Vyloy (zolbetuximab-clzb) / Astellas - LARVOL DELTA

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis, Version 2.2025. (NCCN)

NCCN guideline • Multiple Myeloma • Oncology • Solid Tumor

Synthesis and Preclinical Evaluation of a Novel Radiolabeled Anti-Caudin-18.2 Humanized VHH-Based Recombinant Antibody as Radioimmunotherapy Candidate for Gastric Cancer (SNMMI 2025) - "Compared to Zolbetuximab (150 KDa), the smaller molecular size of hTCE009 (78 KDa) enabled improved tumor penetration and reduced blood toxicity. The radiochemical purity of 177Lu-hTCE009 exceeded 95%. The NUGC4CLDN18.2 cell line exhibited a higher expression of CLDN18.2 compared to the SNU620 cell line and the strong membrane antigen-antibody binding ability of hTCE009, Zolbetuximab, respectively, according to the results of flow cytometry and cell immunofluorescence."

IO biomarker • IO Companion diagnostic • Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Hematological Disorders • Oncology • Solid Tumor • CLDN18

Biomarker-Driven Approach to the Treatment of Metastatic Gastric or Gastroesophageal Adenocarcinoma. (PubMed, J Natl Compr Canc Netw) - "Following the pivotal ToGA trial and the approval of trastuzumab for HER2-positive disease, the search for biomarkers has advanced exponentially. Two recent phase III trials have demonstrated survival benefits with the addition of zolbetuximab to frontline chemotherapy. A number of other biomarker-driven clinical trials are in progress, investigating new targeted agents that are expected to further transform the management of gastric or gastroesophageal adenocarcinoma."

Biomarker • IO biomarker • Journal • Review • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • CLDN18 • HER-2 • MSI • PD-L1

Phase II RAINSPOT: Zolbetuximab-Paclitaxel-Ramucirumab for CLDN18.2 Positive Gastro-esophageal Cancer (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: Universitaire Ziekenhuizen KU Leuven

New P2 trial • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Treatment Selection for Patients with HER2-Negative Metastatic Gastric Cancer Expressing Claudin 18.2 and PD-L1. (PubMed, Cancers (Basel)) - "Combination therapy of chemotherapy and immune checkpoint inhibitors (ICIs)-either nivolumab or pembrolizumab-is a standard first-line therapy for patients with HER2-negative mGCs that are positive for programmed death-ligand 1 (PD-L1) expression, as defined by a combined positive score (CPS). Treatment selection under this condition has become a critical issue. In this review, we discuss the appropriate treatment selection for HER2-negative mGC patients who are double-positive for CLDN 18.2 and PD-L1 based on clinical data and differences in the mechanism of action and safety profile between zolbetuximab and ICI."

IO biomarker • Journal • Review • Gastric Cancer • Oncology • Solid Tumor • CLDN18 • HER-2 • PD-L1

ILUSTRO: A Study of Zolbetuximab (IMAB362) in Adults With Gastric Cancer (clinicaltrials.gov) - P2 | N=143 | Active, not recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial primary completion date: Apr 2025 ➔ Jan 2026

Monotherapy • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18 • PD-L1

Unlocking the potential of zolbetuximab in CLDN18.2-positive gastric cancer: A comprehensive systematic review of clinical efficacy and safety. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Review • Gastric Cancer • Oncology • Solid Tumor • CLDN18

A Study to Observe the Safety of VYLOY (Zolbetuximab) in People in South Korea With Gastric or Gastroesophageal Junction Cancer. (clinicaltrials.gov) - P=N/A | N=377 | Recruiting | Sponsor: Astellas Pharma Korea, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Claudin 18.2 Expression in Gastric Tumors and Other Tumor Types With Gastric Epithelium-like Differentiation. (PubMed, In Vivo) - "Overall, claudin 18.2 positivity occurred primarily in a significant proportion of gastric tumors and other tumors with gastric epithelium-like differentiation. Evaluating claudin 18.2 expression in all such tumors can benefit patients by guiding targeted therapy. Additionally, claudin 18.2 immunostaining serves as a lineage marker for gastric origin or gastric-like differentiation."

