapy Immune checkpoint inhibitors Personalised neoantigen (mRNA) vaccines	-
Institut Jules Bordet Brussels · cancer center	Belgium	none recorded	489	8,689	Liquid biopsy (ctDNA)Monoclonal antibodies RNA sequencing & expression profiling Endocrine therapy (SERMs, AIs, SERDs)	-
Kyoto University Hospital Kyoto · hospital	Japan	none recorded	251	1,942	Immune checkpoint inhibitors Allogeneic (off-the-shelf) cell therapy CAR-NK & CAR-macrophage	-
Advanced Centre for Treatment, Research and Education in Cancer Navi Mumbai · research institute	India	none recorded	175	1,127	CAR-T cell therapy Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems	-
GOG Foundation Philadelphia, PA · consortium	United States	none recorded	165	1,237	Immune checkpoint inhibitors Antibody-drug conjugate (ADC)Anti-angiogenic therapy	-
Dartmouth Cancer Center Lebanon, NH · cancer center	United States	NCI comprehensive	112	687	Immune checkpoint inhibitors Monoclonal antibodies	-
Alliance for Clinical Trials in Oncology Chicago, IL · consortium	United States	none recorded	42	482	Sentinel lymph node biopsy	-
SWOG Cancer Research Network Portland, OR · consortium	United States	none recorded	42	1,880	none recorded	-
German Hodgkin Study Group Cologne · consortium	Germany	none recorded	not matched	-	FDG PET Antibody-drug conjugate (ADC)Cytotoxic chemotherapy	-
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health New York, NY · cancer center	United States	NCI comprehensive	not matched	-	Digital pathology & AI PROTACs & molecular glues (targeted protein degradation)Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	-
National Cancer Center Hospital East Kashiwa, Chiba · cancer center Programme: Gastric and oesophageal cancer trials	Japan	none recorded	not matched	-	Proton therapy Comprehensive genomic profiling Liquid biopsy (ctDNA)MRD / molecular residual disease testing +2	-
Renji Hospital, Shanghai Jiao Tong University Shanghai · hospital	China	none recorded	not matched	-	CAR-T cell therapy	-

(showing the first 15)

These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Claudin 18.2-positive gastric cancer but is thinly recorded here will look small.

Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost. The second-opinion finder explains how referral works in your country.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about Claudin 18.2-positive gastric cancer

Generated from this cancer's standard of care, biomarkers, and pipeline · 16 questions

Newly diagnosed

What is my exact diagnosis, stage, and grade, and which tests established them?
Why: Everything else follows from an accurate stage and subtype.
Which biomarkers have been tested on my tumour (for example Claudin 18.2 by immunohistochemistry, HER2, PD-L1 combined positive score, Claudin 18.2 expression in metastases and after prior therapy), and what were the results?
Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
Which subtype is my cancer, and does that change the recommended treatment?
Why: Recognised subtypes for this cancer include Claudin 18.2-positive, HER2-negative, Claudin 18.2-positive diffuse-type gastric cancer, Claudin 18.2-positive with PD-L1 CPS 5 or above.
Is germline (inherited) genetic testing recommended for me or my family?
Why: Inherited variants can change treatment and matter for relatives.

Advanced, first line

For my situation (advanced, first line), which of the standard options do you recommend and why?
Why: Guideline options include: 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.
Am I a candidate for Zolbetuximab, FOLFOX (5-FU, leucovorin, oxaliplatin), CAPOX (capecitabine, oxaliplatin) or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of SPOTLIGHT & GLOW apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Second line

For my situation (second line), which of the standard options do you recommend and why?
Why: Guideline options include: Ramucirumab with paclitaxel; claudin 18.2 antibody-drug conjugates and CAR-T in trials.
Am I a candidate for Ramucirumab, Paclitaxel / nab-paclitaxel, Sonesitatug vedotin or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Toxicity management

For my situation (toxicity management), which of the standard options do you recommend and why?
Why: Guideline options include: Antiemetic prophylaxis and slowed infusion for the nausea and vomiting of the first cycles.
Am I a candidate for Zolbetuximab, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

Are there clinical trials I could join, for example of Sonesitatug vedotin, Satricabtagene autoleucel, LM-302, ASP2138?
Why: Trials are how the next standard of care is set; asking early keeps options open.
Would a second opinion at a high-volume centre change anything, and can you help arrange it?
Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
Why: Supportive care improves quality of life and helps patients complete treatment.
I read that “Whether zolbetuximab or PD-1 blockade should come first when both PD-L1 and claudin 18.2 are positive”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.
I read that “Tumours below the 75 percent threshold have no approved claudin 18.2 therapy”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.