What Is Bizengri (Zenocutuzumab-zbco)? FDA Approval, Licensing in Turkey, and Reimbursement Status

• FDA Approval: Yes (First approval date: December 4, 2024)
• Brand Name: Bizengri
• Active Ingredient: Zenocutuzumab-zbco
• Route of Administration: Intravenous infusion
• Class: Bispecific HER2- and HER3-directed monoclonal antibody
• Category: Targeted biological cancer treatment
• Manufacturer: Merus N.V.
• Availability in Turkey: Not currently licensed in Turkey.
• Approved Cancer Indications: Used to treat previously systemically treated adults with advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) or pancreatic adenocarcinoma that is positive for a neuregulin 1 (NRG1) gene fusion.

What Is Bizengri? How Does It Work?

Bizengri (zenocutuzumab-zbco) is a bispecific monoclonal antibody used to treat solid tumors positive for NRG1 (neuregulin 1) gene fusions. It offers a targeted option particularly for previously treated patients with advanced NRG1-positive disease, such as non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma.

How Does It Work?

• Blocking the HER2–HER3 Signaling Pathway: NRG1 gene fusions cause abnormal activation through the HER3 receptor. HER3 combines with HER2 to form a heterodimer, activating intracellular growth and survival pathways such as PI3K/AKT/mTOR. This leads to uncontrolled tumor cell proliferation and metastasis. Bizengri binds simultaneously to HER2 and HER3 receptors, physically blocking this dimerization. The tumor cell can therefore no longer receive these growth signals.
• Inhibiting Tumor Proliferation and Survival: Blocking the HER2-HER3 interaction slows cell proliferation, triggers apoptosis (programmed cell death), and reduces metabolic activity.
• Selective Target Binding: Zenocutuzumab acts only in cells that co-express HER2 and HER3. This property keeps potential harmful effects on healthy cells to a minimum.
• Immune System Interaction (Secondary Mechanism): After binding to tumor cells, the antibody component may be recognized by immune effector cells, contributing to tumor cell killing through ADCC (antibody-dependent cellular cytotoxicity).

FDA (US Food and Drug Administration) Approval History

• December 4, 2024: The FDA granted accelerated approval to Bizengri (zenocutuzumab-zbco) for NRG1-positive pancreatic adenocarcinoma and NRG1-positive non-small cell lung cancer (NSCLC).
• November 5, 2024: Merus announced an FDA extension of the PDUFA review period for zenocutuzumab. (PDUFA = the drug review period)
• May 6, 2024: Merus announced that the FDA had accepted the Biologics License Application (BLA) for zenocutuzumab and granted priority review. Indication: NRG1-positive NSCLC and pancreatic cancer (PDAC).
• July 5, 2023:  Second Breakthrough Therapy Designation: The FDA awarded zenocutuzumab breakthrough therapy designation for the second time.
• June 29, 2023: Breakthrough Therapy Designation: Zenocutuzumab received breakthrough therapy designation for NRG1-positive pancreatic cancer.
• November 2, 2021: Regulatory Update and Financial Results: Merus announced regulatory updates on zenocutuzumab and its financial results for the 3rd quarter of 2021.
• January 7, 2021: The FDA granted zenocutuzumab fast track designation for the treatment of neuregulin 1 fusion-positive cancers.

Licensing in Turkey

It is not currently officially licensed in Turkey. Access through overseas medicine procurement may be possible. However, it is not on the current “Active Overseas Medicines List” published by the Turkish Pharmacists' Association (TEB).

Mechanism of Resistance

• Resistance to Bizengri (zenocutuzumab-zbco), as with other targeted treatments, may arise through various biological adaptations. It may be primary resistance in patients who do not respond from the outset, or acquired (secondary) resistance when treatment is initially effective but loses efficacy over time.
• By binding simultaneously to HER2 and HER3, Bizengri aims to block receptor interaction and subsequent intracellular growth signals, particularly in NRG1 fusion-positive tumors. However, tumor cells may develop alternative escape routes to compensate for the inhibited pathways.
• Receptors or pathways other than HER2–HER3 may become active. For example, other cell-surface receptors such as EGFR, MET, or IGF-1R may be activated, allowing tumor cells to continue transmitting growth signals through different routes. Cell proliferation may therefore continue despite HER2–HER3 blockade.
• Structural changes or mutations in HER3 may prevent antibody binding. The medicine then cannot bind its target receptor and becomes ineffective. Similarly, reduced or lost expression of the NRG1 fusion gene in a tumor cell means that a target for Bizengri binding or activity is no longer present.
• Tumor cells may also develop resistance through their microenvironment. To evade the immune system, they may increase immunosuppressive cells, such as Tregs and MDSCs, or overexpress immune checkpoint proteins such as PD-L1. This immune microenvironment suppresses the immune-mediated effects of treatment.
• The physical and biochemical structure of the tumor may also limit drug activity. For example, insufficient antibody penetration into large tumor masses or areas with low oxygen or low pH may prevent the medicine from reaching its target.
• Because these mechanisms may limit the effect of Bizengri when used alone, combination treatment or approaches supported by alternative targeted agents may be considered, particularly in patients with resistance. Dynamic monitoring of molecular biomarkers, such as NRG1 expression and HER3 mutations, is important for tracking these resistance processes.

Absorption

• Because Bizengri is infused intravenously directly into the systemic circulation, conventional gastrointestinal or subcutaneous absorption does not occur.
• Bioavailability is 100%, because the entire dose enters the bloodstream directly.
• Infusion time matters rather than absorption time; administration generally takes approximately 60 minutes.