Journal • Biliary Cancer • Epstein-Barr Virus Infections • Gastric Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • CLDN18

Modeling and Use of Engineering to Overcome On-Target/Off-Tumor Toxicity of Claudin 18.2-Targeted CAR-T cells in Gastric Cancer (ASGCT 2025) - "Claudin 18.2 (CLDN18) targeted therapies, such as monoclonal antibody, zolbetuximab, and CAR-T cell, Satri-cel (CT041) are expanding access to immunotherapy in gastric cancer, however, high rates of nausea and vomiting were seen...We demonstrate that appropriate modeling of anticipated toxicity and careful examination of binding kinetics is critical to engineering a CAR with an optimal therapeutic window. Disease Focus of Abstract:Cancer Solid Tumors"

CAR T-Cell Therapy • IO biomarker • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Graft versus Host Disease • Immunology • Oncology • Solid Tumor • CLDN18

Zolbetuximab in combination with chemotherapy in HER2-negative and CLDN 18.2-positive locally advanced unresectable or metastatic gastric or esogastric junction adenocarcinomas (PubMed, Bull Cancer) - No abstract available

Journal • Gastric Cancer • Oncology • HER-2

Computer-aided diagnostics helps to accurately determine different expression levels of claudin-18.2 in gastric cancer. (PubMed, Pathobiology) - "Introduction Determination of claudin-18.2 expression by immunohistochemistry (IHC) is prerequisite for targeted treatment of gastric cancers (GC) with zolbetuximab...Conclusion Computer-aided diagnostics helps to accurately measure claudin-18.2 expression levels, allowing to precisely determine claudin-18.2 status in GC patients. Previously uncaptured categorization of staining intensities may enhance the understanding of claudin-18.2 threshold for patient stratification."

Biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor • CLDN18

Vyloy: Final analysis data from P2 GLEAM trial (NCT03816163) for pancreatic cancer in Q2 FY2025 (Astellas) - FY 2024 Results

P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Comparison of ADCC-mediated efficacy of zolbetuximab in hCD16A-CB17SCID humanized mice and CB17SCID WT mice bearing the SNU-601 tumor model (AACR 2025) - "This study indicates that hCD16A-CB17SCID HuGEMM models exhibit enhanced tumor growth inhibition in response to zolbetuximab treatment compared to CB17SCID WT models, demonstrating the potential of this model as a more effective preclinical model for evaluating ADCC-mediated therapies."

Preclinical • Oncology • CLDN18 • ITGA2 • LAMP1

A preclinical in vitro platform for evaluating the potency of bispecific T cell engagers in 2D and 3D models (AACR 2025) - "In this study in vitro assays were established to evaluate the tumor cell-killing and T cell activation of BiTEs, specifically using a claudin18.2-targeted BiTE AMG910 and the monoclonal antibody zolbetuximab. Target expression on tumor cells for claudin18.2 and AMG910/zolbetuximab binding to tumor and T cells was evaluated via flow cytometry. Successful in vitro assays were developed for preclinical BiTEs testing. 2D co-cultures efficiently assess direct tumor cell killing and T cell activation mediated by antibody treatments. Additionally, 3D organoid co-cultures offered a more physiologically relevant setup, mimicking the tumor microenvironment and representing patient diversity."

Preclinical • Oncology • CD69 • CLDN18 • GZMB • IFNG • IL2RA

Retrospective analysis of claudin-18.2 expression in ethnically diverse patients with gastroesophageal adenocarcinoma (AACR 2025) - "Recent phase III trials demonstrated improved survival with the addition of an anti-CLDN18.2 antibody (zolbetuximab) to first-line chemotherapy... This study provides new information on CLDN18.2 expression in an ethnically diverse population and suggests that Hispanic patients may have higher rates of CLDN18.2 positivity than non-Hispanic patients. However, this finding lacks statistical significance, likely due to the small sample size. We also demonstrate the association between CLDN18.2 and female sex and lack of association with survival, consistent with published data."

Retrospective data • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • CLDN18 • HER-2 • TP53

Efficacy of a claudin 18.2/TGFβ bi-specific CAR-T in preclinical mouse models of gastric cancer (AACR 2025) - "Claudin 18.2, a tight junction protein that is expressed on the GC cell surface, has been validated as a bona fide target in GC with recent FDA approval of zolbetuximab, a Claudin 18.2 directed antibody. We also demonstrate remodeling of the tumor immune microenvironment in our GC model in an immune competent background with an increase in CD19+ B cells in mice treated with our bispecific Claudin18.2/TGFβ CAR-T versus mice treated with untransduced T cells. Our data suggest that a bi-specific claudin18.2/TGFβ CAR T cell candidate may be an effective therapeutic approach for the treatment of gastric tumors that express Claudin 18.2."

Preclinical • Gastric Cancer • Oncology • Solid Tumor • CLDN18 • TGFB1

The co-expression and prognostic significance of the HER-family members, EGFRvIII, CD44, CD109 and Claudin 18.2 in patients with stomach adenocarcinoma (AACR 2025) - "While targeted therapies with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab, antibody-drug-conjugate trastuzumab deruxtecan, and more recently zolbetuximab, an anti-claudin 18.2 (CLDN 18.2) mAb, have been approved for the treatment of stomach cancer, many patients may not respond or have a response of short duration to such treatments. All these remained as independent prognostic factors for overall survival in multivariate analysis. Taken together, our results suggest co-expression of HER-2 with other members of the HER family, EGFRvIII, CD44, CD109 and CLDN 18.2 occurs in patients with stomach cancer and warrants further investigation on the predictive value of such biomarkers for the response to therapy with inhibitors to HER family members and CLDN 18.2."

Clinical • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • CD44 • CLDN18 • EGFR • ERBB3 • ERBB4

Humanized PD1 mouse with MC38-hCLDN18.2 cell line provide powerful syngeneic model platform for evaluating Claudin18.2-targeted therapies (AACR 2025) - "Human PD-1 protein expression was validated by FACS analysis after in vivo anti-CD3 stimulation.The tumor growth inhibition of two CLDN18.2 monoclonal antibodies (IMAB362 and ASKB589) was evaluated in hPD1 mice engrafted with MC38-CLDN18.2 syngeneic tumors. The therapeutic effects of these antibodies were also investigated in combination with anti-PD-1 treatment. Both anti-CLDN18.2 monotherapies demonstrated moderate antitumor efficacy, while their combination with PD-1/PD-L1 immune checkpoint blockade produced significant synergistic effects, resulting in enhanced tumor suppression and increased antitumor immunity with robust T-cell infiltration.In summary, the humanized PD-1 mouse model and MC38-CLDN18.2 cell line provide robust in vivo platforms to evaluate novel therapeutic candidates targeting CLDN18.2."

IO biomarker • Preclinical • Colon Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CLDN18 • PD-1

VBC108: a first-in-class CDH17/CLDN18.2 targeted bispecific antibody drug conjugate (ADC) to overcome tumor heterogeneity of gastrointestinal cancers (GC, PADC, CRC, etc.) (AACR 2025) - "However, these therapies face challenges due to the heterogeneous expression of CLDN18.2, leading to inconsistent efficacy and the need of patient stratification, as observed with Zolbetuximab, AZD0901 and IBI343. VBC108 also exhibited excellent developability in a comprehensive developability assessment (DA) test, making it a strong candidate for further CMC development. In summary, VBC108, with its unique design, shows the potential as a first-in-class ADC for GI cancer and supports the advancement to clinical trials."

Heterogeneity • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CDH17 • CLDN18

A novel approach of Claudin 18 immunohistochemistry testing demonstrated comparable performance and high concordance compared to Ventana 43-14A in gastric cancer (AACR 2025) - "Zolbetuximab is the first CLDN18.2 therapeutic monoclonal antibody approved by FDA... Two Claudin 18 testing approaches demonstrated high concordance. It has potential versatility in future clinical practice."

Discordant • Gastric Cancer • Oncology • Solid Tumor • CLDN18

Astellas says Vyloy's sales debut "beyond expectation" (Firstwordpharma Press Release) - "Astellas said Friday that sales of Vyloy have 'expanded beyond expectation' since being cleared in Japan last year as the first-ever approved CLDN18.2-targeting antibody, reaching JPY 12.2 billion ($85 million) in fiscal 2024...The drugmaker forecasts that the product will generate revenue of JPY 40 billion in the current fiscal year, with a 'substantial contribution' from both the US and Japan...Sales of Vyloy in the US are predicted to reach $120 million, with revenue in Japan of JPY 14 billion. Astellas added that the product's launch in China is anticipated in the first quarter. The company forecasts peak sales for Vyloy of between JPY 100 billion and JPY 200 billion, although key opinion leaders interviewed by FirstWord see looming competition in the shape of antibody-drug conjugates and combination regimens."

Sales projection • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Spotlight: A Study to Compare Zolbetuximab (IMAB362) and Chemotherapy With Placebo and Chemotherapy in Adults With Gastric Cancer. (clinicaltrials.gov) - P3 | N=565 | Active, not recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial completion date: Mar 2025 ➔ Sep 2025

Trial completion date • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18 • HER-2

Managing patients with advanced G/GEJ cancer who are receiving VYLOY (zolbetuximab-clzb) (ONS 2025) - "Sponsored by Astellas: Managing patients with advanced G/GEJ cancer who are receiving VYLOY (zolbetuximab-clzb)"

Clinical • Metastases • Gastric Cancer • Gastroesophageal Cancer • Oncology

A Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX as First-line Treatment of Subjects With Claudin (CLDN) 18.2-positive, HER2-negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (GLOW). (clinicaltrials.gov) - P3 | N=507 | Active, not recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Trial completion date: Mar 2025 ➔ Sep 2025

Trial completion date • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18 • HER-2