Commercial

Medical Policy

Title:

Zenocutuzumab-zbco (Bizengri®)

Policy #:

08.02.38a

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member's medical needs and condition.

MEDICALLY NECESSARY

NON-SMALL CELL LUNG CANCER

Zenocutuzumab-zbco (Bizengri^®), as a single agent, is considered medically necessary and, therefore, covered as subsequent therapy for the treatment of individuals with recurrent, advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) if neuregulin 1 (NRG1) gene fusion–positive disease with BOTH of the following:

Disease progression on or after prior systemic therapy
Left ventricular ejection fraction (LVEF) 50 percent or greater prior to initiation of treatment

PANCREATIC ADENOCARCINOMA

Zenocutuzumab-zbco (Bizengri), as a single agent, is considered medically necessary and, therefore, covered for the treatment of individuals with advanced, unresectable, or metastatic pancreatic adenocarcinoma if NRG1 gene fusion positive with ALL of the following:

Disease progression on or after prior systemic therapy
LVEF 50 percent or greater prior to initiation of treatment
In ONE of the following scenarios:

As alternate systemic therapy not previously used for local recurrence in the pancreatic operative bed after resection with ONE of the following:

Good Eastern Cooperative Oncology Group (ECOG) performance status (PS) (PS 0-1)
Intermediate PS (PS 2)

As alternate systemic therapy not previously used for recurrent metastatic disease with or without local recurrence after resection with ONE of the following:

Good PS (PS 0-1)
Intermediate PS (PS 2)

As subsequent therapy for locally advanced or metastatic disease with ONE of the following:

Good PS (PS 0-1 with good biliary drainage and adequate nutritional intake)
Intermediate PS (PS 2)

EXPERIMENTAL/INVESTIGATIONAL

All other uses for zenocutuzumab-zbco (Bizengri) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

MANDATES

PENNSYLVANIA MEMBERS
In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings for zenocutuzumab-zbco (Bizengri).

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, zenocutuzumab-zbco (Bizengri) is covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.

THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS

The Eastern Cooperative Oncology Group (ECOG) has developed the ECOG performance status. It was originally published in 1982 in the American Journal of Clinical Oncology.* ECOG states, "These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. They are included here for health care professionals to access."

ECOG Performance Status
Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50 percent of waking hours
3	Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours
4	Completely disabled. Cannot carry on any self-care: Totally confined to bed or chair
5	Dead

*Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

US FOOD AND DRUG ADMINISTRATION STATUS

The US Food and Drug Administration (FDA) approved zenocutuzumab-zbco (Bizengri) on December 4, 2024, for the treatment of 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. Zenocutuzumab-zbco (Bizengri) was also approved the same day for the treatment of adults with advanced, unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy. Both indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

PEDIATRIC USE
The safety and effectiveness of zenocutuzumab-zbco (Bizengri) in pediatric individuals have not been established.

Description

NEUREGULIN 1

Neuregulin 1 (NRG1) is an epidermal growth factor (EGF) involved in the development of the nervous and cardiac systems, and homeostasis. Diverse cancers have been identified with recurrent chromosomal rearrangements in part of the NRG1 domain. Oncogenic fusions of NRG1 can occur in invasive mucinous lung adenocarcinoma and pancreatic Kirsten rat sarcoma (KRAS) wild-type adenocarcinoma. NRG fusions bind to human epidermal growth factor receptor 3 (HER3), using an EGF-like binding domain, resulting in HER2/HER3 heterodimerization. Downstream, growth and proliferation signaling pathways are activated resulting in worsening disease.

ZENOCUTUZUMAB-ZBCO (BIZENGRI)

Zenocutuzumab-zbco (Bizengri) is an immunoglobulin G1 (IgG1) bispecific HER2- and HER3-directed antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, causing inhibition of HER2:HER3 dimerization and preventing NRG1 from binding to HER3. Zenocutuzumab-zbco (Bizengri) can decrease cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K) v-akt murine thymoma viral oncogene homologue 1 (AKT)-mammalian target of rapamycin (mTOR) pathway. Zenocutuzumab-zbco (Bizengri) also mediates antibody-dependent cellular cytotoxicity (ADCC).

NON-SMALL CELL LUNG CANCER

Lung cancer caused close to 2 million deaths worldwide in 2020. Annually in the United States, approximately 240,000 new cases are identified and approximately 130,000 individuals die from lung cancer. Lung cancers are generally divided into two groups, based on the size of the cells that make up the tumor. Small cell lung cancer makes up about 12 percent of lung cancers, and begin in neuroendocrine cells that line the inner airways. Non-small cell lung cancers make up most of the remainder of cancers, and can be further subdivided into two subtypes. Adenocarcinomas begin in the cells that line the alveoli and produce mucus. Squamous cell carcinomas begin in the cells that line the inside of the lungs. Each type of cancer responds differently to treatment, so must be differentiated via histology in order to determine a therapy regimen. With the development of therapies that are targeted at a specific biomarker, the prognosis for lung cancer has improved.

PANCREATIC CANCER

Pancreatic cancer is a highly deadly form of cancer, and is the fourth leading cause of cancer deaths in the United States. Often, because the initial symptoms are so generalized, it is not identified until the cancer is advanced and has spread to other organs. It is also difficult to treat. By the time the cancer is identified, curative surgery may not be possible. Common cancer therapies often only work for a short period of time, and may only add a few months to the individual's lifespan. As with lung cancer, with the development of therapies that are targeted at a specific biomarker, the prognosis for pancreatic cancer has improved.

