What Is Zolbetuximab-clzb (Vyloy)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes (Initial Approval Date: October 18, 2024)
• Brand Name: Vyloy
• Active Ingredient: Zolbetuximab-clzb (a cytolytic monoclonal antibody targeting Claudin 18.2 (CLDN18.2))
•  Route of Administration: Intravenous infusion (administered into a vein after preparation and dilution)
• Class: Monoclonal antibody (CLDN18.2-targeted cytolytic antibody)
• Category: Antineoplastic
• Manufacturer: Astellas Pharma US, Inc. (developed by Ganymed Pharmaceuticals and commercialized by Astellas)
• Availability in Turkey: Not yet licensed in Turkey.
• Approved Cancer Indications: Advanced, unresectable, or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Tumors must be CLDN18.2-positive.

What Is Vyloy? How Does It Work?

Vyloy is a biological cancer medicine containing the monoclonal antibody zolbetuximab-clzb, used to treat Claudin 18.2 (CLDN18.2)-positive gastric or gastroesophageal junction adenocarcinoma.

It was approved by the FDA in 2024. It is used particularly in addition to chemotherapy for advanced, unresectable or metastatic tumors.

How Does It Work?

Claudin 18.2: CLDN18.2 is present to a limited extent in normal gastric mucosa but is overexpressed in gastric cancers and some pancreatic cancers. The medicine was developed against this target on the tumor cell surface.

Zolbetuximab Binding: Zolbetuximab, the active ingredient in Vyloy, binds to the surface of cancer cells carrying the CLDN18.2 protein.

Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are initiated. This binding activates immune cells, which attack and destroy the cancer cell.

Tumor-Specific Effect: Because CLDN18.2 expression in normal tissues is limited, the effect is selective and generally focused on cancer cells.

FDA (US Food and Drug Administration) Approval History

• November 17, 2022: Astellas announced that zolbetuximab met the primary endpoint in the phase 3 SPOTLIGHT trial, demonstrating efficacy as first-line treatment for Claudin 18.2-positive, HER2-negative, locally advanced or metastatic gastric and GEJ cancers.
• December 15, 2022: Astellas announced that zolbetuximab met the primary endpoint in the phase 3 GLOW trial and was successful as first-line treatment for Claudin 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric and GEJ cancers.
• March 21, 2023: Astellas announced positive findings from the phase 3 GLOW trial of zolbetuximab during the March ASCO Plenary Series.
• April 14, 2023: Results of the phase 3 SPOTLIGHT trial of Astellas's investigational medicine zolbetuximab were published in The Lancet.
• July 6, 2023: Astellas announced that the US FDA had granted Priority Review to the Biologics License Application for zolbetuximab.
• January 8, 2024: Astellas provided an update on the US Biologics License Application for zolbetuximab.
• May 30, 2024: The US Food and Drug Administration (FDA) accepted Astellas's resubmitted Biologics License Application for zolbetuximab and set a new decision date.
• October 21, 2024: The FDA approved Vyloy (zolbetuximab-clzb) for treating advanced gastric and gastroesophageal junction (GEJ) cancer.

Licensing in Turkey

It has not yet been officially licensed in Turkey. It may be obtained from abroad under the Ministry of Health's special authorization procedures. It is not included in the TİCK overseas medicines list.

Mechanisms of Resistance

• Loss of the Target Antigen (Reduced Claudin 18.2 Expression): Zolbetuximab's effectiveness depends on the presence of Claudin 18.2 (CLDN18.2) on the tumor cell surface. Under selective pressure, some cells may reduce or completely lose expression of this protein, leaving the drug without a target to bind to. This is called antigen escape.
• Inhibition of the Antibody-Mediated Immune Response: Zolbetuximab activates the immune system and acts through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, some tumors may suppress natural killer (NK) cell activity, or increase expression of proteins that inhibit the complement system, such as CD55 and CD59. These mechanisms prevent immune cells from damaging the cancer cell.
• Tumor Heterogeneity: The coexistence of CLDN18.2-positive and negative cells within a tumor may mean that treatment affects only part of it. Over time, CLDN18.2-negative subpopulations may become dominant through clonal selection, leading to treatment-resistant tumors.
• Suppression by the Tumor Microenvironment: Immunosuppressive cells surrounding the tumor, such as Treg cells and M2 macrophages, may weaken zolbetuximab's immune-mediated effect. Dense stroma (fibrous tissue) may also prevent adequate antibody penetration into the tumor.
• Activation of Secondary Signaling Pathways: Zolbetuximab targets Claudin 18.2, but some cancer cells may reduce drug dependence by activating alternative growth signaling pathways, such as PI3K/AKT/mTOR and MAPK. This represents resistance through bypass pathways.

Absorption

• As a monoclonal antibody, zolbetuximab is not administered orally.
• It is administered directly by intravenous infusion, entering the systemic circulation with full bioavailability.
• Absorption does not involve passage through the intestines in the conventional sense.
• Blood levels rise gradually in relation to infusion duration and dose.
• Maximum serum concentration (Cmax) is reached at the end of the infusion.

Distribution

• Zolbetuximab is distributed differently from conventional small molecules.
• Its large molecular structure restricts distribution to extracellular fluids.
• Its plasma protein binding is low.
• The volume of distribution (Vd) is low, approximately 3–5 L, indicating that it does not spread extensively throughout body fluids.
• It may accumulate selectively in tumor regions with high Claudin 18.2 expression.

