CLDN18.2 positive

P1, N=29, Recruiting, Sichuan University | Not yet recruiting --> Recruiting

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

Our findings establish CLDN18.2 as a robust negative prognostic indicator for overall survival in GC patients. While its impact on PFS was not statistically significant, the association with OS suggests CLDN18.2 may serve as a marker for complex biological processes underlying tumor advancement.

CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting anti-tumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.

A significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.

AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.

Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced αCLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells...Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in αCLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.

P1, N=34, Completed, Zai Biopharmaceutical (Suzhou) Co., Ltd. | Phase classification: P1/2 --> P1

P1/2 | "Updated data indicate that the combination of TST001 plus nivolumab and CAPOX as the 1L treatment for patients with G/GEJ cancer is safe and well tolerated with very encouraging anti-tumor activities, especially for patients with high/medium CLDN18.2 expression when cross comparing to historical data."

CLDN18.2 will be an important target in GAC. Early understanding of how to target CLDN18.2 based on the level of expression (high, moderate, low) will be the key to success in this area. Studying these as separate entities should be considered. Resistance patterns, loss of CLDN18.2 expression, role in the refractory setting, and if any role in localized disease are questions that remain. Other targets for claudin that target claudin six and four are under investigation. Their role in GI malignancies will soon be further clarified.

In vivo, we established a xenograft GC model and observed the antitumor effects and off-target toxicity of CAR-T cells. These results support that synthetic anti-CLDN18.2 CAR-T cells have antitumor effect and anti-CLDN18.2-PD1/CD28 CAR could provide a promising design strategy to improve the efficacy of CAR-T cells in advanced gastric cancer.

Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%...CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials...Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

P1, N=17, Completed, Turning Point Therapeutics, Inc. | Active, not recruiting --> Completed | N=42 --> 17

Compared with 18F-FDG, 68Ga-NC-BCH showed significant differences in uptake in lesions with different levels of CLDN18.2 expression. A clear correlation was detected between PET SUV and CLDN18.2 expression, suggesting that 68Ga-NC-BCH PET could be used as a companion diagnostic tool for optimizing treatments that target CLDN18.2 in tumors.

P1, N=228, Recruiting, Beijing Mabworks Biotech Co., Ltd. | Trial completion date: Aug 2023 --> Aug 2025 | Trial primary completion date: Aug 2023 --> Aug 2025

CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

Data suggested CLDN18.2 expression levels were independent of PD-L1 status, and support the use of Transcenta 14G11 antibody for CLDN18.2 detection regardless of sample collection methods, location, and patient demographics. An anti-CLDN18.2 companion diagnostic device based on 14G11 is being developed (CLDN18.2 IHC 14G11 pharmDx, Agilent Technologies, Inc.).

In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

CLDN18.2+ expression is associated with early stage GACs, but with metastatic disease in E/GEJACs. CLDN18.2+ expression is not affected by preoperative treatment or HER2 status. These findings expand our recognition of subsets of patients who may benefit from targeted CLDN18.2 therapy.

Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further...Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA...Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.

P1, N=94, Recruiting, Zhejiang Doer Biologics Co., Ltd. | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Sep 2023 --> Jun 2024

P1, N=15, Terminated, Amgen | Completed --> Terminated; Business Decision

These results indicate that radionuclide-labeled scFv-Fc molecular probes ([I]I-SF106 and [Lu]Lu-DOTA-SF106) provide a new possibility for the diagnosis and treatment of CLDN18.2-positive cancer patients in clinical practice.

Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract.

We propose that the enhanced anti-tumor potency of BsAbs in vivo is due to the monovalent binding of single-chain antibodies to more targets due to weaker affinity, resulting in a more potent immune effect function. Therefore, HC-2G4S could be a productive agent for treating GC that is HER2-positive, CLDN18.2-positive, or both, with the potential to overcome trastuzumab resistance and provide significant clinical benefits and expanded indications.

From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.

P1/2, N=162, Recruiting, Zai Biopharmaceutical (Suzhou) Co., Ltd.

In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.

P1/2, N=110, Active, not recruiting, CARsgen Therapeutics Co., Ltd. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

The Ga-DOTA-T37 probe exhibits good in vitro properties and high stability as a hydrophilic probe; it has high biological safety, and positron emission tomography/computed tomography (PET/CT) studies have shown that it can specifically target CLDN18.2 protein and CLDN18.2-positive tumors in mice. Ga-DOTA-T37 demonstrated the superiority and feasibility of using a CLDN18.2-specific probe in PCT/CT imaging, which deserves further development and exploitation.

In preclinical studies, [Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.

No data analysis is available as of the submission deadline. Clinical trial information: NCT05862324.

The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m2 Q3W regimen as well as an 800/400 mg/m2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025, NCT01671774, NCT03528629, NCT04086758, NCT01197885, NCT01630083, NCT03505320, NCT03504397, NCT03653507.

After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel... The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC. In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595.

We report preliminary safety and efficacy data from an ongoing Phase Ib/II, dose-escalation and expansion study of ASKB589 combined with capecitabine, oxaliplatin(CAPOX) and Sintilimab as first-line treatment of G/GEJ adenocarcinoma (NCT05632939). ASKB589 combined with CAPOX and PD-1 inhibitor has manageable safety and promising antitumor activity. 6mg/kg is chosen as the recommended dose in subsequent studies. Clinical trial information: NCT05632939.

Sponsored by No funding sources reported Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.

These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase 1 clinical studies.

P2, N=25, Not yet recruiting, First Affiliated Hospital of Anhui Medical University