On 18 October 2024, the US Food and Drug Administration (FDA) approved 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 gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours are CLDN18.2-positive, as determined by an FDA-approved test.
FDA also 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.
Efficacy was evaluated in SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. Both were randomised (1:1), double-blind, multicentre 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 studies was progression-free survival (PFS), as assessed per RECIST v1.1 by an independent review committee. Overall survival (OS) was an additional efficacy outcome measure.
In SPOTLIGHT, 565 patients were randomised to receive zolbetuximab-clzb with mFOLFOX6 chemotherapy or placebo with mFOLFOX6 chemotherapy. Median PFS was 10.6 months (95% confidence interval [CI] 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy arm and 8.7 months (95% CI 8.2, 10.3) in the placebo/chemotherapy arm (hazard ratio [HR] 0.751, 95% CI 0.598, 0.942; 1-sided p-value = 0.0066). Median OS was 18.2 months (95% CI 16.4, 22.9) and 15.5 months (95% CI 13.5, 16.5) with HR 0.750 (95% CI 0.601, 0.936; 1-sided p-value = 0.0053).
In GLOW, 507 patients were randomised to receive either zolbetuximab-clzb with CAPOX chemotherapy or placebo with CAPOX chemotherapy. Median PFS was 8.2 months (95% CI 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy arm and 6.8 months (95% CI 6.1, 8.1) in the placebo/chemotherapy arm (HR 0.687, 95% CI 0.544, 0.866; 1-sided p-value = 0.0007). Median OS was 14.4 months (95% CI 12.3, 16.5) and 12.2 months (95% CI 10.3, 13.7) with HR of 0.771 (95% CI 0.615, 0.965; 1-sided p-value = 0.0118).
The most common serious adverse reactions in SPOTLIGHT (≥2%) were vomiting, nausea, neutropenia, febrile neutropenia, diarrhoea, 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 haemorrhage, diarrhoea, pneumonia, pulmonary embolism, and pyrexia.
The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is at first dose 800 mg/m2 intravenously, and subsequent dosages of 600 mg/m2 intravenously every 3 weeks, or 400 mg/m2 intravenously every 2 weeks.
This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review, fast track, and orphan drug designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.