Vyloy (zolbetuximab-clzb)

Despite assay variability, even under stringent clinical trial criteria, a meaningful subset of patients may qualify for CLDN18.2-targeted therapy. These findings highlight the need for standardized testing and further clinical evaluation of CLDN18.2-directed strategies in PDAC.

In Japanese patients, zolbetuximab plus chemotherapy improved PFS versus placebo plus chemotherapy and showed a numerical improvement in OS. These results support zolbetuximab plus chemotherapy as a potential new standard-of-care first-line option for Japanese patients with CLDN18.2-positive, HER2-negative, LA unresectable or metastatic gastric or GEJ adenocarcinoma.

Pivotal trials (MONO, FAST, SPOTLIGHT/GLOW, ILUSTRO) confirmed its monotherapy efficacy and superior PFS/OS when combined with chemotherapy (EOX, mFOLFOX6, CAPOX) in CLDN18.2-positive (≥70% staining), HER2-negative advanced GC/EGJC patients, with manageable safety...However, MMAE's long-term cumulative toxicity, uncertain safety in special populations, and rare severe adverse reactions require real-world validation. This review systematically summarizes zolbetuximab's research progress, providing a reference for clinical application and future studies.

These national guidelines on gastric cancer are intended to facilitate decision-making in daily clinical practice. These recommendations are subject to ongoing review. Each individual case should be discussed within a multidisciplinary team.

However, despite the development of new drugs and the approval of zolbetuximab, there are significant challenges to be addressed, such as intratumoural heterogeneity, sampling bias, and the absence of assay standardization with thresholds suitable for the modality. This review synthesizes the biology and clinical significance of claudins-particularly CLDN18.2 and CLDN6-, highlighting their potential as biomarkers for guiding precision medicine and future development of novel therapeutic agents in gastric cancer patients.

The approved antibody zolbetuximab requires higher expression levels (≥75% of tumor cells with 2-3+ membranous staining), yet broader thresholds are increasingly explored...Broadening the threshold for positivity identified nearly three-quarters of patients as CLDN18.2 positive, underscoring the impact of selection cut points on trial eligibility. These findings highlight the potential to expand patient access to CLDN18.2-targeted therapies using lower thresholds.

Specimen type (biopsy or surgical resection) had no apparent impact on treatment outcomes. Within the approved CLDN18-positive threshold, the semiquantitative staining proportion showed no detectable differences in the efficacy or safety of zolbetuximab plus chemotherapy.

Anti-CLDN18.2 therapy, primarily consisting of first-line zolbetuximab combined with chemotherapy, significantly improved progression-free survival (PFS) (hazard ratios [HR] 0.564; 95% confidence interval [CI]: 0.417-0.711) and overall survival (OS) (HR 0.716; 95% CI: 0.631-0.802), along with enhanced 1- and 2-year survival rates...Standardized definitions for CLDN18.2 positivity and high expression are urgently needed. www.crd.york.ac.uk/prospero identifier is CRD420251123719.

Identifying practice barriers and proactively addressing them can result in a more rapid adoption of new therapies. This study identified 4 major challenges to the adoption of the novel targeted agent, zolbetuximab, in the community practice setting: limited awareness of clinical trial data, inadequate biomarker testing infrastructure, uncertainty in identifying optimal patient populations, and access barriers related to cost and insurance coverage. By implementing strategies identified from this study, we hope to accelerate and improve future adoption to innovative treatments in the community oncology setting, ultimately improving patient outcomes.