CLDN18.2 expression

Approximately 2% of all CRC cases in this study were CLDN18.2 positive and had unfavorable features (e.g., mucinous or poorly differentiated adenocarcinoma, T3-4 disease, lymphatic invasion, BRAF V600E mutation) and deficient MMR status. CLDN18.2 positivity did not have a significant impact on RFS or OS.

Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy...We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

Characterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC.

Question The study resolves the clinical issue of determining the correlation between [18F]FDG PET/CT imaging and claudin 18.2 expression in metastatic gastric cancer. Findings Claudin 18.2-positive metastatic gastric cancers exhibit relatively lower [18F]FDG uptake than negative ones. The SUVmax of 10.9 moderately predicts claudin 18.2 expression. Clinical relevance [18F]FDG PET/CT imaging could be a noninvasive way to predict claudin 18.2 status in metastatic gastric cancer, helping to improve personalized treatment plans.

Additionally, low CLDN18.2 expression was linked to favorable prognosis. Our study reveals the potential value of CLDN18.2 for tumor prognosis and targeted therapy in various cancers, especially upper gastrointestinal tract cancers.

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

P1, N=12, Completed, Innovent Biologics (Suzhou) Co. Ltd. | Recruiting --> Completed | Phase classification: P1a/1b --> P1 | N=48 --> 12

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.

The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.

This study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.

P2, N=393, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Apr 2025 --> Aug 2026 | Trial primary completion date: Sep 2024 --> Aug 2026

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.

P2, N=393, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

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.

Furthermore, after incubation with human PBMCs and CLDN18.2 expressing cells, DR30318 induced TDCC activity and the production of interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Notably, DR30318 demonstrated significant tumor suppression effects on gastric cancer xenograft models NUGC4/hCLDN18.2 and pancreatic cancer xenograft model BxPC3/hCLDN18.2 without affecting the body weight of mice.

P2, N=25, Not yet recruiting, Harbin Medical University

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.).

P1/2, N=114, Recruiting, Phanes Therapeutics | N=72 --> 114

Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed HER2, and has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting VEGFR2 and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed FGFR2, while zolbetuximab targets overexpressed CLDN18.2, significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer; and the treatment strategies for gastric cancer based on targeting HER2, VEGF, FGFR2, CLDN18.2, MET and other tumor driver genes, aiming to provide reference for clinical application of targeted therapy for gastric 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.

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.

P1/2, N=72, Recruiting, Phanes Therapeutics | Phase classification: P1 --> P1/2 | Trial completion date: Apr 2024 --> Apr 2026 | Trial primary completion date: Nov 2023 --> Dec 2025

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.

P2, N=123, Recruiting, AstraZeneca

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.

P1, N=96, Recruiting, Peking University | Not yet recruiting --> Recruiting

P1, N=320, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Phase classification: P1a/1b --> P1 | Trial completion date: Apr 2024 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

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.

41, 2023. Clinical trial information: NCT05980416.

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.

P1/2, N=269, Suspended, Sotio Biotech Inc. | Recruiting --> Suspended

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

P2, N=143, Recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Jul 2024 --> Dec 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).

P1/2, N=13, Terminated, BioNTech SE | N=96 --> 13 | Trial completion date: Sep 2024 --> Jul 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Jul 2023; Sponsor decision