CLDN18.2 expression

Our findings demonstrated that CLDN18.2-directed CAR-T cells exhibit potential as a potent therapeutic strategy for management of LUAD expressing CLDN18.2.

Its expression was rarely observed in other histological types of lung cancer. CLDN18.2 is frequently expressed in IMAs but rarely in other major lung cancer subtypes, suggesting that zolbetuximab may represent a promising targeted therapy for IMA.

Remnant gastric carcinoma demonstrated distinct characteristics from conventional gastric carcinoma, with highly prevalent CLDN18.2 expression. Patients with remnant gastric carcinoma may benefit from CLDN18.2-targeting therapeutics.

We performed [89Zr]Zr-zolbetuximab immuno-PET imaging to quantify and localized CLDN18.2 expression in vivo, comparing uptake with [89Zr]Zr-trastuzumab in matched human epidermal growth factor receptor 2-positive patient-derived xenograft models. These findings outline a clinically relevant roadmap for CLDN18.2 radiotheranostics in which imaging enables patient selection and dosimetry, therapy delivers targeted tumor control, and rational combinations with chemotherapy or immunotherapy may further extend efficacy. Ultimately, this approach could make antibody-based radiopharmaceuticals a transformative modality in gastric cancer.

The target population for these recommendations is patients with unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. Results from testing for actionable biomarkers should be available as soon as possible to inform treatment decision making. Immunotherapy with doublet chemotherapy is recommended for patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal adenocarcinoma or squamous cell carcinoma and PD-L1 expression ≥1; patients with higher PD-L1 expression are more likely to benefit from immunotherapy. Zolbetuximab is recommended for patients with gastroesophageal adenocarcinoma, PD-L1 <1, and positive CLDN18.2 expression. Patients with dual PD-L1 and CLDN18.2 positivity should engage in shared decision making, considering the factors outlined in the guideline. Doublet chemotherapy alone is recommended for patients who are not positive for actionable biomarkers or are not considered candidates for targeted therapy or immunotherapy. For patients with pMMR/MSS HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma, trastuzumab and doublet chemotherapy is recommended; for patients with PD-L1 expression ≥1, the addition of pembrolizumab is recommended. Immunotherapy alone or with doublet chemotherapy is recommended for patients with mismatch repair deficient/microsatellite instability-high gastroesophageal cancer. Second-line therapy options include ramucirumab with paclitaxel, trastuzumab deruxtecan for HER2-positive gastric/GEJ adenocarcinoma, and immunotherapy for PD-L1 ≥1 esophageal squamous cell carcinoma after first-line combination chemotherapy without immunotherapy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

P3, N=2130, Recruiting, AstraZeneca

P2, N=40, Not yet recruiting, Zhejiang University

P1/2, N=17, Recruiting, AstraZeneca AB

P3, N=565, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Mar 2026 --> Sep 2026

P3, N=565, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Sep 2025 --> Mar 2026

P3, N=565, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Mar 2025 --> Sep 2025

In conclusion, CLDN18.2-positive colorectal adenocarcinomas are frequently MMR deficient, BRAF V600E mutated, and demonstrate distinct histologic features. Future studies addressing the efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.