Zolbetuximab-clzb Plus Chemotherapy Approved for Gastric or Gastroesophageal Junction Adenocarcinoma
Expert Perspectives · Lyn Brook · 2024-10-22
The FDA has granted approval to zolbetuximab-clzb (Vyloy™, Astellas Pharma US, Inc.), a claudin 18.2 (CLDN18.2)–directed cytolytic antibody, with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2–positive, as determined by an FDA-approved test. This is the first approval of zolbetuximab-clzb and the first approval of a CLDN18.2-directed antibody for gastric or GEJ adenocarcinoma in the United States.
In addition, the FDA approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma who may be eligible for treatment with zolbetuximab.
Why it matters: “Zolbetuximab, a monoclonal antibody targeting CLDN18.2, has shown efficacy in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma,” wrote Kohei Shitara, MD, Director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East, Japan, and colleagues, in their published results of the SPOTLIGHT (NCT03504397) trial, on which approval was partially based.
What they studied: Efficacy was measured in the SPOTLIGHT and GLOW (NCT03653507) trials which enrolled patients with CLDN18.2-positive advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.
- SPOTLIGHT: 565 patients were randomized 1:1 to receive either zolbetuximab-clzb with mFOLFOX6 chemotherapy or placebo with mFOLFOX6 chemotherapy
- GLOW: 507 patients were randomized 1:1 to receive either zolbetuximab-clzb with CAPOX chemotherapy or placebo with CAPOX chemotherapy
The primary efficacy end point measured in both trials was progression-free survival as assessed by RECIST v1.1 by an independent review committee. Each trial also included a key secondary end point of overall survival.
What they found:
- SPOTLIGHT: The median progression-free survival was 10.6 months in those receiving zolbetuximab-clzb plus chemotherapy compared with 8.7 months in those receiving placebo plus chemotherapy. The median overall survival was 18.2 months in the zolbetuximab-clzb arm compared with 15.5 months in the placebo arm
- GLOW: The median progression-free survival was 8.2 months in those receiving zolbetuximab-clzb plus chemotherapy compared with 6.8 months in those receiving placebo plus chemotherapy. The median overall survival was 14.4 months in the zolbetuximab-clzb arm compared with 12.2 months in the placebo arm
Adverse events: The most common serious adverse events in SPOTLIGHT experienced by ≥2% of patients receiving zolbetuximab-clzb were vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, pyrexia, pneumonia, respiratory failure, pulmonary embolism, decreased appetite, and sepsis.
The most common adverse events in GLOW experienced by ≥2% of patients receiving zolbetuximab-clzb were vomiting, nausea, decreased appetite, decreased platelet count, upper gastrointestinal hemorrhage, diarrhea, pneumonia, pulmonary embolism, and pyrexia.
Conclusion: “GLOW and SPOTLIGHT showed a similar reduction in the risk of disease progression or death (~31% and ~25%, respectively) and a similar reduction in the risk of death (~25% in both studies) with the addition of zolbetuximab to chemotherapy when compared with placebo plus chemotherapy,” concluded Manish Shah, Director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, New York, and colleagues, in their published results of the GLOW and SPOTLIGHT trials, on which approval was based.
Instructions: The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m2 intravenously on the first dose, followed by subsequent dosages of 600 mg/m2 intravenously every three weeks or 400 mg/m2 intravenously every two weeks.