ModifiedPremera BluecrossPolicy N/A

Use of VEGF and angiogenesis inhibitors in oncology

Defines medical necessity, coverage criteria, coding, and documentation requirements for vascular endothelial growth factor (VEGF) inhibitors and other angiogenesis inhibitors used to treat various cancers for Premera Blue Cross members and providers.

Policy Summary

PayerPremera Bluecross

PolicyUse of VEGF and angiogenesis inhibitors in oncology

Policy CodePolicy N/A

Change TypeMultiple coverage and criteria updates (added agents, revised authorization and sequencing)

Effective DateN/A

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of prior therapies, NCCN evidence category, and clinical response; initial oral drug authorizations are for 6 months.

SourceLink

POLICY UPDATE CHANGES

Added coverage criteria for generic pomalidomide and updated Pomalyst (pomalidomide) to require inadequate response or intolerance to generic pomalidomide.

Updated initial authorization duration for oral drugs from 3 months to 6 months for all other reviews.

Removed requirement to have tried two prior chemotherapy regimens for bevacizumab products when used in combination for platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Added Avzivi (bevacizumab-tnjn) as a non-preferred bevacizumab product and included Fruzaqla (fruquintinib) coverage for certain metastatic colorectal cancer.

Updated bevacizumab product criteria to include metastatic colorectal cancer in combination with Lonsurf for patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy.

≥7bevacizumab biosimilars and originator products listed

6 monthsinitial oral authorization

HCPCS listed

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safety signalGI perforation risk (ovarian cancer)

Phase III n=1,226ziv-aflibercept pivotal trial

Coverage Criteria and Medical Necessity

Policy-Level Coverage Updates

Policy-Level Coverage Updates — summary of recent and prior policy changes, effective dates, and operational clarifications.

2024 Update: Reviewed prescribing information for all drugs. Removed requirement for bevacizumab products to have tried two prior chemotherapy regimens for epithelial ovarian, fallopian tube, or primary peritoneal cancer when used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease. Added Avzivi (bevacizumab-tnjn) as a non-preferred bevacizumab product. Updated bevacizumab product criteria to include treatment of metastatic colorectal cancer in combination with Lonsurf (trifluridine and tipiracil) for individuals previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. Added coverage for Fruzaqla (fruquintinib) for certain adults with metastatic colorectal cancer. Removed ECOG requirement from the policy.

2026 Update: Reviewed prescribing information for all drugs. Updated initial authorization for "all other" reviews for oral drugs listed in the policy from 3 months to 6 months. Added coverage criteria for generic pomalidomide. Updated criteria for Pomalyst (pomalidomide) to require an inadequate response or intolerance to generic pomalidomide. Added related medical policy 5.01.591 Immune Checkpoint Inhibitors.

2025 Changes (effective Jan 3, 2025): Changed Mvasi (bevacizumab-awwb) to a preferred product and Avastin (bevacizumab) to a non-preferred product. Updated coverage criteria for Alymsys (bevacizumab-maly), Avastin, Avzivi (bevacizumab-tnjn), and Vegzelma (bevacizumab-adcd) to require an adequate trial and failure with Mvasi or Zirabev.

2024–2026 Operational and Coding Updates: Added Avzivi HCPCS code J9999 (2024). Added HCPCS/Q codes and made coding updates across 2022–2026 (e.g., Q5126, Q5129, Q5160, J9999, C9399). Added Jobevne (bevacizumab-nwgd) as a non-preferred product and HCPCS code C9399 (2025). Added HCPC code J9999 for Avzivi and updated code term dates as noted.

2023–2024 Clinical and Policy Clarifications: Added biosimilars Alymsys (bevacizumab-maly) and Vegzelma (bevacizumab-adcd) with requirement for inadequate response or intolerance to Avastin or Zirabev first (2022–2023). Clarified that medications listed are subject to FDA dosing and administration. Clarified non-formulary exception approvals may be granted up to 12 months.

