On October 18, 2024, FDA approved Vyloy (zolbetuximab-clzb) as the first and only claudin-18.2-targeted antibody to treat gastric cancer. The drug has been approved to be used in combination with fluoropyrimidine and platinum containing chemotherapy for patients suffering from locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Who is the treatment target?
This first-line treatment is effective for adults with HER2-negative, CLDN18.2-positive gastroesophageal junction (GEJ) adenocarcinoma. It is a type of cancer that occurs where the esophagus connects to the stomach, accounting for approximately 8,810 new cases diagnosed annually in the United States. It includes 5-15% of all esophageal cancers with a 5-year survival rate of around 21.7%. Claudin (CLDN) 18.2 is a junction protein and helps in the attachment of epithelial cell. Its overexpression facilitates the tumor growth.
How does Vyloy work?
Vyloy or Zolbetuximab-clzb (Astellas Pharma/Ganymed) is a CLDN18.2-directed cytolytic antibody that targets and depletes CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). When combined with chemotherapy, zolbetuximab-clzb exhibits enhanced antitumor activity in CLDN18.2-expressing tumor models. This synergistic effect improves treatment outcomes for patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. By selectively targeting CLDN18.2-positive cells, zolbetuximab-clzb minimizes harm to healthy cells, providing a targeted therapeutic approach.
Clinical Studies, Efficacy and and Side Effects
The efficacy of Vyloy with mFOLFOX6 was determined by SPOTLIGHT, a double-blind, randomized, multicenter study, whereas its effect in combination with CAPOX was evaluated by GLOW, a double-blind, randomized, multicenter study. 565 and 507 adults suffering from locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma with CLDN18.2 positive tumors were enrolled respectively in SPOTLIGHT and GLOW.
50% of the patients from each study were administered with Zolbetuximab-clz and the rest with placebo when they were being treated CAPOX or mFOLFOX6. The efficacy was measured using progression free survival (PFS) as a primary endpoint.
A significant improvement of the overall survival was observed in each study, though with common side effects such as nausea, vomiting and loss of appetite.
Market and upcoming competitors
CLDN18.2 is a validated target for gastric cancer treatment. High expression (40-60%) in cancer cells, limited in healthy tissues, and associated with poor prognosis. Success of zolbetuximab trials with improved survival. Suitable for combination therapies, will attract competitors in the market. Antibodies like Osemitamab (Transecta), ZL-1211 (Zai Lab), IBI360 (Innovent Biologics) and many more at their prominent stage of development, Zolbetuximab-clzb might be first of many pivotal treatment options for patients suffering from gastroesophageal junction cancers.
Dr. Avraneel Paul, Ph.D.
Sources
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761365s000lbl.pdf
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