Vyloy (zolbetuximab) / Astellas - LARVOL DELTA

Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer. (PubMed, Dig Dis Sci) - "Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value."

Journal • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • CLDN18 • HER-2

Astellas Showcases Scientific Advancements Across its Oncology Portfolio at 2024 ASCO Annual Meeting (PRNewswire) - "Final overall survival (OS) results from the Phase 3 SPOTLIGHT study, evaluating the efficacy and safety of zolbetuximab....Two new post-hoc analyses of the Phase 3 EMBARK trial, which evaluated enzalutamide plus leuprolide, placebo plus leuprolide, and enzalutamide (single agent) in patients with nonmetastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with high-risk biochemical recurrence (BCR), including an oral presentation on the impact of treatment suspension on health-related quality of life and a poster presentation on sexual activity patient-reported outcomes."

P3 data • Retrospective data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

State of the art and upcoming trends in claudin-directed therapies in gastrointestinal malignancies. (PubMed, Curr Opin Oncol) - "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."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • CLDN18

Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. (ASCO 2024) - P3 | "Clinical Trial Registration Number: NCT03504397"

Clinical • Metastases • P3 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • CLDN18 • HER-2

Consensus guidance for management of nausea/vomiting in patients treated with zolbetuximab + chemotherapy: A RAND/UCLA modified Delphi panel study (ESMO-GI 2024) - No abstract available

Clinical

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs; approval of elranatamab for multiple myeloma, CPX-351 for myeloid leukemia, inotuzumab ozogamicin for lymphoblastic leukemia, capivasertib for breast cancer, and zolbetuximab for gastric cancer in Japan. (PubMed, Int J Clin Oncol) - No abstract available

Japanese regulatory • Journal • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Solid Tumor

A Study of Zolbetuximab With Chemotherapy in Adults With Pancreatic Cancer (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Astellas Pharma Global Development, Inc.

Combination therapy • Metastases • New P1 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

8951-CL-0104: A Study of IMAB362 in Japanese Subjects With Locally Advanced or Metastatic Gastric or Gastro-esophageal Junction (GEJ) Adenocarcinoma (clinicaltrials.gov) - P=N/A | N=18 | Completed | Sponsor: Astellas Pharma Inc | Phase classification: P1 ➔ P=N/A

Metastases • Phase classification • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18

A Study to Assess the Efficacy and Safety of IMAB362 in Combination With Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects With Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma (clinicaltrials.gov) - P2 | N=393 | Active, not recruiting | Sponsor: Astellas Pharma Global Development, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CLDN18

An anti-claudin 18.2/CD3 bispecific antibody for the treatment of claudin 18.2 positive gastric cancer (AACR 2024) - "However, Zolbetuximab (IMAB362) has successfully reached the Phase III end point, indicating positive clinical outcomes and establishing CLDN18.2 as a promising cellular and antibody therapeutic option. In conclusion, the novel anti-CLDN18.2 × anti-CD3 bispecific antibody LNF2007 demonstrates similar efficacy to AMG 910 and AZD5863 and is safer. LNF2007 provides a promising therapy for claudin 18.2-positive cancer patients.Taishan Industry Leading Talents Project of Shandong Province was a sponsor of this research."

IO biomarker • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CLDN18

New therapeutic target molecules for gastric and gastroesophageal junction cancer. (PubMed, Int J Clin Oncol) - "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."

Journal • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5 • CLDN18 • DKK1 • EGFR • FGFR2 • HER-2

Immune checkpoint inhibitors or anti-claudin 18.2 antibodies? A network meta-analysis for the optimized first-line therapy of HER2-negative gastric cancer. (PubMed, Ther Adv Med Oncol) - "For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94-1.07], sintilimab (HR = 0.99, 95% CI: 0.89-1.09), sugemalimab (HR = 0.98, 95% CI: 0.87-1.10), tislelizumab (HR = 0.97, 95% CI: 0.87-1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91-1.07), and nivolumab (HR = 1.00). In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95-1.04) and PFS (HR = 1.01, 95% CI: 0.91-1.12) compared to immunotherapy, although their toxicity profiles were distinct. Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers."

Checkpoint inhibition • Journal • Retrospective data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • HER-2

Claudin 18.2 Positive Colorectal Carcinoma is Frequently Mismatch Repair Deficient with BRAF V600E Mutation: An Immunohistochemical Survey of Claudin 18.2 Expression in 805 Adenocarcinomas of the Digestive System (USCAP 2024) - "Claudin 18.2 positive colorectal adenocarcinomas (26/576, 5%) are frequently MMR deficient (19/26, 73%) and demonstrate distinct histologic features. Future studies addressing efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed."