Metabolism

• Zolbetuximab does not undergo hepatic enzymatic breakdown in the same way as conventional medicines.
• Because it is an antibody, lysosomal enzymes break it down in the body, particularly in the reticuloendothelial system.
• Enzymatic breakdown produces small peptides and amino acids.
• This breakdown occurs through intracellular degradation systems rather than hepatic CYP enzymes.

Elimination

• It is eliminated through proteolytic catabolism, the typical pathway for antibodies.
• Excretion in unchanged form through the kidneys or bile is negligible.
• Breakdown products generally enter the recyclable amino acid pool within cells.
• The average half-life (t½) is approximately 10–12 days, an important parameter determining infusion frequency.
• It has dose-proportional pharmacokinetics.

Dosing Schedule

• Initial Dose: 800 mg/m², with treatment starting by infusion on day 1.
• Maintenance Dose: 600 mg/m² by intravenous infusion, followed by administration every 3 weeks (every 21 days).
• Administration Time: Infusion generally takes approximately 2 hours.
• Premedication is recommended: An antihistamine, antipyretic, and corticosteroid to reduce infusion reactions.
• Doses are calculated according to body surface area (BSA), in mg/m².
• It is administered with chemotherapy, typically the mFOLFOX6 regimen.
• Routine use as monotherapy is not recommended.

Drug Interactions

• Interactions With Cytochrome P450 (CYP) Enzymes: Zolbetuximab is not metabolized by hepatic CYP enzymes. Conventional CYP3A4-, CYP2D6-, or similar enzyme-mediated interactions are therefore not expected. It does not interact directly at the pharmacokinetic level with oral antineoplastic agents, antifungals, antiepileptics, or similar medicines.
• Interactions With Immunosuppressive Medicines: Because zolbetuximab acts through the immune system, medicines that suppress immune function, such as corticosteroids, TNF-α inhibitors, and calcineurin inhibitors, may weaken its effect.
• Combination With Other Anticancer Treatments: Clinical trials have found use with chemotherapy combinations, particularly mFOLFOX6, to be effective and safe. No specific pharmacokinetic interaction associated with poisoning risk or synergistic toxicity has been identified. However, overlapping toxicities such as neurotoxicity, gastrointestinal toxicity, or hematological suppression may increase.
• Vaccines: Live vaccines may pose a risk of serious infection in immunocompromised patients. Live vaccines, such as MMR and yellow fever vaccines, are not recommended for patients receiving zolbetuximab. Inactivated vaccines, such as influenza and inactivated COVID-19 vaccines, are generally considered safe, although the immune response may be weak.

Precautions

• Infusion Reactions: These are the most common category of adverse effects and generally occur during the first infusion. Symptoms include chills, fever, flushing, shortness of breath, and hypotension. Premedication with an antihistamine, antipyretic, and steroid should be given before treatment. If a severe reaction develops, the infusion should be slowed and treatment stopped if necessary.
• Gastrointestinal Toxicity: Nausea, vomiting, loss of appetite, and diarrhea may occur. These effects are related to the limited presence of Claudin 18.2 in normal gastric tissue. Antiemetic and antidiarrheal supportive treatment should be planned if needed.
• Electrolyte Imbalances: Hypokalemia and hypomagnesemia may occur. Electrolytes should be monitored during treatment, with replacement when necessary.
• Liver Function: ALT/AST elevations may occur but are mild in most cases. Liver enzymes should be monitored regularly, particularly in patients with liver metastases.
• Weakened Immune Response:Because this medicine depends on the immune system, its effectiveness may be reduced in patients receiving immunosuppressive treatment. Live vaccines should be avoided.
• Pregnancy and Breastfeeding: Adequate data on zolbetuximab use during pregnancy are lacking. It may theoretically cross the placenta and affect the fetal immune system. It should not be used during pregnancy, and effective contraception should be recommended. Use during breastfeeding is also not recommended; breastfeeding should be stopped throughout treatment and for a period afterward.
• Biomarker Requirement for Patient Selection: It is effective only in Claudin 18.2-positive patients. In accordance with FDA approval, the companion diagnostic VENTANA CLDN18 (43-14A) RxDx Assay should be used. Administration to CLDN18.2-negative patients is not recommended.

Adverse Effects

These rates come from patient groups receiving the medicine with combination chemotherapy (mFOLFOX6). Severe adverse effects (grade ≥3) were more frequent for nausea, vomiting, hypokalemia, and infusion reactions.

• Nausea 82%
• Vomiting 67%
• Diarrhea 46%
• Loss of appetite 44%
• Fatigue 39%
• Abdominal pain 36%
• Indigestion (dyspepsia) 25%
• Constipation 22%
• Headache 21%
• Dizziness 19%
• Taste disturbance: 16%
• Fever 14%
• Itching 13%
• Skin rash 12%
• Infusion-related reactions 11%
• Hypokalemia (low potassium) 10%
• Hypomagnesemia (low magnesium) 8%
• Elevated liver enzymes (AST, ALT) 7–9%
• Dry mouth 7%
• Difficulty swallowing 5%
• Neutropenia (low neutrophil count) 4%
• Injection-site pain/reaction 3%
• Excessive saliva production (hypersalivation) 2%