Vyloy (zolbetuximab-clzb)

Clinical trials of Claudin 18.2-targeted therapies (e.g., Zolbetuximab) further expand personalized treatment options...Despite the abundance of research in this field, this paper prioritizes the analysis and discussion of prospective or high-quality retrospective studies that include explicit efficacy prediction endpoints (such as pCR, TRG, AUC) to ensure the reliability of the evidence presented. This review emphasizes that multi-omics integrated predictive models and the clinical translation of targeted therapies represent critical directions for future research, aiming to optimize the neoadjuvant treatment strategies for locally advanced gastric cancer.

Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies-such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies-is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer.

The CLDN18.2 expression demonstrated an acceptable concordance between biopsy and surgically resected specimens. However, high prevalence of heterogeneous expression and tendency for CLDN18.2 positivity to shift to negativity following chemotherapy existed.

Discontinuation of 5-FU and supportive care consisting of hydration and rasburicase led to rapid clinical improvement. Chemotherapy, which was resumed after a dosage adjustment, achieved tumor shrinkage and resolved the hydronephrosis. To the best of our knowledge, the present study is the first to describe concurrent TLS and 5-FU-induced encephalopathy during the administration of a zolbetuximab-based regimen and highlights the need for proactive prophylaxis against TLS and for controlling nausea in AGC patients with a high tumor burden, baseline renal impairment, and cachexia.

Zolbetuximab-based chemotherapy followed by conversion surgery is a promising therapeutic strategy for patients with CLDN-positive advanced gastric cancer.

Zolbetuximab, the first monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved as first-line treatment for patients with HER2-negative and CLDN18.2-positive gastric or gastroesophageal junction cancers, offering new hope to patients who previously derived limited benefit from molecular targeted therapies or immune checkpoint inhibitors...Next-generation modalities such as ADCs, bispecific antibodies, and CAR-T cell therapies have shown efficacy even in patients with lower CLDN18.2 expression, suggesting potential to expand treatment eligibility. Moving forward, deeper understanding of gastrointestinal toxicities associated with CLDN-targeted therapies, elucidation of resistance mechanisms, and development of rational combination strategies will be essential to maximize therapeutic benefit in patients with CLDN18.2-positive gastric cancer.

Zolbetuximab exemplifies a novel therapeutic class which can be classified as targeted cytolytic antibodies. Future work should test combinations with checkpoint blockade, refine biomarkers and define resistance mechanisms.

SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC...Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.

Patients with more advanced-stage disease should receive gastrectomy, perioperative chemotherapy with 5-fluorouracil, oxaliplatin, and docetaxel and immunotherapy (durvalumab)...For PD-L1-expressing gastric cancer, adding immune checkpoint inhibitors, such as nivolumab and pembrolizumab, is associated with an additional 3 months of survival when compared with chemotherapy alone...Localized gastric cancer is treated with gastrectomy, and locally advanced disease is treated with surgery and chemoimmunotherapy. For patients with unresectable or metastatic gastric cancer, chemotherapy with immune checkpoint inhibitors and targeted therapies such as trastuzumab or zolbetuximab improves survival by several months.

These measures reflect reporting disproportionality within a spontaneous-reporting system and should not be interpreted as incidence or causality. These exploratory findings support proactive, guideline-based antiemetic strategies-particularly for younger female patients-and warrant prospective confirmation.

The CR101 antibody exhibits high affinity and specificity for claudin18.2, demonstrating superior tumor cell-killing efficiency compared to IMAB362...Transcriptomic analysis revealed that CR101-ADC primarily affects cytoskeletal, inflammatory, and stress pathways and represents a promising candidate for the treatment of gastrointestinal malignancies. Collectively, these findings demonstrate that CR101-ADC combines high specificity, potent intracellular drug delivery, and favorable safety, representing a promising next-generation therapeutic candidate for CLDN18.2-positive gastrointestinal cancers.