Mismatch repair • Breast Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRAF • CDX2 • CLDN18 • HER-2 • KRAS • MLH1 • MSH2 • MSH6 • PMS2

New CLDN18.2 protein offers breakthrough in stomach cancer treatment (Korea Biomedical Review) - "As the Claudin 18.2 protein, also called CLDN18.2, emerges as a new target for treating gastric cancer, Astellas' first CLDN18.2-targeted cancer drug, zolbetuximab, is in the final stage of its launch, drawing the industry’s attention. However, the changing landscape of metastatic gastric cancer treatment and the rapid development of follow-on therapies make it unclear whether zolbetuximab will claim the 'first in class' title in the market, according to industry insiders....Based on these findings, zolbetuximab is under review for approval in the U.S., China, and Japan. It is also preparing to get approval in Korea next year....Expectations that ADCs containing cytotoxic anticancer agents, such as CMG901 and ATG-022, will show better therapeutic outcomes than traditional monoclonal antibodies have market insiders paying attention to how their clinical trial results and market access will impact the competitive landscape in gastric cancer treatment."

Launch • Non-US regulatory • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Astellas' VYLOY (zolbetuximab) Approved in Japan for Treatment of Gastric Cancer (PRNewswire) - "Astellas Pharma Inc...announced that on March 26, 2024, Japan's Ministry of Health, Labour and Welfare (MHLW) approved VYLOY (zolbetuximab), an anti-claudin 18.2 (CLDN18.2) monoclonal antibody for patients with CLDN18.2 positive, unresectable, advanced or recurrent gastric cancer. VYLOY is the first and only CLDN18.2-targeted therapy approved by any regulatory agency in the world....The approval is based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials for first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors were CLDN18.2 positive....Astellas has also submitted applications for VYLOY to regulatory agencies around the world, and review is ongoing."

Japanese regulatory • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Claudin 18.2 as a novel therapeutic target. (PubMed, Nat Rev Clin Oncol) - "Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy...This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours."

Journal • Review • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18

Japan Panel Clears Astellas’ Gastric Cancer Med for Approval after FDA Rejection (Pharma Japan) - "A key Japanese health ministry panel on March 4 gave the thumbs-up to the approval of Astellas Pharma’s zolbetuximab, a first-in-class anti- Claudin 18.2 (CLDN18.2) monoclonal antibody, two months after the US FDA declined its application over manufacturing issues."

Japanese regulatory • Gastric Cancer

Astellas’ Claudin 18.2 gastric cancer drug will be discussed at the second subcommittee meeting on the 4th of next month, with 8 new active ingredients [Google translation] (JIHO) - "On March 4th, the Ministry of Health, Labor and Welfare will hold a meeting of the Pharmaceutical Affairs and Food Sanitation Council's Second Subcommittee on Pharmaceutical Affairs to approve the approval of Astellas Pharma's chimeric IgG1 monoclonal antibody 'Viroy for Intravenous Injection 100 mg' (generic name: zolbetuximab (genetical recombination))."

Japanese regulatory • Gastrointestinal Cancer

MONO, FAST, SPOTLIGHT, GLOW: Clinical data on the efficacy, safety and quality of life of zolbetuximab (OeGHO-AHOP 2024) - "Sponsored by Astellas"

Clinical data • HEOR

Advances in targeted therapy for gastric cancer based on tumor driver genes. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "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."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • FGFR2 • HER-2 • KDR

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma. (PubMed, Curr Oncol) - "Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome."

IO biomarker • Journal • Metastases • Review • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • HER-2

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials. (PubMed, BMC Cancer) - "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."

Clinical • Journal • Metastases • Retrospective data • Review • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • HER-2

The tight junction protein claudin 18.2 is markedly and therapeutically relevant heterogeneously distributed in carcinomas of the upper gastrointestinal tract (DKK 2024) - "Zolbetuximab is a therapeutic monoclonal antibody against Claudin 18.2 for therapy of HER2/neu-negative upper GI-tract carcinomas... Claudin 18.2 is a heterogeneously expressed biomarker. In the case of negative claudin 18.2 results, it must be clear on what evidence this result is based. If necessary, a re-biopsy of the tumor or a biopsy of metastases should be considered."

Heterogeneity • IO biomarker • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • CLDN18 • HER-2 • PD-L1

Top Gastric Cancer Articles from 2022 and 2023 to Inform Your Cancer Practice. (PubMed, Ann Surg Oncol) - "This article summarizes the findings and implications of several important studies published over the past 2 years that are fundamentally changing the way we treat patients with gastroesophageal cancer."

Clinical • Journal • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN18 • HER-2

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials (BMC Cancer) - "Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49–0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62–0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87–1.53; p = 0.34)."

Retrospective data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma