On October 18, 2024, the U.S. Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy), 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.
The FDA also approved the Ventana CLDN18 (43-14A) RxDx Assay as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma who may be eligible for treatment with zolbetuximab.
Efficacy and Safety
Efficacy was evaluated in trials SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). Both were randomized (1:1), double-blind, multicenter trials that enrolled patients with CLDN18.2-positive advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma. The major efficacy outcome measure in both trials was progression-free survival, as assessed per RECIST v1.1 by an independent review committee. Overall survival was an additional efficacy outcome measure.
In SPOTLIGHT, 565 patients were randomly assigned to receive zolbetuximab-clzb with mFOLFOX6 chemotherapy or placebo with adjuvant modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy. Median progression-free survival was 10.6 months (95% confidence interval [CI] = 8.9–12.5 months) in the zolbetuximab-clzb/chemotherapy arm and 8.7 months (95% CI = 8.2–10.3 months) in the placebo/chemotherapy arm (hazard ratio [HR] = 0.751; 95% CI = 0.598–0.942; 1-sided P = .0066). Median overall survival was 18.2 months (95% CI = 16.4–22.9 months) and 15.5 months (95% CI = 13.5 = 16.5 months), respectively, (HR = 0.750; 95% CI = 0.601–0.936; 1-sided P = .0053).
In GLOW, 507 patients were randomly assigned to receive either zolbetuximab-clzb with CAPOX chemotherapy or placebo with or capecitabine and oxaliplatin (CAPOX) chemotherapy. Median progression-free survival was 8.2 months (95% CI = 7.5–8.8 months) in the zolbetuximab-clzb/chemotherapy arm and 6.8 months (95% CI = 6.1,–8.1 months) in the placebo/chemotherapy arm (HR = 0.687; 95% CI = 0.544– 0.866; 1-sided P = .0007). Median overall survival was 14.4 months (95% CI = 12.3–16.5) and 12.2 months (95% CI = 10.3–13.7 months), respectively (HR = 0.771; 95% CI = 0.615–0.965; 1-sided P =.0118).
The most common serious adverse reactions in SPOTLIGHT (≥ 2%) were vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, pyrexia, pneumonia, respiratory failure, pulmonary embolism, decreased appetite, and sepsis. The most common serious adverse reactions in GLOW (≥ 2%) were vomiting, nausea, decreased appetite, decreased platelet count, upper gastrointestinal hemorrhage, diarrhea, pneumonia, pulmonary embolism, and pyrexia.
The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m2 intravenously as a first dose, with subsequent dosages of 600 mg/m2 intravenously every 3 weeks, or 400 mg/m2 intravenously every 2 weeks.
For additional information, visit FDA.gov.
