CLDN18.2 positive

P3, N=387, Active, not recruiting, LaNova Medicines Zhejiang Co., Ltd. | Recruiting --> Active, not recruiting

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.

P3, N=752, Not yet recruiting, Shanghai Chia Tai Tianqing Pharmaceutical Technology Development Co., Ltd.

P3, N=524, Not yet recruiting, FutureGen Biopharmaceutical (Beijing) Co., Ltd

Among patients undergoing nivolumab treatment, CPS ≥1 was significantly associated with longer survival outcomes in CLDN18.2-positive patients, and a tendency toward improved Nivo-OS in TROP2-positive patients.

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, 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.

CLDN18.2 overexpression is associated with poor prognosis in GC patients. Transcriptomic and proteomic analyses demonstrate that CLDN18.2 promotes tumor progression and metastasis, underscoring its potential as an independent prognostic factor in regions with a high incidence of GC.

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.