CurrentPremera BluecrossPolicy 5.01.517

Angiogenesis inhibitors (VEGF and related agents) medical necessity coverage

Defines medical necessity coverage criteria, managed benefit channel (medical vs pharmacy), length of approval, documentation and coding for various angiogenesis-inhibiting drugs (bevacizumab products and biosimilars, ramucirumab, ziv-aflibercept, fruquintinib, lenalidomide, pomalidomide and others) across multiple oncologic indications.

Policy Summary

PayerPremera Bluecross

PolicyAngiogenesis inhibitors (VEGF and related agents) medical necessity coverage

Policy CodePolicy 5.01.517

Change TypeMultiple material updates (product preference, coding, step edits)

Effective Date

Next Review Date

Key ActionSubmit office visit notes with diagnosis, relevant history, physical exam and medication history to demonstrate medical necessity criteria are met.

SourceLink

POLICY UPDATE CHANGES

Added Avzivi (bevacizumab-tnjn) as a non-preferred bevacizumab product (03/01/24).

Removed requirement to try two prior chemotherapy regimens for bevacizumab products for platinum-resistant recurrent ovarian/fallopian tube/primary peritoneal cancer when used with specified agents (03/01/24).

Changed Mvasi to preferred and Avastin to non-preferred effective January 3, 2025 (approved 10/01/24).

Added Jobevne (bevacizumab-nwgd) as a non-preferred bevacizumab product and HCPCS code C9399 (09/01/25).

Updated Revlimid (lenalidomide) criteria to require inadequate response or intolerance to generic lenalidomide for all indications (01/01/26).

Initial authorization duration for oral drugs updated from 3 months to 6 months (05/01/26).

Added coverage criteria for generic pomalidomide (05/01/26).

Plan will continue to approve off-label use of bevacizumab for breast cancer as medically necessary when supported by NCCN despite FDA withdrawal of indication (2011 entry).

Added Jobevne (bevacizumab-nwgd) as a non-preferred bevacizumab product and added HCPCS code C9399 for Jobevne.

Added HCPCS code Q5160 effective January 1, 2026.

Updated coverage criteria for Revlimid (lenalidomide) for all indications to require trial and inadequate response or intolerance to generic lenalidomide.

Updated initial authorization for oral drugs listed in the policy from 3 months to 6 months.

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

MultipleCovered Indications (broad)

Medical/PharmacyBenefit channel

12 moMax prior auth duration

Q5160, C9399New HCPCS codes

Some usesInvestigational exclusions

Coverage Summary

This policy addresses angiogenesis inhibitors including bevacizumab products and biosimilars (Avastin, Mvasi, Zirabev, Alymsys, Avzivi, Vegzelma, Jobevne), ramucirumab (Cyramza), ziv‑aflibercept (Zaltrap), fruquintinib (Fruzaqla), and the oral immunomodulatory/anti‑angiogenic agents lenalidomide (Revlimid and generic) and pomalidomide (Pomalyst and generic). Benefit channel management varies by product: several agents (Alymsys, Avastin, Avzivi, Cyramza, Jobevne, Mvasi, Vegzelma, Zaltrap, Zirabev) are managed via the medical benefit, while Fruzaqla, generic lenalidomide, generic pomalidomide, Pomalyst, and Revlimid are managed through the pharmacy benefit as noted. The policy stance is mixed (indication‑specific medically necessary coverage with investigational exclusions). Maximum prior authorization/approval durations are up to 12 months per policy. Key operational points: multiple bevacizumab products are listed with product‑preference and sequencing requirements that have been updated over time (preferred versus non‑preferred status changes are reflected in the history), oral drug initial authorization durations were updated (3 → 6 months for initial oral drug reviews effective 05/01/26), and brand lenalidomide/Pomalyst require documented trial and inadequate response or intolerance to the generic product prior to approval.

Key thresholds & quick facts

Policy (payer / id)Premera Bluecross / 5.01.517

Policy statusCURRENT

Alpha fetoprotein threshold>= 400 ng/mL

Minimum age (oral VEGF/IMiD agents)>= 18 years

Lenalidomide dose limit (MDS)10 mg per day

Pomalidomide dose limit (MM)4 mg per day

Max authorizationUp to 12 months

Oral drug initial auth duration6 months (effective 05/01/26)

Medical-Necessity Criteria

Bevacizumab products - First-line (Mvasi, Zirabev)

Bevacizumab products Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) may be considered medically necessary no earlier than 28 days following major surgery and until the surgical wound is fully healed.