Historical Notes and Review Cadence: Policy reviewed annually with interim reviews as noted. Key prior additions included Cyramza (ramucirumab) coverage criteria (approved 2020), Pomalyst indications and dose limits (2013–2021), addition of Zaltrap and criteria (2012), and ongoing NCCN-driven recognition of indications.

Operational Note: Non-formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months. Initial authorizations for oral drugs (other reviews) are 6 months as of the 2026 update.

Coding and Billing Codes

HCPCS codes for listed agentsHCPCS

C9399	Unclassified drugs or biologicals (use to report: Jobevne)
J9035	Injection, bevacizumab (Avastin), 10 mg
J9308	Injection, ramucirumab (Cyramza), 5 mg
J9400	Injection, ziv-aflibercept (Zaltrap), 1 mg
J9999	Not otherwise classified, antineoplastic drugs (use: to report Avzivi and Jobevne)
Q5107	Injection, bevacizumab-awwb, biosimilar (Mvasi), 10 mg
Q5118	Injection, bevacizumab-bvzr, biosimilar (Zirabev), 10 mg
Q5126	Injection, bevacizumab-maly, biosimilar (Alymsys), 10 mg
Q5129	Injection, bevacizumab-adcd biosimilar (Vegzelma), 10 mg
Q5160	Injection, bevacizumab-nwgd (Jobevine), biosimilar, 10 mg (new code effective 01/01/26)

Policy-related HCPCS/administrative codesHCPCS

J1725	bevacizumab-related HCPCS code added historically
J9400	historical HCPCS code added to policy
Q5107	HCPCS code added effective 1/1/19
Q5118	HCPCS code added effective 10/1/19
J9999	HCPCS code added for Avzivi
Q5126	HCPCS code added
Q5129	HCPCS code added
Q5160	HCPCS code added effective 1/1/26
C9399	HCPCS code added for Jobevne
C9142	HCPCS code added previously for Alymsys (later removed)

1–10 of 11

1/2

inv-16: AFP for ramucirumab HCC indication — alpha fetoprotein >= 400 ng/mL.

AFP thresholdAlpha fetoprotein (AFP) >= 400 ng/mL is required for ramucirumab (Cyramza) use in HCC after sorafenib

ContextApplies to individuals with hepatocellular carcinoma treated previously with sorafenib

Evidence/sourceRequirement referenced in injectable drug medical necessity criteria

inv-17: Initial authorization for oral drugs — 6 months.

Initial authorization periodInitial authorization for oral drugs: 6 months

Policy change noteUpdated from 3 months to 6 months (05/01/26 review)

Prior Authorization, Documentation, and Provider Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for drugs in this policy. Initial authorizations for non-formulary exception reviews for both oral and injectable drugs listed in this policy may be approved up to 12 months. For other initial reviews, initial authorization durations vary by drug per the policy; recent updates set initial authorization for oral drugs (other reviews) to 6 months. Re-authorizations (including non-formulary exception reviews) may be approved up to 12 months provided drug-specific criteria are met and chart notes document continued positive clinical response.

Initial non-formulary exception approvals: up to 12 months
Oral drug initial authorization for other reviews: 6 months (updated 05/01/26)
Re-authorization: up to 12 months if criteria and clinical response documented

Documentation Required

NCCN Category 2B Uses — Evidence Submission Required

Off-label uses supported only by NCCN Category 2B require the provider to submit significant peer‑reviewed Phase II or Phase III studies demonstrating treatment effectiveness. Uses supported by NCCN Categories 1 or 2A are recognized as proven; Category 2B and 3 are considered unproven absent submitted evidence.

Line of Therapy Rules and Sequencing

first-line | second-line

First-line bevacizumab uses: Bevacizumab products (e.g., Mvasi, Zirabev) may be used first-line in combination with specified chemotherapies for metastatic colorectal cancer and non-squamous NSCLC (carboplatin + paclitaxel), and in first-line combination with atezolizumab for unresectable/metastatic HCC per indication.

Second-line bevacizumab biosimilars: Alymsys, Avastin, Avzivi, Jobevne, and Vegzelma may be used second-line for individuals with inadequate response or intolerance to Mvasi or Zirabev and for other listed second-line indications such as second-line mCRC in combination with irinotecan or oxaliplatin following progression on a first-line bevacizumab-containing regimen.

first-line | second-line | salvage

First-line and later-line examples: Evidence and trials document bevacizumab use across first-line, second-line, and salvage settings: examples include first-line combinations with paclitaxel in metastatic breast cancer and with paclitaxel/carboplatin in non-squamous NSCLC (E4599), and later-line or salvage use in recurrent ovarian cancer, glioblastoma, and RCC per trial evidence and NCCN listings.

Biomarker and Laboratory Requirements

inv-49: AFP — >= 400 ng/mL.

AFP thresholdAFP >= 400 ng/mL

Indication linkedRequired for ramucirumab use in HCC after prior sorafenib

Source sectionInjectable Drugs, Medical Necessity criteria

inv-50: RAS — wild-type (if RAS wild-type, prior anti-EGFR therapy required).

RAS status requiredRAS — wild-type

Sequencing implicationIf RAS wild-type, prior anti-EGFR therapy (e.g., cetuximab or panitumumab) is required before certain subsequent treatments

Context/example

Covered Regimens and Indications

Indication	Regimen / combination	Coverage status
{"text":"Metastatic colorectal cancer","status":""},{"text":"Bevacizumab products in combination with intravenous 5-fluorouracil (or equivalent, e.g., capecitabine, floxuridine) and with irinotecan- or oxaliplatin-based regimens; or in combination with trifluridine/tipiracil (Lonsurf) for later-line therapy after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and prior anti-VEGF biologic (and if RAS wild-type, prior anti-EGFR therapy)","status":""},{"text":"covered","status":"covered"}

Indication	Regimen / combination	Coverage status
{"text":"Unresectable locally advanced or metastatic non-squamous non-small cell lung cancer (first-line)","status":""},{"text":"Bevacizumab products in combination with carboplatin and paclitaxel (as studied in trial E4599 showing improved RR, PFS and modest OS) — note bleeding/hemoptysis risk","status":""},{"text":"covered","status":"covered"}

Indication	Agent / regimen	Coverage status
{"text":"Unresectable or metastatic hepatocellular carcinoma (no prior systemic therapy)","status":""},{"text":"Bevacizumab (or biosimilars) in combination with atezolizumab (Tecentriq) for first-line treatment","status":""},{"text":"covered","status":"covered"}
{"text":"Hepatocellular carcinoma after sorafenib with elevated AFP","status":""},{"text":"Ramucirumab (Cyramza) for individuals with alpha-fetoprotein >= 400 ng/mL following prior sorafenib","status":""},{"text":"covered","status":"covered"}

Indication	Key evidence summary	Coverage status
{"text":"First-line metastatic breast cancer","status":""},{"text":"Bevacizumab plus paclitaxel demonstrated significant improvement in progression-free survival and response rate (e.g., median PFS 10.97 vs 6.11 months in a randomized study), but overall survival benefit is variable and regulatory positions (FDA withdrawal of breast indication) and reimbursement differ","status":""},{"text":"mixed","status":"neutral"}

Indication	Trial / benefits	Safety considerations / coverage status
{"text":"Non-squamous non-small cell lung cancer (selected patients)","status":""},{"text":"Bevacizumab added to paclitaxel/carboplatin (E4599): increased response rate, longer PFS (6.4 vs 4.5 months) and modest OS benefit (12.5 vs 10.2 months)","status":""},{"text":"Bleeding/hemoptysis risk noted; covered with criteria","status":"covered"}

Indication	Evidence summary	Coverage status
{"text":"Recurrent epithelial ovarian cancer (platinum-resistant or -sensitive contexts described)","status":""},{"text":"Single-agent bevacizumab shows modest activity (response rates ~16–28% in trials) but has an increased risk of gastrointestinal perforation, particularly in heavily pretreated individuals; NCCN categorizations should guide use","status":""},{"text":"restricted","status":"restricted"}

Indication	Trial outcome	Coverage status
{"text":"Advanced adenocarcinoma of the pancreas","status":""},{"text":"Addition of bevacizumab to gemcitabine in Phase III trials did not demonstrate a statistically significant overall survival benefit","status":""},{"text":"not_covered","status":"not_covered"}

Indication	Regimen (dose per pivotal trial)	Coverage status
{"text":"Metastatic colorectal cancer resistant to or progressed after an oxaliplatin-containing regimen","status":""},{"text":"Ziv-aflibercept (Zaltrap) 4 mg/kg IV every 2 weeks in combination with FOLFIRI (per VELOUR Phase III trial showing median OS 13.5 vs 12.1 months; PFS 6.9 vs 4.7 months)","status":""},{"text":"covered","status":"covered"}

Indication	Regimen / setting	Coverage status
{"text":"Unresectable or metastatic hepatocellular carcinoma (no prior systemic therapy)","status":""},{"text":"Bevacizumab (or biosimilars) in combination with atezolizumab (Tecentriq) as first-line therapy","status":""},{"text":"covered","status":"covered"}

Indication	Regimen / historical note	Coverage status
{"text":"Metastatic colorectal cancer resistant to or progressed after oxaliplatin-containing regimen","status":""},{"text":"Ziv-aflibercept (Zaltrap) in combination with FOLFIRI — historical policy addition reflecting VELOUR trial inclusion and coverage for this indication","status":""},{"text":"covered","status":"covered"}

Indication	Regimen / policy change	Coverage status
{"text":"Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer","status":""},{"text":"Bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease — prior requirement to have tried two prior chemotherapy regimens was removed effective 03/01/24","status":""},{"text":"covered","status":"covered"}

Definitions and Drug Descriptions

inv-37: Angiogenesis / VEGF inhibition — definition and mechanism summary.

DefinitionAngiogenesis: formation of new blood vessels necessary for tumor growth; VEGF is a primary inducer and therapeutic target

Mechanism summaryVEGF-targeting agents inhibit VEGF signaling to reduce endothelial cell proliferation and tumor neovascularization

Clinical relevanceInhibiting angiogenesis can slow tumor growth and is the rationale for VEGF/angiogenesis inhibitors in oncology

inv-38: Ziv-aflibercept — definition as recombinant fusion protein.

Agent descriptionZiv-aflibercept (Zaltrap) is a recombinant fusion protein composed of VEGF-binding portions of human VEGF receptors 1 and 2 fused to an IgG1 Fc

MechanismActs as a soluble receptor that binds VEGF-A, VEGF-B, and PlGF, inhibiting ligand–receptor activation and neovascularization

Background and Clinical Rationale

Angiogenesis—the formation of new blood vessels—is essential for tumor growth and is primarily driven by vascular endothelial growth factor (VEGF) signaling. Therapeutic targeting of angiogenesis, including VEGF or VEGF‑receptor inhibition and related pathways (for example, agents that interfere with EGFR signaling which can interact with growth factor pathways), underlies the use of monoclonal antibodies and tyrosine kinase inhibitors described in this policy. These agents are used alone or combined with cytotoxic chemotherapy for multiple solid tumors where inhibition of neovascularization may limit tumor progression.

Policy Revision History

2026 Update (05/01/26)policy_revisionLatest

Updated initial authorization duration for oral drugs from 3 months to 6 months and revised Pomalyst (pomalidomide) to require inadequate response or intolerance to generic pomalidomide; added generic pomalidomide coverage and updated brand step requirements.

2024 Update (03/01/24)policy_revision

Removed the requirement to have tried two prior chemotherapy regimens for bevacizumab products when used in combination for platinum‑resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Policy Summary

PayerPremera Bluecross

PolicyUse of VEGF and angiogenesis inhibitors in oncology

Policy CodePolicy N/A

Change TypeMultiple coverage and criteria updates (added agents, revised authorization and sequencing)

Effective DateN/A

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of prior therapies, NCCN evidence category, and clinical response; initial oral drug authorizations are for 6 months.

SourceLink

On This Page

Applies toAll oral drugs listed in this policy for initial authorizations

Category 1 or 2A: recognized as medically accepted
Category 2B: requires provider-submitted peer-reviewed Phase II/III evidence to be considered
Category 3: not recognized

Documentation Required

Documentation Required with Prior Authorization

Providers must include thorough documentation with authorization requests. The medical record should demonstrate that medical necessity criteria are met and include office visit notes with diagnosis, relevant history, physical exam, and medication history. For NCCN Category 2B uses, submitted evidence should be significant peer-reviewed Phase II or III studies. For agents supported by pivotal phase III evidence or with prior-therapy prerequisites, document prior therapies (for example prior oxaliplatin-containing regimens when applicable) and treatment sequencing per NCCN guidance.

Office visit notes with diagnosis, history, physical evaluation, medication history and chart notes demonstrating medical necessity
For Category 2B: attach peer-reviewed Phase II/III studies supporting the off-label use
Document prior therapy regimens (e.g., prior oxaliplatin-containing regimens, prior anti-VEGF biologic therapy, anti‑EGFR therapy when RAS wild-type)

Billing Rule

Bevacizumab Step and Coding Requirements

Bevacizumab products have formulary preferences and step/trial requirements. Some non-preferred bevacizumab biosimilars (added as non-preferred in recent updates) require an adequate trial and failure with preferred products (e.g., Mvasi or Zirabev) before they are considered medically necessary. Coding/HCPCS updates are reflected in the policy history and product coding sections.

Preferred products: Mvasi (bevacizumab-awwb) designated preferred effective 01/03/2025
Non-preferred products (examples): Avastin, Avzivi, Jobevne, Vegzelma — require trial/failure with preferred product(s) such as Mvasi or Zirabev
HCPCS/Coding changes are maintained in the policy history (see coding updates)

Step Therapy

Step Requirement for Certain Bevacizumab Biosimilars

For certain bevacizumab biosimilars and other non-preferred products, a step-therapy requirement applies: coverage is contingent on an inadequate response or intolerance to a preferred bevacizumab product (e.g., Mvasi or Zirabev) before authorizing non-preferred agents.

Requirement: inadequate response or intolerance to preferred bevacizumab product (Mvasi or Zirabev) before approving non-preferred biosimilars
Effective dates and product status are in policy history (provider notification timelines apply)

Note

Therapy Sequencing Considerations

Therapy sequencing must follow NCCN guidance and specific policy criteria. For example, sequencing notes for NSCLC and targeted therapies (such as osimertinib for EGFR-mutated advanced NSCLC) and requirements for prior biologic or chemotherapies for mCRC/Lonsurf combination are applicable — document prior lines of therapy as required.

NSCLC: follow NCCN-preferred sequencing (osimertinib preferred for EGFR exon 19 deletion or L858R)
mCRC + Lonsurf: individual must have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti‑VEGF biologic, and if RAS wild-type, an anti‑EGFR therapy

Denial Risk

Investigational Indication and NCCN Evidence-Related Denial Risk

Coverage risk exists when requested uses are investigational or unsupported by recognized NCCN evidence levels. Bevacizumab for advanced pancreatic adenocarcinoma is considered investigational based on phase III trial evidence showing no overall survival benefit; requests for investigational indications are at high risk for denial. Additionally, uses supported only by NCCN Category 2B without submitted Phase II/III evidence may be denied.

Bevacizumab for advanced pancreatic adenocarcinoma: investigational — phase III trials did not demonstrate OS benefit
NCCN Categories 1 and 2A accepted; Category 2B requires submitted peer-reviewed Phase II/III studies or risk of denial
FDA withdrawal of some indications (e.g., metastatic breast cancer) affects coverage stance — see policy notes

Note

Verify Member Benefits — Benefit Limitations May Trigger Denial

Coverage is subject to the member’s specific benefit plan limits and conditions. Before submitting an authorization request, providers must verify member benefits and any applicable limitations in the member benefit booklet or by contacting customer service/member services.

Always consult the member benefit booklet or contact member services to determine coverage and benefit limitations
This policy does not apply to Medicare Advantage; benefits vary by contract

second-line

Ziv-aflibercept (second-line): Zaltrap (ziv-aflibercept) is indicated for metastatic colorectal cancer resistant to or progressed following an oxaliplatin-containing regimen and is used in combination with FOLFIRI as demonstrated in the VELOUR Phase III trial (improved OS and PFS); documentation of prior oxaliplatin-containing therapy is required.

first-line

Atezolizumab + bevacizumab for HCC (first-line): Bevacizumab (or biosimilars) in combination with atezolizumab is covered for unresectable or metastatic hepatocellular carcinoma in patients who have not received prior systemic therapy.

mixed

Mixed line-of-therapy designations: Policy history and sections document mixed line-of-therapy assignments across agents and indications (e.g., first- and second-line designations for bevacizumab products in CRC, NSCLC, ovarian cancer; sequencing and prior-regimen requirements updated over time).

mCRC patients considered for bevacizumab + Lonsurf combinations per updated criteria

inv-51: EGFR mutation — EGFR mutation requirement noted where applicable.

EGFR mutation considerationEGFR mutation status guides preferred therapy in NSCLC (e.g., osimertinib preferred for sensitizing EGFR exon 19 or exon 21 L858R mutations)

Clinical implicationEGFR-mutant status affects sequencing of VEGF/other therapies in NSCLC per NCCN guidance

Source wordingPreferred therapy noted in lung cancer section and EGFR description

inv-52: RAS — wild-type.

RAS statusRAS — wild-type

ApplicationUsed as a biomarker requirement in colorectal cancer sequencing and therapy decisions

Policy referenceIncluded in policy coverage criteria and 2024 update language

inv-53: RAS — RAS wild-type required for anti-EGFR therapy prior to certain subsequent treatments.

RAS and anti-EGFR sequencingIf RAS wild-type, an anti-EGFR therapy should be given prior to certain subsequent treatments (e.g., prior to bevacizumab + Lonsurf in mCRC)

Policy updateRAS-related sequencing language added/clarified in the 2024 update

Clinical useApplies to metastatic colorectal cancer therapy sequencing in policy criteria

Production noteProduced by recombinant DNA technology in CHO K-1 cells; dimeric glycoprotein ~97 kDa

inv-39: Fruquintinib — oral VEGFR inhibitor definition.

Agent classFruquintinib (Fruzaqla) is an oral small-molecule kinase inhibitor of VEGFR-1, -2, and -3

MechanismInhibits VEGF-mediated endothelial cell proliferation and VEGFR-2 phosphorylation (in vitro/in vivo evidence)

Indication in policyCovered for certain adult patients with metastatic colorectal cancer after prior chemotherapies and anti-VEGF therapy

inv-40: Lenalidomide / Pomalidomide — oral immunomodulatory agents with anti-angiogenic properties.

Agent classLenalidomide and pomalidomide are oral immunomodulatory agents with anti-angiogenic properties (pharmacology similar to thalidomide)

Clinical usesBoth agents are approved for multiple myeloma; lenalidomide also approved for certain MDS; pomalidomide has specified MM indications with prior therapy requirements

Policy sequencingPolicy requires trial of generic lenalidomide before brand Revlimid; pomalidomide coverage updated to require generic trial where applicable

inv-41: NCCN category — explanation of NCCN Categories of Evidence and Consensus.

