Zenocutuzumab-zbco (Bizengri)

Number: 1076

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses zenocutuzumab-zbco (Bizengri) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of zenocutuzumab-zbco (Bizengri) is required of all Aetna participating providers and members in applicable plan designs. For precertification of zenocutuzumab-zbco (Bizengri), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

1. Criteria for Initial Approval

   Aetna considers zenocutuzumab-zbco (Bizengri) medically necessary for treatment of the following indications:

   1. Non-Small Cell Lung Cancer (NSCLC)

      For treatment of advanced unresectable, metastatic, or recurrent NSCLC when all of the following criteria are met:
      
      
      1. Member has experienced disease progression on or after prior systemic therapy; and
      2. Member has neuregulin 1 (NRG1) gene fusion positive disease; and
      3. The requested medication will be used as a single agent.

   2. Pancreatic Adenocarcinoma

      For treatment of advanced unresectable, metastatic, or recurrent pancreatic adenocarcinoma when all of the following criteria are met:
      
      
      1. Member has experienced disease progression on or after prior systemic therapy; and
      2. Member has neuregulin 1 (NRG1) gene fusion positive disease; and
      3. The requested medication will be used as a single agent.

   3. Biliary Tract Cancers

      For treatment of unresectable, gross residual (R2), or metastatic biliary tract cancer (including intrahepatic and extrahepatic cholangiocarcinoma) when all of the following criteria are met:

      1. Member has experienced disease progression on or after prior systemic therapy; and
      2. Member has neuregulin 1 (NRG1) gene fusion positive disease; and
      3. The requested medication will be used as a single agent.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers zenocutuzumab-zbco (Bizengri) therapy medically necessary in members requesting reauthorization for an indication listed in the Criteria for Initial Approval section when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Zenocutuzumab-zbco is supplied as Bizengri 375 mg/18.75 mL (20 mg/mL) in a single-dose vial for injection for intravenous use.

• Select persons for treatment with Bizengri based on the presence fo an NRG1 gene fusion.
• Evaluate left ventricular ejection fraction (LVEF) before initiating Bizengri.
• The recommended dosage of Bizengri is 750 mg every 2 weeks until disease progression or unacceptable toxicity.
• Administer premedications before each infusion to reduce the risk of infusion-related reactions.
• Administer as an intravenous infusion, after dilution, over 4 hours.

Source: Partner Therapeutics, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
Neuregulin 1 (NRG1) gene testing – No specific code
96413	Chemotherapy administration, IV infusion technique; up to 1 hour, single or initial substance/drug
96415	each additional hour (list in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9382	Injection, zenocutuzumab-zbco, 1 mg
ICD-10 codes covered if selection criteria are met:
C22.1	Intrahepatic bile duct carcinoma
C23	Malignant neoplasm of gallbladder
C24.0 – C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C25.0 – C25.9	Malignant neoplasm of pancreas
C34.00 – C34.92	Malignant neoplasm of bronchus and lung

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Adults with advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.
• Adults with advanced unresectable or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy.

Compendial Uses

• Recurrent NSCLC
• Recurrent Pancreatic Adnenocarcinoma
• Biliary Tract Cancers

Zenocutuzumab-zbco is available as Bizengri (Merus US, Inc.), a low-fructose humanized full-length immunoglobulin GI (IgGI) bispecific HER2- and HER3-directed antibody. Bizengri binds to the extracellular domains of HER2 and HER3 expressed on the surface cells, including tumor cells, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3. In addition to decreased cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway, Bizengri mediates antibody-dependent cellular cytotoxicity (ADCC). Bizengri demonstrated antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers (Partner Therapeutics, 2025).

The prescribing information notes that Bizengri carries the following boxed warning:

• Exposure to Bizengri during pregnancy can cause embryo-fetal harm. Advise patients of this risk and the need for effective contraception.

Additionally, Bizengri carries the following warnings and precautions and adverse reactions:

• Warnings and precautions
  
  
  • Infusion-related reactions (IRR)/hypersensitivity/anaphylactic reactions:
    
    
    • Administer Bizengri in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications.
    • Monitor for signs and symptoms of IRR.
    • Interrupt infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed.
    • Resume infusion at a reduced rate after resolution of symptoms. 
    • Immediately stop the infusion and permanently discontinue Bizengri for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis.
      
      
  • Interstitial lung disease (ILD)/pneumonitis:
    
    
    • Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. 
    • Permanently discontinue Bizengri in patients with ≥ Grade 2 ILD/pneumonitis.
      
      
  • Left ventricular dysfunction:
    
    
    • Assess LVEF before initiating Bizengri and at regular intervals during treatment as clinically indicated.
    • Manage through treatment interruption or discontinuation.
    • Permanently discontinue Bizengri in patients with symptomatic congestive heart failure (CHF).
      
      
• Adverse reactions
  
  
  • The most common adverse reactions (≥ 10%) include diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema.
  • The most common Grade 3 or 4 laboratory abnormalities (>2%) include increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT, and increased bilirubin.
    
    

On December 4, 2024, the U.S. Food and Drug Administration (FDA) granded accelerated approval to zenocutuzumab-zbco (Bizengri) for adults with the following:

• advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or
• advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy.

The FDA approval was based on supporting data from the eNRGy study (FDA, 2024).

In the eNRGy study, a multicenter, open-label, multi-cohort clinical study, investigators evaluated the efficacy of Bizengri in 64 adult patients with advanced or metastatic NRG1 fusion-positive NSCLC and in 30 adult patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who had disease progression following standard of care treatment for disease. Patients received a median of 2 prior systemic therapies. (FDA, 2024; Partner Therapeutics, 2025).

Patients received an intravenous infusion of Bizengri 750 mg every 2 weeks until unacceptable toxicity or disease progression. Patients had tumor assessments every 8 weeks (Partner Therapeutics, 2025).

The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), determined by a blind independent central review (BCIR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (FDA, 2024; Partner Therapeutics, 2025).

For NSCLC, ORR was 33% (95% confidence interval [CI]: 22%, 46%) and median DOR was 7.4 months (95% CI: 4.0, 16.6). For pancreatic adenocarcinoma, ORR was 40% (95% CI: 23%, 59%) and the DOR range was 3.7 months to 16.6 months (FDA, 2024).

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References