ONE of the following indications must be met:

Metastatic colorectal cancer, in combination with an intravenous 5-fluorouracil or equivalent (e.g., capecitabine, floxuridine) based regimen for first- or second-line treatment

Metastatic colorectal cancer, in combination with irinotecan or oxaliplatin for second-line treatment in individuals who have progressed on a first-line bevacizumab product-containing regimen

Metastatic colorectal cancer in combination with Lonsurf (trifluridine and tipiracil) for individuals previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic therapy, and if RAS wild-type, an anti-EGFR therapy (e.g., cetuximab or panitumumab)

Provider Actions and Prior Authorization

Prior Authorization

Prior authorization required and durations

Prior authorization required for drugs listed; approvals may be issued up to 12 months. Initial authorization for oral drugs revised to 6 months.

Affected timing/date: 05/01/26 change
Initial authorization for oral drugs: 6 months (revised)
Non-formulary exception and injectable approvals may be issued up to 12 months

Documentation Required

Medical record documentation required

Submit office visit notes that include the diagnosis, relevant history, physical evaluation, and a complete medication history. Include supporting documentation for any off-label use (see separate callout). Reauthorization requests must include documentation of clinical benefit while on therapy (e.g., imaging, tumor markers, clinical notes) and current medication administration records. For step-therapy requests, include prior drug trial dates, doses, and reason for discontinuation.

Coding

HCPCS - Covered/product reportingHCPCSCovered

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 (Jobevne), biosimilar, 10 mg (new code effective 01/01/26)

HCPCS referenced in history and updatesHCPCS

J1725	Bevacizumab (historically added to policy 12/11/12)
J9400	HCPCS code added 11/20/14 (policy mention)
Q5107	Added 01/01/19 (new code effective 1/1/19)
Q5118	Added 10/01/19 (new code effective 10/1/19)
J9999	Added for Avzivi (policy history)
C9399	Added for Jobevne (bevacizumab-nwgd)
Q5160	Added effective January 1, 2026
C9142	Previously added for Alymsys; later removed per coding updates
J3590	Previously used for Vegzelma; later removed
Q5126	Added 01/01/23

1–10 of 11

1/2

HCPCS / J-code updatesHCPCS

C9399	Specific HCPCS code added for Jobevne (bevacizumab-nwgd)
J9999	Parenthetical updated to include Jobevne
Q5160	New HCPCS code effective January 1, 2026 (added in policy history)

Billing for bevacizumab biosimilars and related products should follow current HCPCS guidance and the policy's reporting instructions: use C9399 to report Jobevne (bevacizumab‑nwgd) (policy history adds C9399 for Jobevne), note that J9999 is used parenthetically for Avzivi (and Jobevne is also referenced parenthetically with J9999 in history), and the Q‑code Q5160 for bevacizumab‑nwgd becomes effective 01/01/26. Providers must adhere to current HCPCS coding guidance and submit required documentation per the policy.

Background and Evidence Rationale

Clinical background: angiogenesis (mediated largely by VEGF signaling) and EGFR pathways are central to tumor blood‑vessel growth and progression; EGFR activation can stimulate VEGF. Bevacizumab and its biosimilars are recombinant humanized monoclonal antibodies that inhibit VEGF binding to its receptors and thereby inhibit angiogenesis. Ramucirumab is a VEGFR2 antagonist that blocks VEGFR ligand binding and signaling. Ziv‑aflibercept is a VEGF 'trap' fusion protein that binds VEGF‑A/B and PlGF ligands. Fruquintinib is an oral small‑molecule inhibitor of VEGFR‑1, ‑2, and ‑3. Lenalidomide and pomalidomide have anti‑angiogenic properties similar to thalidomide though their precise mechanisms are not fully understood; both are oral agents used in hematologic malignancies. Safety considerations noted in the evidence base include modest single‑agent activity but meaningful risk (for example, gastrointestinal perforation risk in recurrent ovarian cancer with bevacizumab, with perforation rates reported up to 11.4% in one series and lower rates in others), as well as expected class adverse events (hypertension, proteinuria, hemorrhage) described in pivotal trials.

Selected evidence metrics

Study E4599 - PFS (NSCLC)PC+B 6.4 months vs PC 4.5 months (P<0.0001)

Study E4599 - OS (NSCLC)PC+B 12.5 months vs PC 10.2 months (P=0.0075)

VELOUR trial (Zaltrap) - OS/PFS (mCRC)OS 13.5 vs 12.1 months (HR 0.82; p=0.003); PFS 6.9 vs 4.7 months (HR 0.76; p<0.001)

Policy Operations, Product Preference & Authorization Rules

Revlimid (lenalidomide) coverage requirement

Updated requirement for all indications of lenalidomide:

Member must have tried and had inadequate response or intolerance to generic lenalidomide prior to approval of Revlimid (lenalidomide).

Change effective 01/01/26 per interim review.

Pomalyst (pomalidomide) coverage requirement

Updated requirement for Pomalyst (pomalidomide):

Member must have had an inadequate response or intolerance to generic pomalidomide prior to approval of Pomalyst.

Addition noted in 05/01/26 Annual Review; generic pomalidomide coverage added.

Definitions

Definitions / policy interpretations

InvestigationalUses not specified as medically necessary in this policy are considered investigational.

Transfusion-dependent anemia (MDS study)Defined as having received >= 2 units of RBCs within eight weeks prior to study treatment.

NCCN Category 2A/2B/3 interpretationPolicy treats NCCN Categories 1 and 2A as proven (may be covered); Categories 2B and 3 are considered unproven (2B may be considered if provider supplies significant peer-reviewed phase 2/3 evidence).

Revision History

03/01/24added

Added Avzivi (bevacizumab-tnjn) as a non-preferred bevacizumab product and added HCPCS J9999 for Avzivi (policy history entry).

03/01/24revised

Operational change: Removed requirement to try two prior chemotherapy regimens for bevacizumab products when used with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum‑resistant recurrent epithelial ovarian/fallopian tube/primary peritoneal cancer.

10/01/24 (effective 01/03/25)added

Product-preference and sequencing update: Mvasi (bevacizumab-awwb) changed to preferred and Avastin (bevacizumab) changed to non-preferred; criteria updated to require trial/failure of Mvasi or Zirabev prior to certain non-preferred bevacizumab products (effective January 3, 2025).

Policy Summary

PayerPremera Bluecross

PolicyAngiogenesis inhibitors (VEGF and related agents) medical necessity coverage

Policy CodePolicy 5.01.517

Change TypeMultiple material updates (product preference, coding, step edits)

Effective Date

Next Review Date

Key ActionSubmit office visit notes with diagnosis, relevant history, physical exam and medication history to demonstrate medical necessity criteria are met.

SourceLink

On This Page

Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel for first-line treatment

Recurrent glioblastoma in adults

Metastatic renal cell carcinoma in combination with interferon alfa

Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan

Epithelial ovarian, fallopian tube, or primary peritoneal cancer in the following settings: (a) in combination with carboplatin and paclitaxel, followed by a bevacizumab product as a single agent, for stage III or IV disease following initial surgical resection; (b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease; (c) in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by a bevacizumab product as a single agent, for platinum-sensitive recurrent disease

Bevacizumab products - Second-line (Alymsys, Avastin, Avzivi, Jobevne, Vegzelma)

Alymsys (bevacizumab-maly), Avastin (bevacizumab), Avzivi (bevacizumab-tnjn), Jobevne (bevacizumab-nwgd), and Vegzelma (bevacizumab-adcd) may be considered medically necessary no earlier than 28 days following major surgery and until the surgical wound is fully healed.

Used for individuals with an inadequate response or intolerance to Mvasi (bevacizumab-awwb) OR Zirabev (bevacizumab-bvzr).

ONE of the following indications must be met:

Metastatic colorectal cancer, in combination with an intravenous 5-fluorouracil or equivalent (e.g., capecitabine, floxuridine) based regimen for first- or second-line treatment

Metastatic colorectal cancer, in combination with irinotecan or oxaliplatin for second-line treatment in individuals who have progressed on a first-line bevacizumab product-containing regimen

Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel for first-line treatment

Recurrent glioblastoma in adults

Metastatic renal cell carcinoma in combination with interferon alfa

Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan

Hepatocellular carcinoma (HCC) in combination with Tecentriq (atezolizumab) for individuals with unresectable or metastatic HCC who have not received prior systemic therapy

Note: Alymsys, Avzivi, Jobevne, and Vegzelma are biosimilars to Avastin (bevacizumab).

Bevacizumab biosimilars - Investigational exclusions

Alymsys (bevacizumab-maly), Avzivi (bevacizumab-tnjn), Jobevne (bevacizumab-nwgd), and Vegzelma (bevacizumab-adcd) are considered investigational for all other uses not listed as medically necessary.

Investigational/exclusion determination applies to the listed biosimilars when used for indications not specified as medically necessary in this policy, including advanced adenocarcinoma of the pancreas.

