CurrentPremera BluecrossPolicy N/A

Angiogenesis inhibitors (VEGF and related agents) coverage criteria

Medical necessity coverage criteria for multiple angiogenesis-inhibiting drugs (injectable and oral) including bevacizumab products and biosimilars, ramucirumab, ziv-aflibercept, fruquintinib, lenalidomide, and pomalidomide across listed oncologic indications; includes length of approval, documentation and coding guidance. This is part 1 of 2 of the policy.

Policy Summary

PayerPremera Bluecross

PolicyAngiogenesis inhibitors (VEGF and related agents)

Policy CodePolicy N/A

Change TypeMultiple additions, removals, and sequencing updates

Effective DateJan 1, 2026

Next Review Date

Key ActionSubmit office visit notes with diagnosis, relevant history, physical evaluation and medication history showing that medical necessity criteria are met.

POLICY UPDATE CHANGES

Added Zaltrap (ziv-aflibercept) for mCRC with HCPCS code J1725 added historically.

Removed requirement that bevacizumab products must try two prior chemotherapy regimens for platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Changed product preferences: Mvasi changed to preferred and Avastin to non-preferred effective 2025-01-03 (provider notified).

Added Avzivi, Alymsys, Vegzelma, Zirabev, Avzivi, Jobevne, and other biosimilars to policy at various dates with sequencing/adequate trial requirements.

Clarified that medications are subject to FDA dosing and administration and non-formulary exceptions may be approved up to 12 months.

MultipleDrugs / indications listed

28 days

Post-surgery initiation delay for bevacizumab

12 monthsMax non-formulary exception approval duration

PancreaticInvestigational example cited

SeveralBiosimilars added

Coverage Summary

This policy (Part 1 of 2) describes the medical necessity coverage criteria for angiogenesis‑inhibiting drugs — including injectable and oral agents such as bevacizumab products and biosimilars (e.g., Avastin, Mvasi, Zirabev, Alymsys, Avzivi, Jobevne, Vegzelma), ramucirumab (Cyramza), ziv‑aflibercept (Zaltrap), fruquintinib (Fruzaqla), lenalidomide (generic and Revlimid), and pomalidomide (Pomalyst) — across the listed oncologic and selected hematologic indications. The policy includes length of approval, documentation and coding guidance, and notes that some agents are managed through the medical benefit while certain oral agents are managed through the pharmacy benefit. Effective date: Jan. 1, 2026; Last review: Dec. 9, 2025; Status: CURRENT.

Key Thresholds and Limits (not shown in stats_bar)

Age requirement>= 18 years

Post-surgery initiation delayNo earlier than 28 days following major surgery and until surgical wound fully healed

Max non-formulary exception approval durationUp to 12 months

Alpha fetoprotein (AFP) threshold>= 400 ng/mL

Pomalyst progression windowDisease progression within 60 days of completion of last prior therapy

Lenalidomide dose limitsMDS 10 mg/day; Mantle cell lymphoma 25 mg/day; FL/MZL 20 mg/day

Medical-Necessity Criteria (by drug / use-case)

Injectable Bevacizumab First-line (Mvasi, Zirabev)

Covered when ALL of the following are met:

ALL of the following

Drug is Mvasi (bevacizumab-awwb) IV or Zirabev (bevacizumab-bvzr) IV
Major surgery timing: Initiation is no earlier than 28 days following major surgery and until surgical wound is fully healed
Indication (ONE of)
- Metastatic colorectal cancer, in combination with an intravenous 5-fluorouracil or equivalent (e.g., capecitabine, floxuridine) based regimen for first or second-line treatment

Coding

Covered HCPCS / J-codes (medical benefit)HCPCSCovered

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)
J9035	Injection, bevacizumab (Avastin), 10 mg
J9308	Injection, ramucirumab (Cyramza), 5 mg
J9400	Injection, ziv-aflibercept (Zaltrap), 1 mg

Added HCPCS/administrative codes referenced in historyHCPCS|mixed

J1725	Bevacizumab (historical addition to policy)
J9400	Code added to policy (new code at 11/20/14)
Q5107	Code added effective 1/1/19
Q5118	Code added (effective 10/1/19)
J9308	Added for Cyramza
J9999	Added for Avzivi
Q5126	Added 01/01/23
Q5129	Added 04/01/23
C9399	Added for Jobevne (bevacizumab-nwgd) in 09/01/25 update
Q5160	New HCPCS code effective 01/01/26

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Provider Actions & Prior Authorization Requirements

Documentation Required

Medical record documentation

Submit office visit notes that contain the diagnosis, relevant history, physical evaluation, and medication history demonstrating that the medical necessity criteria are met.

