The U.S. Food and Drug Administration (FDA) has granted approval to Astellas Pharma's Vyloy (zolbetuximab-clzb) in combination with fluoropyrimidine- and platinum-containing chemotherapy, marking a significant advancement in the treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. This approval is specifically for patients whose tumors exhibit Claudin 18.2 (CLDN18.2) positivity, as determined by an FDA-approved test.
Vyloy is a first-in-class claudin 18.2-directed cytolytic antibody. The approval is based on the outcomes of the Phase 3 SPOTLIGHT and GLOW clinical trials, which demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) when zolbetuximab was added to standard chemotherapy regimens.
Clinical Trial Data
The SPOTLIGHT trial evaluated Vyloy in combination with mFOLFOX6 (a chemotherapy regimen including oxaliplatin, leucovorin, and fluorouracil), while the GLOW trial assessed Vyloy with CAPOX (capecitabine and oxaliplatin). Key findings from these trials include:
- SPOTLIGHT: Median PFS was 10.61 months in the zolbetuximab plus mFOLFOX6 arm compared to 8.67 months in the placebo plus mFOLFOX6 arm (HR, 0.751; 95% CI, 0.598-0.942; one-sided P-value = .0066). Median OS was 18.23 months and 15.54 months, respectively (HR, 0.750; 95% CI, 0.601-0.936; one-sided P-value = .0053).
- GLOW: Median PFS was 8.21 months in the zolbetuximab plus CAPOX arm compared to 6.8 months in the placebo plus CAPOX arm (HR, 0.687; [95% CI, 0.544-0.866]; one-sided P-value = .0007). Median OS was 14.39 months vs 12.16 months, respectively (HR 0.771; 95% CI, 0.615-0.965; one-sided P-value = .0118).
Companion Diagnostic
Concurrent with this approval, the FDA also approved Roche's VENTANA CLDN18 (43-14A) RxDx Assay, an immunohistochemistry (IHC) test, as a companion diagnostic. This assay will identify patients with gastric or GEJ adenocarcinoma eligible for Vyloy treatment by determining the CLDN18.2 status of their tumors. CLDN18.2 positivity is defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 immunohistochemical staining.
Expert Commentary
Samuel J. Klempner, M.D., Associate Professor at Harvard Medical School and Medical Oncologist at Massachusetts General Hospital, stated, "While there have been advances in the first-line treatment of locally advanced unresectable and metastatic gastric and GEJ cancers in the last several years, there is still a tremendous unmet need among our patients. The approval of VYLOY, based on the pivotal Phase 3 SPOTLIGHT and GLOW trials, brings forward a novel biomarker and new therapy for patients whose tumors are CLDN18.2 positive, and for those on the frontlines of treatment decision-making."
Adverse Events
Across both trials, the most common treatment-emergent adverse events (TRAEs) reported in the zolbetuximab treatment arms were nausea, vomiting, and decreased appetite.
Global Approvals
Following the FDA decision, Vyloy is now approved in five markets worldwide, including Japan, the United Kingdom, the European Union, and South Korea. Astellas has submitted applications for zolbetuximab to additional regulatory agencies globally, with reviews currently ongoing.
About Zolbetuximab
Zolbetuximab is a first-in-class monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein expressed on gastric tumor cells. This binding leads to the depletion of CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Disease Burden
Gastric and gastroesophageal junction (G/GEJ) cancer is the fifth most commonly diagnosed cancer worldwide. In the U.S., approximately 26,890 people will be diagnosed with G/GEJ cancer in 2024, and 10,880 will die from the disease. Because early-stage symptoms often overlap with more common stomach-related conditions, G/GEJ cancer is frequently diagnosed in advanced stages, resulting in a five-year relative survival rate of just 7% for metastatic patients.