Cyramza (ramucirumab) - Medical necessity

Cyramza (ramucirumab) may be considered medically necessary when used for the following conditions:

ANY of the following indications:

Advanced or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy when used as a single agent or in combination with paclitaxel

Metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) mutations as first-line therapy when used in combination with erlotinib

Metastatic NSCLC with disease progression on or after platinum-based chemotherapy when used in combination with docetaxel (individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza)

Metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine when used in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil)

Hepatocellular carcinoma (HCC) in individuals who have an alpha fetoprotein of at least 400 ng/mL and have been treated with sorafenib when used as a single agent

Zaltrap (ziv-aflibercept) - Medical necessity

Zaltrap (ziv-aflibercept) may be considered medically necessary for metastatic colorectal cancer when ALL of the following are met:

The individual has metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen

Zaltrap is used in combination with 5-fluorouracil or equivalent (e.g., capecitabine, floxuridine), leucovorin, and irinotecan (FOLFIRI)

Fruzaqla (fruquintinib) - Medical necessity (oral)

Fruzaqla (fruquintinib) may be considered medically necessary for metastatic colorectal cancer when ALL of the following are met:

The individual is aged 18 years or older

Has been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy

Has been previously treated with an anti-vascular endothelial growth factor (VEGF) therapy

Has been previously treated with an anti-epidermal growth factor receptor (EGFR) therapy if RAS wild-type

Lenalidomide (generic and Revlimid) - Medical necessity

Lenalidomide (generic) and Revlimid (lenalidomide) medical necessity criteria — preserve product-specific sequencing requirements.

Myelodysplastic syndrome (MDS): The individual is aged 18 years or older AND has transfusion-dependent anemia AND the dose is limited to 10 mg per day

Multiple myeloma: The individual is aged 18 years or older AND lenalidomide is used in combination with dexamethasone at a dose not to exceed 25 mg per day OR as maintenance therapy following autologous hematopoietic stem cell transplantation (auto-HSCT)

Mantle cell lymphoma (MCL): The individual is aged 18 years or older AND has relapsed or progressed after two prior therapies, one of which includes bortezomib AND the dose is limited to 25 mg per day

Previously treated follicular lymphoma (FL): The individual is aged 18 years or older AND lenalidomide is used in combination with a rituximab product AND the dose is limited to 20 mg per day

Previously treated marginal zone lymphoma (MZL): The individual is aged 18 years or older

Revlimid-specific requirement: For MDS, multiple myeloma, and other labeled Revlimid indications, the individual must have tried and had an inadequate response or intolerance to generic lenalidomide prior to coverage of Revlimid

Pomalidomide (generic and Pomalyst) - Medical necessity

Pomalidomide (generic) and Pomalyst (pomalidomide) may be considered medically necessary for the following conditions. Preserve sequencing and dose limits.

Multiple myeloma: Used in combination regimens per product labeling (e.g., with dexamethasone and/or other agents) consistent with FDA-approved indications and dosing

Kaposi sarcoma (KS): Indication entries consistent with product labeling where applicable

Dose limits and sequencing: Adhere to product-specific maximum doses and require that Pomalyst is only covered when the member has tried and had an inadequate response or intolerance to generic pomalidomide when such sequencing is specified in this policy

General - Investigational uses

General investigational determinations and coverage rationale:

All other uses of angiogenesis-inhibiting agents not explicitly listed as medically necessary in this policy are considered investigational.

When FDA-approved dosing exists for an indicated use, coverage aligns with FDA dosing and administration recommendations unless otherwise stated.

Length of Approval / Reauthorization

Length of approval and reauthorization rules:

All of the following must be met for approval:

Non-formulary biologic products require prior authorization per payer rules

Initial and reauthorization reviews may be granted for up to 12 months based on clinical indication and physician documentation

Documentation Requirements

Documentation required in the medical record to support medical necessity:

Office visit notes supporting the indication and plan of care

Relevant diagnosis and staging information

History and physical examination findings

Comprehensive medication history including prior biologic/targeted therapies, responses, and intolerances

Office visit notes with diagnosis, relevant history, physical exam, medication history
Reauthorization documentation: evidence of clinical benefit (imaging, labs, progress notes) and current meds/administration records
Step prior therapy documentation: dates, doses, and reason for failure/intolerance

Prior Authorization

Timing relative to surgery

Do not initiate bevacizumab products earlier than 28 days following major surgery and only resume when the wound is fully healed. For reauthorization, document that wound healing is complete prior to restarting therapy.

