Zenocutuzumab-zbco, a humanized immunoglobulin G1-based bispecific antibody directed against human epidermal growth factor receptor type 2 (HER2) and human epidermal growth factor receptor type 3 (HER3), is an antineoplastic agent.1, 2
Zenocutuzumab-zbco is used for the treatment of advanced unresectable or metastatic neuregulin 1 (NRG1) fusion-positive non-small cell lung cancer (NSCLC) in adults with disease progression on or after prior systemic therapy.1, 2
The current indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR).1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).1
Efficacy and safety of zenocutuzumab-zbco for the treatment of advanced unresectable or metastatic NRG1 fusion-positive NSCLC were evaluated in a multicenter, open-label, multi-cohort study (eNRGy).1, 2 The study included adult patients with advanced or metastatic NSCLC and a documented NRG1 fusion identified through molecular assays who had disease progression following standard of care treatment.1, 2 NRG1 gene fusion was identified through molecular assays such as next-generation sequencing (NGS)-based assays [deoxyribonucleic acid (DNA) or ribonucleic (RNA)].1, 2 Patients received zenocutuzumab-zbco 750 mg by IV infusion every 2 weeks until unacceptable toxicity or disease progression.1, 2 Premedication (i.e., antipyretics, antihistamines, and corticosteroids) was administered prior to each infusion.2 Corticosteroids were used at the investigator's discretion after the first infusion.2 Tumor assessments were performed every 8 weeks.1, 2 The primary efficacy outcome measures were confirmed ORR and DOR as determined by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).1, 2
Of the 64 patients evaluated in the study, the median age was 63.5 years (range 32-86 years); about half of the patients were 65 years of age or older and the majority of patients (98%) had metastatic disease.1 Patients received a median of 2 prior systemic therapies (range: 1-6); 95% received prior platinum-based chemotherapy and 64% received prior anti-PD-1/PD-L1 therapy.1, 2 A total of 54 patients (84%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 9 patients (14%) had an NRG1 gene fusion detected by DNA-based NGS.1, 2 The confirmed BICR-assessed ORR in patients receiving zenocutuzumab-zbco was 33%; complete response rate was 1.6% and partial response rate was 31%.1, 2 The median DOR was 7.4 months with 43% of patients with DOR ≥6 months.1, 2
NRG1 gene fusions are rare, accounting for about 0.3% of patients with NSCLC and most commonly occurring in patients with adenocarcinoma histology.2, 4 Treatment strategies including chemotherapy, immunotherapy, and targeted therapies are not highly effective against NRG1 fusion-positive NSCLC.4, 5 No specific therapies are FDA-labeled for the treatment of NRG1 cancer and patients are managed based on treatment guidelines specific for the underlying tumor histology and disease setting.2 Zenocutuzumab-zbco is the first NRG1 directed therapy with reported efficacy when administered to patients diagnosed with NRG1 fusion-positive NSCLC.2
The American Society of Clinical Oncology (ASCO) has published a guideline on the management of stage IV NSCLC harboring driver alterations.7 Zenocutuzumab-zbco is not discussed in the guideline because the drug was approved after guideline publication.7
Zenocutuzumab-zbco is used for the treatment of advanced unresectable or metastatic NRG1 fusion-positive pancreatic adenocarcinoma in adults with disease progression on or after prior systemic therapy.1, 2
The current indication is approved under accelerated approval based on ORR and DOR.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).1 Zenocutuzumab-zbco has been designated an orphan drug by FDA for the treatment of pancreatic cancer.6
Efficacy and safety of zenocutuzumab-zbco for the treatment of advanced unresectable or metastatic NRG1 fusion-positive pancreatic adenocarcinoma were evaluated in a multicenter, open-label, multi-cohort study (eNRGy).1, 2 The study included 30 adults with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who had disease progression following standard of care treatment.1, 2 Patients received zenocutuzumab-zbco 750 mg by IV infusion every 2 weeks, until unacceptable toxicity or disease progression.1, 2 Premedication (i.e., antipyretics, antihistamines, and corticosteroids) was administered prior to each infusion.2 Corticosteroids were used at the investigator's discretion after the first infusion.2 Tumor assessments were performed every 8 weeks.1, 2 The primary efficacy outcome measures were confirmed ORR and DOR as determined by BICR according to RECIST v1.1.1, 2
Of the 30 patients enrolled in the study, the median age was 49 years (range 21-72 years); 10% of patients were 65 years of age or older and all patients had metastatic disease.1 Patients received a median of 2 prior systemic therapies (range: 0-5); 97% received prior systemic therapy with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), gemcitabine/taxane-based therapy, or both.1, 2 A total of 27 patients (90%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 3 patients (10%) had an NRG1 gene fusion detected by DNA-based NGS.1, 2 The confirmed BICR-assessed ORR was 40%; complete response rate was 3.3% and partial response rate was 37%.1, 2 The DOR ranged from 3.7 to 16.6 months with 67% of patients with DOR ≥6 months.1, 2
NRG1 fusions are estimated to be <0.5% of all cases of pancreatic adenocarcinoma.2 Treatment of patients with unresectable or metastatic pancreatic adenocarcinoma is palliative.2 For eligible patients, first line treatment is combination chemotherapy and selection of therapies is based on general status of the patient and physician/institutional preferences.2 The most commonly prescribed regimens in the US are fluoropyrimidine, oxaliplatin, and irinotecan-based regimens and the combination of gemcitabine and nab-paclitaxel.2 No specific therapies are labeled for treatment of NRG1 fusion-positive pancreatic adenocarcinoma.2 Zenocutuzumab-zbco is the first NRG1 directed therapy with reported efficacy when administered to patients diagnosed with NRG1 fusion-positive pancreatic adenocarcinoma.2
Dispensing and Administration Precautions
Zenocutuzumab-zbco is administered via IV infusion only.1 The drug is supplied as a 20 mg/mL injection concentrate that must be further diluted prior to administration.1
Store zenocutuzumab-zbco vials in a refrigerator at 2-8°C in original carton to protect from light.1 Do not freeze or shake.1
For the initial infusion, prepare zenocutuzumab-zbco as close to administration time as possible to allow for an extended infusion time in the event of an IRR.1
Check that zenocutuzumab-zbco solution is clear to slightly opalescent, colorless to slightly yellow.1 Do not use if discoloration or visible particles are present.1
If not used immediately, store the diluted solution refrigerated at 2-8°C and protect from light after preparation unless the infusion is initiated within 2 hours of preparation.1
Administer premedications prior to zenocutuzumab-zbco (see Premedication and Prophylaxis under Dosage and Administration).1
Administer diluted zenocutuzumab-zbco solution using an infusion set made of either polyvinylchloride (PVC), polyethylene (PE), polyurethane (PUR) or polybutadiene (PB) with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).1
Administer zenocutuzumab-zbco infusion via a peripheral or central line.1
If the diluted zenocutuzumab-zbco solution has been refrigerated, allow it to reach room temperature for approximately 30 minutes prior to administration.1
Do not infuse zenocutuzumab-zbco concomitantly in the same IV line with other agents.1
Withdraw and then discard 37.5 mL of 0.9% sodium chloride injection from a 250 mL infusion bag.1 Only use infusion bags made of PVC, polyolefin, or polyolefin/polyamide coextruded plastic.1
Withdraw and add a total of 37.5 mL of zenocutuzumab-zbco from two vials to the infusion bag.1 The final volume in the infusion bag should be 250 mL.1 Discard any unused portion left in the vial.1
Gently invert the bag to mix the solution.1 Do not shake.1
Administer the diluted solution within 6 hours from end of preparation of infusion solution stored at room temperature (15-25°C) or 28 hours from end of preparation of infusion solution stored refrigerated (2-8°C).1
Infuse zenocutuzumab-zbco over 4 hours.2
The recommended adult dosage of zenocutuzumab-zbco for the treatment of advanced unresectable or metastatic NRG1 fusion-positive NSCLC is 750 mg by IV infusion every 2 weeks until disease progression or unacceptable toxicity.1, 2
The recommended adult dosage of zenocutuzumab-zbco for the treatment of advanced unresectable or metastatic NRG1 fusion-positive pancreatic adenocarcinoma is 750 mg by IV infusion every 2 weeks until disease progression or unacceptable toxicity.1, 2
Dosage Modifications for Toxicity
The recommended dosage modifications of zenocutuzumab-zbco for adverse reactions are provided in Table 1.1 No dose reduction is recommended.1
Adverse Reaction | Severity | Dose Modifications and Management |
|---|---|---|
Infusion-related reactions (IRRs)/Hypersensitivity/Anaphylactic Reactions | ≤Grade 3 IRR | Interrupt zenocutuzumab-zbco infusion if IRR is suspected and monitor patient until reaction symptoms resolve. Provide symptomatic treatment as needed. Resume the infusion at 50% of the infusion rate at which the reaction occurred. The infusion rate may be escalated if there are no additional symptoms. Corticosteroid premedication can be used as necessary for subsequent zenocutuzumab-zbco infusions. |
Infusion-related reactions (IRRs)/Hypersensitivity/Anaphylactic Reactions | Grade 4 IRR or any grade hypersensitivity/anaphylactic reaction | Permanently discontinue zenocutuzumab-zbco. |
Interstitial Lung Disease (ILD)/Pneumonitis | Grade 1 | Interrupt zenocutuzumab-zbco until recovery. Consider prompt initiation of corticosteroids when the diagnosis is suspected. Resume treatment after resolution. |
Interstitial Lung Disease (ILD)/Pneumonitis | ≥Grade 2 | Permanently discontinue zenocutuzumab-zbco. Promptly treat with corticosteroids. |
Left Ventricular Dysfunction | Left ventricular ejection fraction (LVEF) is 45-49% and absolute decrease from baseline ≥10% or LVEF <45% | Interrupt zenocutuzumab-zbco. Repeat LVEF assessment within 3 weeks. If LVEF is <45% or LVEF has not recovered to within 10% from baseline, permanently discontinue zenocutuzumab-zbco. If LVEF is ≥50% or LVEF is 45-49% and recovered to within 10% of baseline, resume zenocutuzumab-zbco and monitor LVEF every 12 weeks while on treatment and as clinically indicated. |
Left Ventricular Dysfunction | Symptomatic congestive heart failure (CHF) | Permanently discontinue zenocutuzumab-zbco. |
Other Clinically Relevant Adverse Reactions | Grade 3 or 4 | Withold zenocutuzumab-zbco until recovery to ≤Grade 1 or baseline. Provide symptomatic treatment as needed. Resume treatment after resolution of symptoms. |
The manufacturer makes no specific dosage recommendations for hepatic impairment.1
The manufacturer makes no specific dosage recommendations for renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, zenocutuzumab-zbco can cause fetal harm when administered to a pregnant woman and a boxed warning about this risk has been included in the prescribing information for the drug.1 In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death.1 Animal studies have demonstrated that inhibition of HER2 and/or HER3 results in impaired embryo-fetal development, including effects on cardiac, vascular, and neuronal development, and embryolethality.1 Advise patients of the potential risk to a fetus.1 Verify the pregnancy status of females of reproductive potential prior to the initiation of zenocutuzumab-zbco.1 Advise females of reproductive potential to use effective contraception during treatment with zenocutuzumab-zbco and for 2 months after the last dose.1, 2
Other Warnings and Precautions
Infusion-related Reactions and Hypersensitivity
Zenocutuzumab-zbco can cause serious and life-threatening infusion-related reactions (IRRs), hypersensitivity, and anaphylactic reactions.1 Signs and symptoms of IRRs may include chills, nausea, fever, and cough.1
In the eNRGy study, 13% of patients experienced IRRs, all of which were Grade 1 or 2; 91% occurred during the first infusion.1 The incidence was similar in both populations of patients (those with NSCLC and those with pancreatic adenocarcinoma).2 The median time to onset was 63 minutes (range: 13 to 240 minutes) from the start of infusion.1
Administer zenocutuzumab-zbco in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications.1 Monitor patients closely for signs and symptoms of reactions during infusion and for at least 1 hour following completion of the first zenocutuzumab-zbco infusion and as clinically indicated.1 Prior to the first zenocutuzumab-zbco infusion, premedicate with a corticosteroid, an H1antihistamine, and acetaminophen to reduce the risk of IRRs.1 Corticosteroid premedication can be used as necessary for subsequent infusions.1
Interrupt zenocutuzumab-zbco infusion in patients with IRRs ≤Grade 3 and administer symptomatic treatment as needed.1 Resume infusion at a reduced rate after symptom resolution.1 Immediately stop the infusion and permanently discontinue zenocutuzumab-zbco for Grade 4 or life-threatening IRRs or hypersensitivity/anaphylaxis reactions.1
Interstitial Lung Disease/Pneumonitis
Zenocutuzumab-zbco can cause serious and life-threatening interstitial lung disease (ILD)/pneumonitis.1
In the eNRGy study, ILD/pneumonitis occurred in 2 (1.1%) patients treated with zenocutuzumab-zbco.1 Grade 2 ILD/pneumonitis resulting in permanent discontinuation of zenocutuzumab-zbco occurred in 1 (0.6%) patient.1
Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).1 Immediately withhold zenocutuzumab-zbco in patients with suspected ILD/pneumonitis and administer corticosteroids as clinically indicated.1 Permanently discontinue zenocutuzumab-zbco if ILD/pneumonitis ≥Grade 2 is confirmed.1
Zenocutuzumab-zbco can cause left ventricular dysfunction.1
Decreased left ventricular ejection fraction (LVEF) has occurred with anti-HER2 therapies, including zenocutuzumab-zbco.1 Treatment with zenocutuzumab-zbco has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.1
In the eNRGy study, Grade 2 LVEF decrease (40-50%; 10-19% drop from baseline) occurred in 2% of evaluable patients.1 Cardiac failure without LVEF decrease occurred in 1.7% of patients including 1 (0.6%) fatal event.1
Before initiating zenocutuzumab-zbco, evaluate LVEF and monitor at regular intervals during treatment as clinically indicated.1 For LVEF <45% or <50% with absolute decrease from baseline of ≥10% confirmed, permanently discontinue zenocutuzumab-zbco.1 Permanently discontinue zenocutuzumab-zbco in patients with symptomatic congestive heart failure (CHF).1
In patients who received zenocutuzumab-zbco 750 mg every 2 weeks for up to 30 months in clinical studies, 7 of 153 (4.6%) patients developed anti-zenocutuzumab antibodies.1, 2 There were no identified clinically significant effects of these antibodies.2 Due to the low occurrence, the effect of these anti-drug antibodies on the pharmacokinetics, pharmacodynamics, safety, and efficacy of zenocutuzumab is unknown.1, 2
Based on its mechanism of action, zenocutuzumab-zbco can cause fetal harm when administered to a pregnant woman.1 There are no available data on the use of zenocutuzumab-zbco in pregnant women to inform a drug-associated risk.1
Animal studies have demonstrated that HER2 and/or HER3 deficiency results in embryo-fetal malformation, including effects on cardiac, vascular, and neuronal development, and embryolethality.1
Human IgG1 is known to cross the placenta; therefore, zenocutuzumab-zbco has the potential to be transmitted from the mother to the developing fetus.1, 2 Advise patients of the potential risk to a fetus.1
Monitor women who received zenocutuzumab-zbco during pregnancy or within 2 months prior to conception for oligohydramnios.1 If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.1
There are no data on the presence of zenocutuzumab-zbco in human milk, the effects on the breastfed child, or the effects on milk production.1 Maternal IgG1 is known to be present in human milk.1, 2 The effects of local GI exposure and limited systemic exposure in the breastfed child to zenocutuzumab-zbco are unknown.1, 2 Consider the developmental and health benefits of breast feeding along with the mother's clinical need for zenocutuzumab-zbco treatment and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.1
Females and Males of Reproductive Potential
Zenocutuzumab-zbco can cause fetal harm when administered to a pregnant woman.1
Verify the pregnancy status of females of reproductive potential prior to initiating zenocutuzumab-zbco.1
Advise female patients of reproductive potential to use effective contraception during treatment with zenocutuzumab-zbco and for 2 months after the last dose.1, 2
The safety and effectiveness of zenocutuzumab-zbco have not been established in pediatric patients.1
Of the 175 patients with NRG1 gene fusion positive tumors in the eNRGy study treated with zenocutuzumab-zbco at a dosage of 750 mg every 2 weeks, 75 patients (43%) were 65 years of age or older and 26 patients (15%) were 75 years of age and older.1 No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.1
There are no clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco in patients with mild hepatic impairment (defined as total bilirubin >1 to 1.5 times ULN or AST>ULN).1, 2 The pharmacokinetics of zenocutuzumab-zbco in patients with moderate to severe hepatic impairment (defined as total bilirubin >1.5 to 3 times ULN with any AST) are unknown.1
There are no clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1, 2 The pharmacokinetics of zenocutuzumab-zbco in patients with severe renal impairment (creatinine clearance <30 mL/minute) are unknown.1
The most common adverse reactions (≥10%) in patients were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRRs), dyspnea, rash, constipation, vomiting, abdominal pain, and edema.1
The most common Grade 3 or 4 laboratory abnormalities (≥2%) were increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT, and increased bilirubin.1
No drug-drug interaction studies were performed.1, 2 Zenocutuzumab-zbco showed small transient elevations of cytokines in patients, which are not expected to modulate activity of cytochrome P450 (CYP450).2 No interactions with concomitant medications are expected.2
Zenocutuzumab-zbco is a bispecific antibody that binds to the extracellular domains of human epidermal growth factor receptor type 2 (HER2) and human epidermal growth factor receptor type 3 (HER3) expressed on the surface of tumor cells; upon binding to its target, the drug blocks HER2:HER3 dimerization and prevents NRG1 binding to HER3, inhibiting downstream signaling.1, 2 Zenocutuzumab-zbco decreases cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway and mediates antibody-dependent cellular cytotoxicity (ADCC).1 In mouse models of NRG1 fusion-positive lung and pancreatic cancers, zenocutuzumab-zbco demonstrated antitumor activity.2
The median time to steady-state concentrations of zenocutuzumab-zbco is 8 weeks.1, 2 The half-life of zenocutuzumab-zbco is 8 days.1, 2 Zenocutuzumab-zbco is expected to be metabolized into small peptides by catabolic pathways.1, 2
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Zenocutuzumab-zbco is obtained through designated distributors.3 Contact manufacturer or consult the zenocutuzumab-zbco website ([Web]) for specific availability information.3
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV use | 20 mg/mL | Bizengri® | Merus US |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Merus US, Inc. BIZENGRI® (Zenocutuzumab) INTRAVENOUS prescribing information. 2025 Jan.
2. Food and Drug Administration. Application number 761352Orig1s000 Multi-Discipline Review. From FDA website. [Web]
3. Partner Therapeutics. Product fact sheet & ordering information. From Partner Therapeutics website. Accessed 2025 Nov 24.
4. Li H, Xu L, Cao H, Wang T, Yang S, Tong Y et al. Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer. Front Oncol 2024.
5. Drilon A, Duruisseaux M, Han JY, Ito M, Falcon C, Yang SR et al. Clinicopathologic features and response to therapy of NRG1 fusion-driven lung cancers: The eNRGy1 global multicenter registry. J Clin Oncol 2021;39:2791-820.
6. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
7. Owen DH, Ismaila N, Ahluwalia A et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, Version 2024.3. J Clin Oncol. 2025 Apr;43(10):e2-e16. Epub 2025 Feb 27. PMID: 40014839.