HER-2 negative + CLDN18.2 positive

This study presents a case of Claudin18.2-positive advanced gastric adenocarcinoma with peritoneal metastasis treated with a multimodal regimen: HIPEC, systemic CapeOx chemotherapy, and Claudin18.2-targeted therapy (ASKB589)...At 893 days post-diagnosis, the patient remains disease-free (PFS/DFS: 893/573 days) on adjuvant capecitabine...However, the absence of cytoreductive surgery and single-case limitations necessitate validation through randomized trials. Future research should prioritize biomarker-driven HIPEC protocols (e.g., nanoparticle-enhanced Claudin18.2-targeted delivery) and dynamic monitoring of Claudin18.2 expression during therapy.

Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.

The significant heterogeneity in poorly cohesive cases and an inverse correlation with signet ring cell content pose diagnostic challenges for pathologists. Moreover, the association between CLDN18.2 positivity and worse progression-free survival in intestinal adenocarcinoma supports a potential role in tumor progression and metastasis, warranting further research.

Early-onset transient gastritis frequently occurred following zolbetuximab-containing therapy and was significantly associated with anorexia and hypoalbuminemia. A deeper understanding of gastritis underlying unique GI toxicities may provide insight into effective management.

Similarly, the DCR, ORR, PFS, and OS outcomes were comparable between the CLDN18.2-positive and -negative patients in the chemo-alone group. CLDN18.2 expression exerted no impact on outcomes of first-line ICI-chemo and chemo-alone in patients with HER2-negative, pMMR, and PD-L1 CPS ⩾1 mGC/GEJC.

PopPK analysis suggests no effect of zolbetuximab on 5-FU or oxaliplatin PK.

Nevertheless, heterogeneous expression was observed in a small percentage of tumors (28% of all tumors), indicating that sampling-related misclassification remains a potential concern. Our study provides detailed insights into CLDN18.2 expression and sheds light on the biomarker landscape in gastric and GEJ cancers.

Patients identified for eligibility using the VENTANA CLDN18 (43-14A) RxDx Assay demonstrated statistically significant improvement in progression-free survival and overall survival with zolbetuximab plus chemotherapy in both phase 3 trials. The VENTANA CLDN18 (43-14A) RxDx Assay demonstrated robust, reproducible analytical performance and clinical utility as a companion diagnostic for first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive.

As a fifth-line treatment, she underwent combination therapy with capecitabine, oxaliplatin, and zolbetuximab (CAPEOX + Zolbe). These adverse events are not widely recognized among clinicians. However, when hypoalbuminemia occurs during zolbetuximab administration, this diagnosis should be considered.

Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy...We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

In PD-L1low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.