Zolbetuximab-clzb with chemotherapy is approved by the USFDA for gastric or gastroesophageal junction adenocarcinoma

On October 18, 2024, the Food and Drug Administration sanctioned zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.), a claudin 18.2 (CLDN18.2)-targeted cytolytic antibody, in conjunction with fluoropyrimidine- and platinum-based chemotherapy, for the initial treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma exhibiting CLDN18.2 positivity, as verified by an FDA-approved assay.

Today, the FDA authorized the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic tool to identify patients with gastric or gastroesophageal junction adenocarcinoma who may qualify for therapy with zolbetuximab.

Efficacy and Safety

The efficacy was assessed in the SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. Both trials were randomized (1:1), double-blind, and multicenter, enrolling patients with CLDN18.2 positive advanced unresectable or metastatic HER2-negative stomach or gastroesophageal junction cancer. The primary effectiveness endpoint in both studies was progression-free survival (PFS), evaluated according to RECIST v1.1 by an independent review committee. Overall survival (OS) constituted an additional efficacy outcome metric.

In the SPOTLIGHT trial, 565 patients were randomized to receive either zolbetuximab-clzb in conjunction with mFOLFOX6 chemotherapy or a placebo alongside mFOLFOX6 chemotherapy. The median progression-free survival (PFS) was 10.6 months (95% CI: 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy group and 8.7 months (95% CI: 8.2, 10.3) in the placebo/chemotherapy group (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). The median overall survival (OS) was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively, with a hazard ratio (HR) of 0.750 (95% CI: 0.601, 0.936) and a one-sided p-value of 0.0053.

In GLOW, 507 patients were randomized to receive either zolbetuximab-clzb in conjunction with CAPOX chemotherapy or a placebo alongside CAPOX chemotherapy. The median progression-free survival (PFS) was 8.2 months (95% CI: 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy group and 6.8 months (95% CI: 6.1, 8.1) in the placebo/chemotherapy group (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). The median overall survival (OS) was 14.4 months (95% CI: 12.3, 16.5) and 12.2 months (95% CI: 10.3, 13.7), respectively (HR 0.771 [95% CI: 0.615, 0.965]; 1-sided p-value=0.0118).

The predominant severe adverse effects in SPOTLIGHT (≥2%) included vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, pyrexia, pneumonia, respiratory failure, pulmonary embolism, diminished appetite, and sepsis. The predominant severe side events in GLOW (≥2%) included vomiting, nausea, reduced appetite, diminished platelet count, upper gastrointestinal bleeding, diarrhea, pneumonia, pulmonary embolism, and fever.

The advised dosage of zolbetuximab-clzb in conjunction with fluoropyrimidine- and platinum-based chemotherapy is:

Initial dose: 800 mg/m² intravenously. Subsequent doses: 600 mg/m² intravenously every 3 weeks, or 400 mg/m² intravenously every 2 weeks.