Distribution

• Zenocutuzumab is soluble in plasma and, as an IgG1 antibody, its distribution is limited to the intravascular and extravascular tissues accessible to antibodies.
• Its volume of distribution (Vd) is low, generally in the range of 3–7 liters.
• Because of its antibody structure, it accumulates largely in the lymphatic system, tumor tissue, and organs associated with the immune system.
• Plasma protein binding does not produce a clinically significant effect.

Metabolism

Zenocutuzumab is metabolized not by liver enzymes but by immune cells, particularly macrophages, which break it down into amino acids through lysosomal degradation. Unlike conventional medicines, it does not interact with CYP450 enzymes, so dose adjustment is not required in hepatic impairment.

Elimination

• Unlike small molecules, antibodies such as zenocutuzumab are not eliminated through liver enzymes or the kidneys. Instead, they are taken up by the reticuloendothelial system, particularly macrophages, and broken down into peptides and amino acids through lysosomal degradation.
• Its half-life is approximately 6–9 days, so dosing every 2 weeks is recommended.
• Its pharmacokinetics are generally linear, with plasma concentrations increasing predictably as the dose increases.

Dosage

• Recommended Dose: 750 mg
• Route of Administration: Intravenous infusion
• Frequency: Every 2 weeks
• Infusion Duration: Usually 90 minutes for the first dose; subsequent doses may be reduced to 60 minutes if tolerated.
• Premedication: Premedication with an antihistamine, antipyretic, and corticosteroid is recommended to prevent infusion reactions.
• Dose adjustment is generally unnecessary; it is given as a fixed dose rather than according to body weight.
• Treatment continues until disease progression or unacceptable toxicity.

Drug Interactions

• Interactions with CYP Enzymes: Zenocutuzumab is not metabolized by hepatic CYP450 enzymes. It therefore does not directly interact with medicines affecting the liver. There is no risk of interaction with CYP inducers, such as rifampin and phenytoin, or inhibitors, such as ketoconazole and verapamil. It can be used safely with many other medicines.
• Interactions with Immunosuppressants: Zenocutuzumab indirectly activates the immune system, particularly through ADCC. Corticosteroids or other immunosuppressants, such as cyclosporine and tacrolimus, may weaken this immune response. Treatment efficacy may decrease if long-term or high-dose steroids are required.
• Vaccine Interactions: Because it generates an active immune response, live vaccines, such as BCG, MMR, and live influenza vaccine, are not recommended during treatment. Inactivated vaccines, such as influenza and COVID-19 vaccines, are generally safe, but the immune response may be reduced.
• Combination with Other Monoclonal Antibodies: Data on combining it with other biologic medicines, such as anti-PD-1 or anti-EGFR antibodies, are limited. Adverse effects, particularly infusion reactions, may be more frequent with combinations.
• Combination with Chemotherapy and Targeted Agents: Zenocutuzumab is currently approved as monotherapy. However, combinations with certain chemotherapies or other targeted agents are being investigated. Close monitoring is needed if a combination is given under a clinical protocol.

Conditions Requiring Attention

• Risk of Infusion Reactions: Infusion-related reactions, including fever, chills, shortness of breath, and rash, are among the most common early adverse effects. Premedication with an antihistamine, antipyretic, and, if needed, a low-dose corticosteroid should be given before each infusion.
• Immunosuppression and Corticosteroid Use: Because zenocutuzumab acts through immune-mediated pathways such as ADCC, immunosuppressive medicines may reduce its efficacy. Caution is needed in patients receiving long-term corticosteroids or immunosuppressive treatment; treatment should be delayed if possible.
• Autoimmune Diseases: Although zenocutuzumab does not directly activate the immune system, its effects may be indirect. A benefit–risk assessment is needed when considering its use in patients with active autoimmune disease, such as lupus or MS.
• Presence of an NRG1 Fusion: Drug efficacy depends on the presence of an NRG1 fusion in tumor cells. Before treatment, an NRG1 fusion should be confirmed by molecular genetic testing, such as NGS or RT-PCR.
• Pregnancy and Breastfeeding: Fetal toxicity has been observed in animal studies. Human data are limited. Use during pregnancy is not recommended. Breastfeeding should be stopped throughout treatment and for at least several weeks afterward.
• Hepatic and Renal Impairment: Because zenocutuzumab is not eliminated through conventional hepatic or renal routes, dose adjustment is not required. Liver function abnormalities may occur during treatment. AST, ALT, and bilirubin should be monitored regularly.
• Vaccinations: Live vaccines in particular are contraindicated during treatment with agents that affect the immune system. Live vaccines must not be given during treatment, and the physician should be consulted if inactivated vaccines are needed.
• Monitoring Treatment Response: Routine imaging, such as CT or PET-CT, and molecular response monitoring should be performed to assess efficacy. Signs of progression should be recognized early during treatment.
• General Clinical Monitoring Recommendations: Before and during treatment: complete blood count, liver and kidney function tests, electrolytes (particularly Mg, K, Na), vital signs, post-infusion observation, and monitoring of NRG1 fusion status (repeat analysis is recommended at progression).

Side Effects

• Diarrhea 37%
• Musculoskeletal pain (myalgia, arthralgia) 29%
• Fatigue 25%
• Nausea 23%
• Elevated AST (liver enzyme) 22%
• Elevated ALT (liver enzyme) 20%
• Infusion reactions 20%
• Low hemoglobin (anemia) 18%
• Shortness of breath (dyspnea) 17%
• Low sodium (hyponatremia) 17%
• Rash 15%
• Low platelets (thrombocytopenia) 15%
• Low magnesium 14%
• Constipation 13%
• Low phosphate 13%
• Vomiting 12%
• Abdominal pain 10%
• Peripheral edema (swelling) 10%
• Elevated bilirubin 10%
• Increased aPTT (prolonged clotting time) 8%