CLINICAL TRIAL

The efficacy and safety of zenocutuzumab-zbco (Bizengri) in the treatment of individuals with solid tumors harboring a neuregulin 1 (NRG1) fusion was evaluated in an open-label, multicenter Phase II clinical trial called A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (NCT02912949). Enrolled individuals received zenocutuzumab-zbco (Bizengri) 750 mg intravenously (IV) every 2 weeks until they experienced disease progression or unacceptable toxicity. A total of 161 individuals were included in the primary efficacy set that consisted of 94 individuals with non-small cell lung cancer (NSCLC), 36 individuals with pancreatic adenocarcinoma, and 31 individuals with other solid tumor types. The coprimary endpoints were objective overall response rate (ORR) and duration of response (DOR).

At the time of data cutoff, the ORR, assessed by blinded independent central review (BICR), was 31 percent (29/94; 95 percent confidence interval [CI], 22–41 percent) for individuals with NSCLC and 44 percent (16/36; 95 percent CI, 28–62 percent) for individuals with pancreatic adenocarcinoma. The median DOR, assessed by BICR, was 13.4 months (range, 1.9–29.5 months) for individuals with NSCLC and 9.1 months (range, 1.9–16.6 months) for individuals with pancreatic adenocarcinoma. Of the total enrolled population, 95 percent of participants experienced at least one adverse event (AE), mostly grade 1 or 2. The most common grade 3 or grade 4 AEs in the total enrolled population were anemia (5 percent), gamma-glutamyl transferase (GGT) elevation (4 percent), and pneumonia (3 percent). Grade 3 or 4 AEs that were considered to be treatment-related occurred in 7 percent of the total enrolled population. Fatal AEs occurred in 4 percent of the total enrolled population, but none were considered to be treatment-related.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Zenocutuzumab-zbco (Bizengri^®). AHFS Drug Information. [UpToDate Lexidrug Web site]. 02/25/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed February 26, 2026.

Castillo CF, Singh H. Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer. [UpToDate Web site]. 09/05/2025. Available at: https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-staging-of-exocrine-pancreatic-cancer?search=Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. [via subscription only]. Accessed February 26, 2026.

ClinicalTrials.gov. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov Identifier: NCT02912949. First Posted: September 23, 2016. Last Update Posted: April 29, 2025. Available at: https://clinicaltrials.gov/. Accessed February 26, 2026.

Elsevier's Clinical Pharmacology Compendium. Zenocutuzumab-zbco (Bizengri^®). [Clinical Key Web site]. 11/07/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed February 26, 2026.

Merative Micromedex^® DRUGDEX^® (electronic version). Zenocutuzumab-zbco (Bizengri^®). [Micromedex Web site]. 02/20/2026. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 26, 2026.

Midthun DE. Overview of the initial treatment and prognosis of lung cancer. [UpToDate Web site]. 10/31/2025. Available at: https://www.uptodate.com/contents/overview-of-the-initial-treatment-and-prognosis-of-lung-cancer?search=Overview of the initial treatment and prognosis of lung cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 [via subscription only]. Accessed February 26, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Non-small cell lung cancer, V3.2026. [NCCN Web site]. 12/24/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. [via subscription only]. Accessed February 26, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Pancreatic adenocarcinoma, V2.2025. [NCCN Web site]. 02/03/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. [via subscription only]. Accessed February 26, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Zenocutuzumab-zbco (Bizengri®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed February 26, 2026.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Engl J Med. 2025;392(6):566-576.

UpToDate^® Lexidrug^TM. Zenocutuzumab-zbco (Bizengri^®). [UpToDate Lexidrug Web site]. 01/02/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed February 26, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Zenocutuzumab-zbco (Bizengri^®). Prescribing information. [FDA Web site]. 12/04/2024. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed February 26, 2026.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

C25.0 Malignant neoplasm of head of pancreas

C25.1 Malignant neoplasm of body of pancreas

C25.2 Malignant neoplasm of tail of pancreas

C25.3 Malignant neoplasm of pancreatic duct

C25.7 Malignant neoplasm of other parts of pancreas

C25.8 Malignant neoplasm of overlapping sites of pancreas

C25.9 Malignant neoplasm of pancreas, unspecified

C33 Malignant neoplasm of trachea

C34.01 Malignant neoplasm of right main bronchus

C34.02 Malignant neoplasm of left main bronchus

C34.11 Malignant neoplasm of upper lobe, right bronchus or lung

C34.12 Malignant neoplasm of upper lobe, left bronchus or lung

C34.2 Malignant neoplasm of middle lobe, bronchus or lung

C34.31 Malignant neoplasm of lower lobe, right bronchus or lung

C34.32 Malignant neoplasm of lower lobe, left bronchus or lung

C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung

C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung

C34.91 Malignant neoplasm of unspecified part of right bronchus or lung

C34.92 Malignant neoplasm of unspecified part of left bronchus or lung

HCPCS Level II Code Number(s)

J9382 Injection, zenocutuzumab-zbco, 1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.02.38a:

06/01/2026

This policy will become effective 06/01/2026.

The following policy criteria have been deleted from this policy:
The parenthetical exclusion in the non-small cell lung cancer criteria in accordance with the National Comprehensive Cancer Network

The following ICD-10 codes were added to this policy:

C25.0,C25.1, C25.2, C25.3, C25.7, C25.8, C25.9, C33, C34.01, C34.02, C34.11, C34.12, C34.2, C34.31, C34.32, C34.81, C34.82, C34.91, C34.92

Revisions From 08.02.38:

07/28/2025

This policy will become effective 07/28/2025.

The following new policy has been developed to communicate the Company's coverage criteria for zenocutuzumab-zbco (Bizengri^®).

Version Effective Date:

6/1/2026

Version Issued Date: