Coverage Policy Manual
Policy #: 2017003
Category: Pharmacy
Initiated: January 2017
Last Review: January 2024
  Ziv-aflibercept (e.g., Zaltrap)
Description:
Ziv-aflibercept is a fully humanized recombinant fusion protein that acts as a soluble receptor to bind vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factors 1 and 2, which prevents other native receptors from binding. Inhibition of native receptor binding can result in decreased neovascularization and decreased vascular permeability.
 
Regulatory Status
 
Ziv-aflibercept (e.g., Zaltrap® ) is FDA approved for individuals with metastatic colorectal cancer (mCRC) in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI) that is resistant to or has progressed following an oxaliplatin-containing regimen.
 
Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in individuals who have received ziv-aflibercept (e.g., Zaltrap®).  Ziv-aflibercept (e.g., Zaltrap®) should be avoided in individuals with severe hemorrhage, GI perforation, and suspended for 4 weeks before and after major surgery until the surgical would is fully healed.
 
Coding
 
See CPT/HCPCS Code section.
 
Policy/
Coverage:
Prior Approval is required for Ziv-aflibercept (e.g., Zaltrap).    
 
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective January  2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ziv-aflibercept meets benefit member primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of unresectable, advanced or metastatic colorectal cancer (mCRC) when ALL the below criteria are met (NCCN 2A):
 
INITIAL TREATMENT:
 
    1.  Individual has been resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab; AND
    2. Ziv-aflibercept will be given in combination with an irinotecan based, 5-fluorouracil, and leucovorin regimen, but will not be used in combination with the same irinotecan based regimen previously used in combination with bevacizumab; AND
    3. The prescribed regimen will not be used in the same regimen with cetuximab, panitumumab, or bevacizumab; AND
    4. Must be dosed in accordance with the FDA label.
 
CONTINUED TREATMENT:
 
    1. The individual has been previously approved and received ziv-aflibercept through a medical benefit in the previous year or the individual has previously met all indication-specific criteria for coverage; AND
    2. The individual has not progressed while receiving treatment with ziv-aflibercept.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose for ziv-aflibercept is 4 mg/kg as an intravenous infusion over 1 hour every 2 weeks.  
 
Do not administer as an intravenous (IV) push or bolus.
 
Ziv-aflibercept is available as 100 mg/4 mL and 200 mg/8 mL solution in single-dose vials.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of ziv-aflibercept, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of ziv-aflibercept, for any indication or circumstance not described above,  is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 1, 2022 to December 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ziv-aflibercept meets benefit member primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of unresectable, advanced or metastatic colorectal cancer (mCRC) when ALL of the below criteria are met (NCCN 2A):
 
INITIAL TREATMENT:
 
        1.  Has been resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab; AND
        2. Ziv-alflibercept will be given in combination with an irinotecan based, 5-fluorouracil, and leucovorin regimen, but will not be used in combination with the same irinotecan based regimen previously used in combination with bevacizumab.
        3. The prescribed regimen is in compliance with FDA-approved dosing (4mg/kg given as IV infusion every 2 weeks); AND
        4. The prescribed regimen will not be used in the same regimen with cetuximab, panitumumab, or bevacizumab; AND
 
CONTINUED TREATMENT:
 
        1. The member has been previously approved and received ziv-alfibercept through a medical benefit in the previous year or the member has previously met all indication-specific criteria for coverage; AND
        2. The member has not progressed while receiving treatment with ziv-alflibercept.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
DOSAGE AND ADMINISTRATION
 
    • 4 mg/kg as an intravenous infusion over 1 hour every 2 weeks.  
    • Do not administer as an intravenous (IV) push or bolus  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of ziv-aflibercept does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of any indication or any circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of ziv-aflibercept (Zaltrap®) for the treatment of any indication or any circumstance other than those outlined above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 1, 2021 to December 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ziv-aflibercept (Zaltrap®) meets benefit member primary coverage criteria that there be scientific evidence of effectiveness for the treatment of unresectable, advanced or metastatic colorectal cancer (mCRC) when ALL of the below criteria are met:
 
INITIAL TREATMENT:
 
        1.  Has been resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab; AND
        2. There is a contraindication-, resistance-, or intolerance-to bevacizumab; AND
        3. Ziv-alflibercept (Zaltrap®) will be given in combination with an irinotecan based, 5-fluorouracil, and leucovorin regimen, but will not be used in combination with the same irinotecan based regimen previously used in combination with bevacizumab
        4. The prescribed regimen is in compliance with FDA-approved dosing (4mg/kg given as IV infusion every 2 weeks); AND
        5. The prescribed regimen will not be used in the same regimen with cetuximab, panitumumab, or bevacizumab; AND
 
CONTINUED TREATMENT:
 
        1. The member has been previously approved and received ziv-alfibercept (Zaltrap®) through a medical benefit in the previous year or the member has previously met all indication-specific criteria for coverage; AND
        2. The member has not progressed while receiving treatment with ziv-alflibercept (Zaltrap®).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
DOSAGE AND ADMINISTRATION
 
    • 4 mg/kg as an intravenous infusion over 1 hour every 2 weeks.  
    • Do not administer as an intravenous (IV) push or bolus  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of ziv-aflibercept (Zaltrap®) soes not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of any indication or any circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of ziv-aflibercept (Zaltrap®) for the treatment of any indication or any circumstance other than those outlined above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 5, 2019 to October 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ziv-aflibercept (Zaltrap®) meets benefit member primary coverage criteria that there be scientific evidence of effectiveness for the treatment of unresectable, advanced or metastatic colorectal cancer (mCRC) when ALL of the below criteria are met:
 
INITIAL TREATMENT:
 
        1.  Has been resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab; AND
        2. There is a contraindication-, resistance-, or intolerance-to bevacizumab; AND
        3. Ziv-alflibercept (Zaltrap®) will be given in combination with an irinotecan based, 5-fluorouracil, and leucovorin regimen, but will not be used in combination with the same irinotecan based regimen previously used in combination with bevacizumab
        4. The prescribed regimen is in compliance with FDA-approved dosing (4mg/kg given as IV infusion every 2 weeks); AND
        5. The prescribed regimen will not be used in the same regimen with cetuximab, panitumumab, or bevacizumab; AND
 
CONTINUED TREATMENT:
 
        1. The member has been previously approved and received ziv-alfibercept (Zaltrap®) through a medical benefit in the previous year or the member has previously met all indication-specific criteria for coverage; AND
        2. The member has not progressed while receiving treatment with ziv-alflibercept (Zaltrap®).
 
DOSAGE AND ADMINISTRATION:
 
    • 4 mg/kg as an intravenous infusion over 1 hour every 2 weeks.  
    • Do not administer as an intravenous (IV) push or bolus  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Off Label (2019)
    • NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of ziv-aflibercept (Zaltrap®) soes not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of any indication or any circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of ziv-aflibercept (Zaltrap®) for the treatment of any indication or any circumstance other than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective 1/17/2017 – 1/4/2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ziv-aflibercept (Zaltrap®) meets primary coverage criteria and is covered for the treatment of unresectable advanced or metastatic colorectal cancer (mCRC) when ALL of the below criteria are met:
 
INITIAL TREATMENT:
        1.  Has been resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab; AND
        2. There is a contraindication-, resistance-, or intolerance-to bevacizumab; AND
        3. Ziv-alflibercept (Zaltrap®) will be given in combination with an irinotecan based, 5-fluorouracil, and leucovorin  regimen, but will not  be used in combination with the same irinotecan based regimen  previously used in combination with bevacizumab
        4. The prescribed regimen is in compliance with FDA-approved dosing (4mg/kg given as IV infusion every 2 weeks); AND
        5. The prescribed regimen will not be used in the same regimen with cetuximab, panitumumab, or bevacizumab; AND
 
CONTINUED TREATMENT:
        1. The member has been previously approved and received ziv-alfibercept (Zaltrap®) through a medical benefit in the previous year or the member has previously met all indication-specific criteria for coverage; AND
        2. The member has not progressed while receiving treatment with ziv-alflibercept (Zaltrap®).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of ziv-aflibercept (Zaltrap®) for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of ziv-aflibercept (Zaltrap®) for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Aflibercept (ziv-aflibercept in the United States) was assessed in combination with FOLFIRI in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen (Van Cutsem, 2012). Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival. The combination significantly improved overall survival as compared to FOLFIRI alone (hazard ratio [HR], 0.817) with median survival times of 13.5 versus 12 months, respectively. Progression-free survival was also significantly improved (HR, 0.758) with median survival times of 6.9 versus 4.67 months, respectively.
 
2018 Update
A literature search conducted through January 2018 did not reveal any new information that would prompt a change in the coverage statement.  
 
2019 Update
A literature search conducted through January 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
A literature search conducted through January 2020 did not reveal any new information that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J9400Injection, ziv aflibercept, 1 mg
References: Chong DQ, Manalo M, Imperial M, et al.(2016) Safety and efficacy of aflibercept in combination with fluorouracil, leucovorin and irinotecan in the treatment of Asian patients with metastatic colorectal cancer. Asia Pac J Clin Oncol. 2016 Sep;12(3):275-83. doi: 10.1111/ajco.12496. Epub 2016 Apr 14.

Folprecht G, Pericay C, Saunders MP, et al.(2016) Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study. Ann Oncol. 2016 Jul;27(7):1273-9. doi: 10.1093/annonc/mdw176. Epub 2016 Apr 18.

National Comprehensive Cancer Network, Inc. 2023. All rights reserved.(2023) NCCN Drugs & Biologics Compendium® for Ziv-aflibercept (e.g., Zaltrap) Accessed [December 27, 2023]. To view the most recent and complete version of the Compendium, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Colon Cancer. Version 1. 2014 [Website]: at: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 11/17/2016

Van Cutsem E, Tabernero J, Lakomy R, et al.(2012) Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen. J Clin Oncol, 2012, 30(28):3499-506. [PubMed 22949147]

Wade R, Duarte A, Simmonds M, et al.(2015) The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: : a Critique of the Evidence. Pharmacoeconomics. 2015 May;33(5):457-66. doi: 10.1007/s40273-015-0257-z.

Zaltrap (ziv-aflibercept) package insert. Bridgewater, NJ:Sanofi-aventis U.S. LLC;2016 June.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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