NCCN categories explainedNCCN Categories of Evidence and Consensus classify uses (Category 1 and 2A recognized as proven; Category 2B and 3 as unproven)

Coverage implicationCategory 2B uses may be considered for coverage only if provider submits significant peer-reviewed phase II/III studies demonstrating effectiveness

Provider actionProviders should reference NCCN listings when seeking coverage for off-label uses

inv-42: Bevacizumab and biosimilars — list and definition.

Bevacizumab and biosimilars listIncludes Avastin (bevacizumab) and biosimilars Mvasi (bevacizumab-awwb), Zirabev (bevacizumab-bvzr), Alymsys (bevacizumab-maly), Vegzelma (bevacizumab-adcd), Avzivi (bevacizumab-tnjn), Jobevne (bevacizumab-nwgd)

Product status notesPolicy designates preferred and non-preferred bevacizumab products (e.g., Mvasi preferred; Avastin non-preferred; Avzivi/Jobevne non-preferred as noted in updates)

Coding referenceHCPCS codes for these agents are listed in coding section and history entries

inv-43: Related VEGF/angiogenesis inhibitors and oral agents — list of other agents covered or referenced.

Related VEGF/angiogenesis inhibitorsIncludes ramucirumab (Cyramza), ziv-aflibercept (Zaltrap), fruquintinib (Fruzaqla), lenalidomide (Revlimid), and pomalidomide (Pomalyst)

Mechanisms/rolesAgents include monoclonal antibodies, fusion proteins, and oral TKIs that inhibit VEGF signaling or have anti-angiogenic immunomodulatory effects

Policy coverage noteThese agents are within the policy scope with agent-specific criteria and prior-therapy requirements as listed

2023 History (01/01/23)

HCPCS coding updates including addition and term-date adjustments for codes such as C9142 and J3590; coding history entries recorded in policy history.

2020 Update (09/01/20)policy_addition

Added Cyramza (ramucirumab) to the policy with coverage criteria for gastric/GEJ and other listed indications.

2019 Updatepolicy_update

Added criteria for Zirabev (bevacizumab-bvzr) biosimilar and updated criteria for Revlimid (lenalidomide); other product-level changes recorded.

2012–2013 Updates (12/11/12; 08/12/13)policy_updates

Added ziv‑aflibercept (Zaltrap) for mCRC (with FOLFIRI) and added Pomalidomide (Pomalyst) coverage for multiple myeloma when criteria met; HCPCS code J1725 added.

2008–2011 History (08/12/08; 12/16/08; 05/12/09; 10/13/09; 01/12/10; 09/14/10; 12/14/10; 05/10/11)historical_revisions

Initial additions to the prescription drug section, multiple policy replacements and literature‑search driven updates including changes to ovarian cancer indications, NCCN category adoption, and FDA‑related updates (e.g., breast cancer label action) across 2008–2011.

Material policy changes in this update include: addition of coverage criteria for generic pomalidomide and adjustment of Pomalyst criteria to require prior inadequate response or intolerance to generic pomalidomide; removal of the two‑prior‑chemotherapy requirement for certain bevacizumab uses in platinum‑resistant ovarian cancer; addition of Avzivi as a non‑preferred bevacizumab product and inclusion of Fruzaqla (fruquintinib) coverage for select metastatic colorectal cancer patients; and an update to initial authorization duration for oral drugs from 3 months to 6 months.

The policy’s material changes listed in history entries include: addition of Avzivi (bevacizumab‑tnjn) and designation of non‑preferred bevacizumab products; addition of Fruzaqla (fruquintinib) for certain mCRC patients; added coverage criteria for generic pomalidomide and updated Pomalyst requirements to require prior trial of generic pomalidomide; updated bevacizumab sequencing and mCRC Lonsurf combination criteria; removal of ECOG requirement; and a uniform change to initial authorization for oral drugs from 3 to 6 months. Several coding and product preference updates (preferred vs non‑preferred biosimilars and new HCPCS codes) are also recorded in the policy history.