CLDN18.2 positive

CLDN18.2 was not significantly associated with PD-L1 or HER2 status regardless of histological subtype (P > 0.05). This study characterized the histological profile of CLDN18.2-positive G/GEJ and broadened our understanding of subgroups likely to benefit from CLDN18.2-targeted therapy.

Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.

Treatment was started with zolbetuximab plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX), which is typically used for CLDN18.2-positive gastric cancer, resulting in a partial response. This is the first case of zolbetuximab-based therapy applied to adenocarcinoma from a Meckel's diverticulum with a gastric phenotype due to a biomarker profile of gastric cancer. This case highlights the importance of identifying both the biomarker profile and tissue of origin of the tumor.

The highest non-severely toxic dose was 5×108 CAR-T cells/kg. In the clinical case report, we present a case with unresectable advanced gastric cancer achieved pathological complete response 10 months after IMC002 infusion and no signs of recurrence were indicated in subsequent clinical and radiological follow-ups. IMC002 shows effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancer and its favorable profiles support further clinical development.

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.