Commercial

Medical Policy

Title:

Zanidatamab-hrii (Ziihera®)

Policy #:

08.02.39a

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

Zanidatamab-hrii (Ziihera®), as a single agent, is considered medically necessary and, therefore, covered for the treatment of adults with previously treated (progression on or after systemic treatment), unresectable (or resected gross residual [R2] disease) or metastatic human epidermal growth factor receptor 2 (HER2)-positive immunohistochemistry (IHC) 3+ biliary tract cancer (BTC), when ALL of the following are met:

Histologically or cytologically confirmed BTC, including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)
Test positive for HER2 amplification by in situ hybridization (ISH) assay as detected by a US Food and Drug Administration (FDA)-approved test
Locally advanced or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies
Received at least one prior systemic chemotherapy regimen for advanced disease, and experienced disease progression after or developed intolerance to the most recent prior therapy
Have not received prior treatment with HER2-targeted agents
Left ventricular ejection fraction 50 percent or greater

EXPERIMENTAL/INVESTIGATIONAL

All other uses zanidatamab-hrii (Ziihera) 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.

BENEFIT APPLICATION

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

US FOOD AND DRUG ADMINISTRATION STATUS

Zanidatamab-hrii (Ziihera) was approved by US Food and Drug Administration (FDA) on November 20, 2024, for the treatment of adult individuals with previously treated, unresectable or metastatic human epidermal growth factor receptor (HER)2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics.

PEDIATRIC USE
The safety and effectiveness of zanidatamab-hrii (Ziihera) in pediatric individuals have not been established.

Description

Biliary tract cancer (BTC) is a type of cancer of the bile ducts. The bile duct system starts in the liver, joins with the cystic duct from the gallbladder, travels through a part of the pancreas, and empties into the small intestine. Bile helps digest fats in food and helps break down some of the waste material that has been filtered from blood by the liver. Bile is produced by the liver and stored in the gallbladder. When needed, bile exits the gallbladder and flows to the small intestine. Gland cells that line the insides of the ducts of the biliary tract can turn cancerous. Cancers of the biliary tract are called cholangiocarcinoma. Cancers of the biliary tract are broken down by location. If the cancer is located in the part of the bile ducts located in the liver, it is called intrahepatic cholangiocarcinoma. If the cancer is located in the part of the bile duct outside of the liver, it is called extrahepatic cholangiocarcinoma. BTCs can also originate in the gallbladder.

BTC is rare in the United States, with only about 8000 individuals diagnosed with the cancer annually. Because the cancer usually does not cause symptoms in the early stages, the cancer is often not identified until it is in late stage, has already spread to other parts of the body, and is harder to treat. The 5-year survival percentages, at the time of diagnosis, range from 2 to 23 percent depending on the location of the cancer and how far it has spread. Treatment for BTC can include surgery, radiation therapy, chemotherapy (with or without immunotherapy), targeted therapy, and/or photodynamic therapy. Because BTC is often identified after it has metastasized outside of the biliary tract, it is often too late to be treated with surgery. Chemotherapy is usually the first line of therapy for advanced BTC, but often does not extend survival beyond 8 to 15 months.

Zanidatamab-hrii (Ziihera) is a humanized, immunoglobulin G (IgG)-like, bispecific human epidermal growth factor receptor (HER)2-directed antibody. Zanidatamab-hrii (Ziihera) binds to two extracellular sites on HER2. Binding of zanidatamab-hrii (Ziihera) with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii (Ziihera) induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death.

The efficacy and safety of zanidatamab-hrii (Ziihera) in individuals with previously treated, unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) BTC was evaluated in a phase II, open-label, single arm, multicenter trial (NCT04466891; HERIZON-BTC-01). Sixty-two individuals were enrolled. Inclusion criteria included having received at least one previous gemcitabine-containing systemic regimen in the advanced disease setting and a left ventricular ejection fraction (LVEF) of 50 percent or greater. The primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DOR) up to 34 months, progression-free survival (PFS), and overall survival (OS). Participants received zanidatamab-hrii (Ziihera) 20 mg/kg intravenously (IV) every 2 weeks until disease progression or unacceptable toxicity. The ORR was 52 percent with 3.2 percent complete responses and 48 percent partial responses. The median DOR was 14.9 months. The median PFS was 5.5 months. The OS was not matured. Seventy-two percent of enrolled individuals experienced a treatment-related adverse event, with diarrhea and infusion-related reactions being the most common. No grade 4 or grade 5 treatment-related adverse events were reported.

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 Cancer Society (ACS). Bile duct cancer early detection, diagnosis, and staging. [ACS Web site]. 10/11/2024. Available at: https://www.cancer.org/cancer/types/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html. Accessed December 26, 2024.

American Cancer Society (ACS). What is bile duct cancer? [ACS Web site]. 10/11/2024. Available at: https://www.cancer.org/cancer/types/bile-duct-cancer/about/what-is-bile-duct-cancer.html. Accessed December 26, 2024.

ClinicalTrials.gov. A study of ZW25 (zanidatamab) in subjects with advanced or metastatic HER2-amplified biliary tract cancers (HERIZON-BTC-01). ClinicalTrials.gov Identifier: NCT04466891. First Posted: July 10, 2020. Last Update Posted: August 21, 2024. Available at: https://clinicaltrials.gov/. Accessed December 26, 2024.

Elsevier's Clinical Pharmacology Compendium. Zanidatamab-hrii (Ziihera®). [Clinical Key Web site]. 12/02/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed December 26, 2024.

Harding JJ, Fan J, Oh DY, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology®. Biliary tract cancers, V5.2024. [NCCN Web site]. 11/27/2024. Available from: https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf. [via subscription only]. Accessed December 26, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Zanidatamab-hrii (Ziihera®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed December 26, 2024.

Stuart KE. Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma. [UpToDate Web site]. 12/17/2024. Available at: https://www.uptodate.com/contents/systemic-therapy-for-advanced-unresectable-and-metastatic-cholangiocarcinoma/print?search=zanidatamab&source=search_result&selectedTitle=2~4&usage_type=default&display_rank=1 [via subscription only]. Accessed December 26, 2024.

UpToDate® Lexidrug^TM. Zanidatamab-hrii (Ziihera®). [UpToDate Lexidrug Web site]. 12/18/2024. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed December 26, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Zanidatamab-hrii (Ziihera®). Prescribing information. [FDA Web site]. 11/20/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed December 26, 2024.

US Food and Drug Administration (FDA). List of cleared or approved companion diagnostic devices (in vitro and imaging tools). [FDA Web site]. 11/15/2024. Available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. Accessed December 26, 2024.

Zanidatamab-hrii (Ziihera®) [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. 11/2024. Available at: https://pp.jazzpharma.com/pi/ziihera.en.USPI.pdf. Accessed December 26, 2024.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

C22.1 Intrahepatic bile duct carcinoma

C23 Malignant neoplasm of gallbladder

C24.0 Malignant neoplasm of extrahepatic bile duct

C24.8 Malignant neoplasm of overlapping sites of biliary tract

C24.9 Malignant neoplasm of biliary tract, unspecified

HCPCS Level II Code Number(s)

J9276 Injection, zanidatamab-hrii, 2 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.02.39a

07/01/2025

This version of the policy will become effective 07/01/2025.
Inclusion of a policy in a Code Update memo does not imply that a full review of
the policy was completed at this time.

The following HCPCS code has been added to this policy:
J9276 Injection, zanidatamab-hrii, 2 mg

The following HCPCS code has been termed (no longer valid code) and removed from this policy:
C9302 Injection, zanidatamab-hrii, 2 mg

The following HCPCS code has been removed from this policy:
J3590 Unclassified biologics

Revisions From 08.02.39:

04/21/2025

This policy will become effective 04/21/2025.

The following new policy has been developed to communicate the Company's coverage criteria for zanidatamab-hrii (Ziihera^®).

Version Effective Date:

7/1/2025

Version Issued Date: