Vyloy (zolbetuximab-clzb)

At a willingness-to-pay threshold of USD 100,000/QALY (Japan's HTA upper reference), SOX was identified as the most cost-effective first-line treatment for HER2-negative unresectable advanced or recurrent GC in Japan.

P3, N=507, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Mar 2026 --> Sep 2026

The phase III trials SPOTLIGHT and GLOW demonstrated improved survival following the addition of the CLDN18.2-targeted antibody zolbetuximab to chemotherapy...The use of different antibodies and definitions of CLDN18.2 positivity in patients with advanced G/GEJ adenocarcinoma poses a challenge for drawing definitive conclusions on the prognostic value of CLDN18.2 and association of CLDN18.2 with patient/disease characteristics. Additional research using a standardized approach to assess CLDN18.2 expression is needed.

CLDN18.2 positivity was retained in 66.7% and 73.3% of patients when applying 40% and 25% cut-off levels, respectively. CLDN18.2 expression above the ≥75% cut-off declined after zolbetuximab, but lower-level expression was often preserved, supporting the potential for subsequent targeted therapy.

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.