FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma

Regulatory approval: On Oct 18, 2024, the FDA approved zolbetuximab-clzb (Vyloy), a CLDN18.2-directed cytolytic antibody, in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive by an FDA-approved test. Approval was supported by the phase 3 SPOTLIGHT and GLOW trials showing improved PFS and OS versus chemotherapy plus placebo.

FDA approval: zolbetuximab-clzb + chemotherapy in CLDN18.2+ gastric/GEJ adenocarcinoma (first line)

Type: Regulatory approval (FDA)
Date: 2024-10-18

The FDA approved zolbetuximab-clzb (Vyloy; Astellas), a CLDN18.2-directed cytolytic antibody, with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or 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 (Ventana/Roche) as a companion diagnostic to identify eligible patients.

Efficacy evidence

Efficacy was evaluated in SPOTLIGHT (NCT03504397) and GLOW (NCT03653507), randomized (1:1), double-blind, multicenter trials in CLDN18.2+, advanced unresectable or metastatic HER2-negative gastric/GEJ adenocarcinoma. Primary endpoint: PFS (RECIST v1.1, IRC); OS was additional.

  • SPOTLIGHT (n=565): zolbetuximab-clzb + mFOLFOX6 vs placebo + mFOLFOX6. Median PFS 10.6 vs 8.7 months (HR 0.751; 95% CI 0.598–0.942; 1-sided p=0.0066). Median OS 18.2 vs 15.5 months (HR 0.750; 95% CI 0.601–0.936; 1-sided p=0.0053).
  • GLOW (n=507): zolbetuximab-clzb + CAPOX vs placebo + CAPOX. Median PFS 8.2 vs 6.8 months (HR 0.687; 95% CI 0.544–0.866; 1-sided p=0.0007). Median OS 14.4 vs 12.2 months (HR 0.771; 95% CI 0.615–0.965; 1-sided p=0.0118).

Safety (serious AEs ≥2%)

Common serious adverse reactions included vomiting, nausea, and hematologic/infectious events (e.g., neutropenia, febrile neutropenia, sepsis) in SPOTLIGHT; and vomiting, nausea, decreased appetite, decreased platelet count, upper GI hemorrhage, pneumonia, pulmonary embolism in GLOW.

Dosing (with chemotherapy)

First dose: 800 mg/m² IV. Subsequent: 600 mg/m² IV q3w or 400 mg/m² IV q2w.

The FDA review used RTOR, and the application received priority review, fast track, and orphan drug designation.

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