zolbetuximab — Drug Monograph

Zolbetuximab (Vyloy) — CLDN18.2 Monoclonal Antibody for Gastric/GEJ Cancer

Zolbetuximab (Vyloy) is a first-in-class anti-Claudin 18.2 (CLDN18.2) monoclonal antibody for HER2-negative gastric and gastroesophageal junction (GEJ) adenocarcinoma. CLDN18.2 is a tight-junction protein retained on the surface of gastric/GEJ tumor cells; on binding, zolbetuximab triggers ADCC and complement-dependent cytotoxicity to lyse CLDN18.2-expressing cells. Only CLDN18.2-positive tumors (≥75% of tumor cells with moderate-to-strong membranous staining by IHC) qualify. This monograph covers zolbetuximab dosing (loading then maintenance with chemotherapy), gastric/GEJ adenocarcinoma indications, CLDN18.2 surface expression and the antibody mechanism, mandatory IHC screening, and proactive management of nausea, vomiting, and infusion reactions.

Indications (FDA / NCCN)

• First-line HER2-negative, CLDN18.2-positive locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma, with fluoropyrimidine + platinum chemotherapy (SPOTLIGHT, GLOW)
• CLDN18.2-positive = ≥75% of tumor cells at 2+/3+ membranous staining by an FDA-approved test
• Order CLDN18.2 IHC alongside HER2 and PD-L1 at diagnosis

Dosing

• Loading dose: 800 mg/m² IV on Cycle 1 Day 1
• Maintenance: 600 mg/m² IV every 3 weeks (with CAPOX)
• Maintenance: 400 mg/m² IV every 2 weeks (with mFOLFOX6)
• Infuse over ~2–3 h; slow or interrupt for infusion reactions and nausea/vomiting

Monitoring

• CLDN18.2 expression (IHC) before starting
• Nausea/vomiting during and after each infusion — multi-agent antiemetic prophylaxis (NK1 + 5-HT3 + corticosteroid)
• Infusion-related reactions, worst during the first infusion
• Fluid status, electrolytes, weight; CBC/LFTs/renal per chemotherapy backbone

Brand names: Vyloy

Drug class: Monoclonal Antibody

Mechanism of Action

Zolbetuximab is a chimeric IgG1 monoclonal antibody that binds Claudin 18.2 (CLDN18.2), a tight-junction protein whose expression is normally confined to gastric mucosa but which becomes retained and exposed on the surface of gastric and gastroesophageal junction (GEJ) adenocarcinoma cells. On binding CLDN18.2-expressing tumor cells, zolbetuximab triggers antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), recruiting immune effector cells and the complement cascade to lyse the target cells. CLDN18.2 expression is assessed by immunohistochemistry…

FDA Indications

• In combination with fluoropyrimidine- and platinum-containing chemotherapy for the 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 (≥75% of tumor cells with moderate-to-strong membranous staining by an FDA-approved test) — approved October 2024 (SPOTLIGHT with mFOLFOX6 and GLOW with CAPOX)

Common Side Effects

• Nausea (very common; most severe during the first infusion)
• Vomiting (very common; often infusion-associated)
• Decreased appetite
• Diarrhea
• Abdominal pain
• Constipation
• Fatigue
• Peripheral sensory neuropathy (largely from the platinum backbone)
• Decreased weight
• Hypoalbuminemia

Clinical Pearl

Zolbetuximab is the first-in-class anti-Claudin 18.2 (CLDN18.2) monoclonal antibody and defines a new biomarker-selected first-line population in gastric/GEJ adenocarcinoma: only CLDN18.2-positive (≥75% of tumor cells at 2+/3+ membranous staining), HER2-negative tumors qualify, so IHC testing must be ordered alongside HER2 and PD-L1 at diagnosis. Two pivotal phase 3 trials support it — SPOTLIGHT (with mFOLFOX6) and GLOW (with CAPOX) — each showing improved progression-free and overall survival…

Related Therapies & Mechanisms

• Pertuzumab (Perjeta) — Monoclonal Antibody · Gastric
• Ramucirumab (Cyramza) — Monoclonal Antibody · Gastric
• Trastuzumab (Herceptin) — Monoclonal Antibody · Gastric
• Alemtuzumab (Campath) — Monoclonal Antibody