FDA Approves Zolbetuximab for HER2-Negative Gastric and GEJ Adenocarcinoma
核心洞察
The FDA has approved zolbetuximab-clzb (Vyloy) in combination with chemotherapy for first-line treatment of CLDN18.2 (搜索)-positive, HER2 (搜索)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Approval was based on the SPOTLIGHT and GLOW trials, which demonstrated statistically significant improvements in progression-free and overall survival.
Zolbetuximab's efficacy is determined using the Ventana CLDN18 (43-14A) RxDx Assay, a companion diagnostic to identify eligible patients.
The U.S. Food and Drug Administration (FDA) has granted approval to zolbetuximab-clzb (Vyloy), a novel claudin 18.2 (CLDN18.2 (搜索))-directed cytolytic antibody, for use in combination with fluoropyrimidine- and platinum-containing chemotherapy. This approval targets the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2 (搜索))-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 Demonstrated in SPOTLIGHT and GLOW Trials
The efficacy of zolbetuximab was evaluated in two randomized, double-blind, multicenter trials: SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). Both trials enrolled patients with CLDN18.2 (搜索)-positive advanced unresectable or metastatic HER2 (搜索)-negative gastric or GEJ adenocarcinoma. The primary efficacy outcome measure in both trials was progression-free survival, as assessed per RECIST v1.1 by an independent review committee. Overall survival was a key secondary outcome measure.
In the SPOTLIGHT trial, 565 patients were randomized to receive either zolbetuximab-clzb with mFOLFOX6 chemotherapy or placebo with mFOLFOX6 chemotherapy. The median progression-free survival was 10.6 months (95% CI = 8.9–12.5 months) in the zolbetuximab-clzb/chemotherapy arm compared to 8.7 months (95% CI = 8.2–10.3 months) in the placebo/chemotherapy arm (HR = 0.751; 95% CI = 0.598–0.942; 1-sided P = .0066). The 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).
The GLOW trial involved 507 patients randomized to receive either zolbetuximab-clzb with CAPOX chemotherapy or placebo with CAPOX chemotherapy. The 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). The median overall survival was 14.4 months (95% CI = 12.3–16.5 months) 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).
Safety Profile
The most common serious adverse reactions observed in the SPOTLIGHT trial (≥ 2%) were vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, pyrexia, pneumonia, respiratory failure, pulmonary embolism, decreased appetite, and sepsis. In the GLOW trial (≥ 2%), the most common serious adverse reactions were vomiting, nausea, decreased appetite, decreased platelet count, upper gastrointestinal hemorrhage, diarrhea, pneumonia, pulmonary embolism, and pyrexia.
Dosage and Administration
The recommended dosage of zolbetuximab-clzb, when administered with fluoropyrimidine- and platinum-containing chemotherapy, is 800 mg/m2 intravenously as an initial dose, followed by subsequent doses of 600 mg/m2 intravenously every 3 weeks, or 400 mg/m2 intravenously every 2 weeks.