CLDN18.2 positive

The significant heterogeneity in poorly cohesive cases and an inverse correlation with signet ring cell content pose diagnostic challenges for pathologists. Moreover, the association between CLDN18.2 positivity and worse progression-free survival in intestinal adenocarcinoma supports a potential role in tumor progression and metastasis, warranting further research.

Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.

In an NUGC‑4‑CLDN18.2 xenograft tumor model, the antitumor efficacy and toxicity of the mAb (SYSA1801mAb), as well as the ADC (SYSA1801) and RDC ([177Lu]Lu‑DOTA‑SYSA1801mAb), and their combinations in different sequences (ADC→RDC and RDC→ADC), were systematically assessed...Furthermore, sequential combination therapy that starts with ADC appears to be more favorable than approaches that start with RDC. Although ADC→RDC sequential therapy did not significantly outperform ADC monotherapy in this model, it may serve as an effective subsequent treatment strategy.

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Feb 2027 --> May 2027 | Trial primary completion date: Jan 2026 --> Jul 2026

CLDN18.2 and FGFR2b were significantly associated with each other, suggesting a considerable overlap. This finding may have important clinical implications on the optimal treatment strategy for CLDN18.2-positive GC.

Although non-Asian patients also demonstrated a trend toward improved survival, the difference was not statistically significant. Further studies are needed to explore the therapeutic and clinical implications of CLDN18.2 expression in diverse populations worldwide.

Early-onset transient gastritis frequently occurred following zolbetuximab-containing therapy and was significantly associated with anorexia and hypoalbuminemia. A deeper understanding of gastritis underlying unique GI toxicities may provide insight into effective management.

CLDN18.2 expression is dynamically regulated during chemoimmunotherapy and is associated with a distinct immunosuppressive and fibrotic TME. These findings highlight the importance of repeated biomarker assessment and suggest potential combinatorial therapeutic strategies targeting both epithelial and stromal compartments in GC.

P1/2, N=280, Recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2026 --> Jun 2027

Tecotabart vedotin demonstrated encouraging anti-tumor activity and manageable safety in CLDN18.2-positive G/GEJ cancer, supporting further clinical development in gastrointestinal malignancies.

Similarly, the DCR, ORR, PFS, and OS outcomes were comparable between the CLDN18.2-positive and -negative patients in the chemo-alone group. CLDN18.2 expression exerted no impact on outcomes of first-line ICI-chemo and chemo-alone in patients with HER2-negative, pMMR, and PD-L1 CPS ⩾1 mGC/GEJC.

PopPK analysis suggests no effect of zolbetuximab on 5-FU or oxaliplatin PK.