CLDN18 (Claudin 18)

These agents demonstrate significant potential in extending overall survival durations, underscoring their translational value and substantial research implications. This comprehensive review delineates recent advancements in GC-targeted therapies to inform precision oncology paradigms and guide future drug discovery initiatives.

P=N/A, N=50, Not yet recruiting, Beijing GoBroad Hospital

It is currently a clinically relevant predictor for adenocarcinomas of the stomach and the gastroesophageal junction, although its use will likely extend also to other diagnoses. The aim of this report is to provide an overview of selected aspects of CLDN18.2 expression testing, including the choice of appropriate tissue, the issue of tumor heterogeneity, antibodies suitable for testing and their evaluation, where such testing can be performed, and the prospects for the future.

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.

In the remaining HER2 cohort, CLDN18.2-positive patients had shorter PFS (3.2 versus 8.0 months, HR 3.40, 95% CI 1.38-8.40, P = 0.008) and OS (7.1 versus 12.9 months, HR 2.44, 95% CI 1.04-5.74, P = 0.041). CLDN18.2 positivity may attenuate the efficacy of T-DXd in HER2-positive mGC/GEJC, supporting the rationale for dual blockade of CLDN18.2 and HER2.

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.

P=N/A, N=968, Enrolling by invitation, Tianjin Medical University Cancer Institute and Hospital

P1/2, N=150, Recruiting, Astellas Pharma Global Development, Inc. | Not yet recruiting --> Recruiting

P3, N=572, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=156, Recruiting, Antengene Biologics Limited | Trial completion date: Jun 2026 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2027

ICI-based therapy with nivolumab plus ipilimumab or with pembrolizumab. The durable responses in locoregional disease suggest the potential to consider nonoperative management in selected individuals. Further research is needed to improve prediction of ICI response and refine treatment strategies.