Do not initiate earlier than 28 days after major surgery
Resume only when surgical wound is fully healed
Reauthorization: document healed wound prior to restart

Step Therapy

Product sequencing / trial of preferred biosimilar(s)

A trial/failure of preferred biosimilar(s) is required before coverage of certain non-preferred bevacizumab products. Product-preference changed effective 2025-01-03: Mvasi is preferred; Avastin is non-preferred. Providers must document prior use, dates, doses, and reason for failure or intolerance to Mvasi or Zirabev prior to approving non-preferred bevacizumab products.

Effective 2025-01-03: Mvasi preferred, Avastin non-preferred
Required to trial/fail Mvasi or Zirabev before certain non-preferred bevacizumab products
Document prior product use (dates, doses) and reason for failure/intolerance

Step Therapy

Revlimid and generic lenalidomide sequencing; Pomalidomide sequencing

Step therapy requires trying the generic formulary alternative before branded products. For lenalidomide, members must try generic lenalidomide prior to Revlimid (effective 01/01/26). For pomalidomide, members must try generic pomalidomide prior to Pomalyst (effective 05/01/26). Document trial dates, doses, and reason for inadequate response or intolerance.

Lenalidomide sequencing: try generic lenalidomide before Revlimid (effective 01/01/26)
Pomalidomide sequencing: try generic pomalidomide before Pomalyst (effective 05/01/26)
Step prior therapy documentation required: trial dates, doses, and reason for failure/intolerance

Billing Rule

Use of new/updated HCPCS codes

Use updated HCPCS/CPT/other billing codes as listed. Follow code guidance for accurate billing and product identification.

C9399, J9999, Q5160 listed for use
Use C9399 for Jobevne (per coding guidance)
Q5160 effective 01/01/26

Prior Authorization

Non-formulary exception duration

Non-formulary exception reviews for oral and injectable drugs may be approved up to 12 months. Reauthorization requires documentation of benefit and ongoing need; approvals beyond the initial period will be based on clinical response and adherence to step-therapy or sequencing requirements.

Non-formulary exception approvals may be issued up to 12 months
Reauthorization requires evidence of clinical benefit and ongoing need
Approvals contingent on adherence to step-therapy/sequencing rules

Documentation Required

Support off-label coverage for NCCN Category 2B uses

Off-label coverage supported for NCCN Category 2B uses requires submission of significant peer-reviewed phase 2 or 3 studies that demonstrate clinical benefit. Include full citations and copies of the relevant publications with the request.

Support for NCCN Category 2B uses: submit significant peer-reviewed phase 2 or 3 studies
Include full citations and copies of publications with the request

Revlimid (MDS) - transfusion independence67% (99/148) achieved RBC-transfusion independence

Ovarian cancer - response / perforationPhase II response rates 16%-28%; GI perforation up to 11.4% in one trial (3% in another series)

Evidence‑based coverage rationale and investigational determinations: the policy distinguishes medically necessary versus investigational uses by considering FDA labeling, NCCN Drugs & Biologics Compendium categories, and peer‑reviewed trial evidence. Uses supported by FDA approval or NCCN categories 1 or 2A are treated as proven and may be covered when other criteria are met; NCCN categories 2B or 3 are considered unproven (Category 2B may be considered for coverage only if the provider submits significant peer‑reviewed Phase II or III evidence). The policy explicitly considers bevacizumab for advanced adenocarcinoma of the pancreas investigational based on two Phase III trials (Kindler; van Cutsem) that did not show overall survival benefit. Conversely, despite FDA withdrawal of the breast cancer indication for bevacizumab, the policy will continue to approve off‑label breast cancer use as medically necessary when supported by NCCN guidance. Medications and uses not specified as medically necessary in the policy are considered investigational.

09/01/25added

Added Jobevne (bevacizumab-nwgd) as a non-preferred bevacizumab product and added HCPCS code C9399 for Jobevne; Jobevne also added to parenthetical of J9999 in coding listings.

01/01/26added

Coding update: Added HCPCS code Q5160 effective January 1, 2026 for bevacizumab-nwgd (Jobevne) reporting.

01/01/26revised

Revlimid (lenalidomide) coverage requirement revised: Brand Revlimid now requires inadequate response or intolerance to generic lenalidomide for all indications.

05/01/26revisedLatest

Initial authorization duration for oral drugs updated from 3 months to 6 months (Annual Review approved April 14, 2026).

05/01/26addedLatest

Policy expanded to add coverage criteria for generic pomalidomide and updated Pomalyst criteria to require inadequate response or intolerance to generic pomalidomide (Annual Review 05/01/26).