Prior Authorization

Prior authorization / non-formulary exception durations

Non-formulary exception reviews for all oral and injectable drugs listed in this policy may be approved up to 12 months. All other reviews for oral drugs listed may be approved up to 3 months. Re-authorization: non-formulary exception reviews and all other reviews for oral and injectable drugs may be approved up to 12 months if drug-specific coverage criteria are met and chart notes demonstrate continued positive clinical response.

Background & Evidence

Background: Angiogenesis inhibitors are drugs that interfere with tumor blood‑vessel growth signals and include VEGF‑targeting monoclonal antibodies (e.g., bevacizumab and its biosimilars), VEGF traps (e.g., ziv‑aflibercept), small‑molecule VEGFR inhibitors (e.g., fruquintinib), and immunomodulatory/anti‑angiogenic agents (e.g., lenalidomide, pomalidomide).

Management: Specific products are managed under either the medical benefit or the pharmacy benefit depending on the agent — for example, injectable biologics (bevacizumab products, ramucirumab, ziv‑aflibercept) are managed via the medical benefit, whereas Fruzaqla (fruquintinib), generic lenalidomide, Revlimid, and Pomalyst are managed via the pharmacy benefit.

Policy intent and evidence framework: The policy recognizes NCCN Drugs & Biologics Compendium categories — Categories 1 and 2A are considered proven (may be covered), while Categories 2B and 3 are considered unproven (Category 2B may be considered for coverage only when supported by significant peer‑reviewed phase 2 or phase 3 studies).

Study/Label	Key finding
Study E4599 (NSCLC: PC vs PC+B)
PC+B: Response rate 27.2% vs 10.0%; PFS 6.4 vs 4.5 months; OS 12.5 vs 10.2 months (improved RR, PFS, OS)
Lenalidomide — MDS transfusion independence
67% (99/148) achieved RBC transfusion independence in MDS trial (10 mg dosing study)
RCC Phase II (Yang et al. 2003)
Bevacizumab 10 mg/kg improved progression-free survival vs placebo (HR=2.55, P<0.001) in immunotherapy-refractory RCC
Pancreatic Phase III (Kindler, van Cutsem)
Two Phase III trials adding bevacizumab to gemcitabine-based therapy did not show overall survival benefit; bevacizumab for advanced pancreatic adenocarcinoma considered investigational
VELOUR (ziv-aflibercept)
In mCRC after oxaliplatin, ziv‑aflibercept + FOLFIRI improved OS (13.5 vs 12.1 months; HR 0.82) and PFS (6.9 vs 4.7 months; HR 0.76)
FDA breast cancer action (2010)
FDA proposed removal of Avastin breast cancer indication citing lack of OS benefit and increased serious adverse events; plan continues to allow off‑label use when NCCN supports

Definitions & Thresholds

Definitions, Product Status, and Additional Thresholds

Major surgery timing (definition)Initiation of certain angiogenesis inhibitors not earlier than 28 days following major surgery and until surgical wound fully healed

RBC-transfusion dependence (MDS trial)Having received >= 2 units of RBCs within eight weeks prior to treatment

NCCN Categories of Evidence and ConsensusCategories 1 and 2A considered proven (may be covered); Categories 2B and 3 considered unproven (2B may be considered with supporting phase 2/3 studies)

Preferred / Non-preferred productFormulary designation affecting sequencing and prior authorization/step requirements for biosimilars and reference biologics

ECOG performance statusRequirement removed from policy (03/01/24)

Post-surgery initiation delay (threshold)

Revision History

11/20/2014added

Zaltrap (ziv-aflibercept) added to policy with HCPCS code J9400; coverage supported by VELOUR trial demonstrating improved OS and PFS for mCRC resistant to or progressed after oxaliplatin-containing regimen.

12/11/2012added

HCPCS code J1725 historically added to the policy for bevacizumab (historical coding update referenced in history).

04/03/2020revised

Mvasi separated from Avastin and Zirabev in policy structure; subsequent coding/sequence requirements initiated (policy sequencing history begins with separation).

Policy Summary

PayerPremera Bluecross

PolicyAngiogenesis inhibitors (VEGF and related agents)

Policy CodePolicy N/A

Change TypeMultiple additions, removals, and sequencing updates

Effective DateJan 1, 2026

Next Review Date

Key ActionSubmit office visit notes with diagnosis, relevant history, physical evaluation and medication history showing that medical necessity criteria are met.

On This Page

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) after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy (e.g., cetuximab or panitumumab)

Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, 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 (various settings described later in policy)

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

Covered when ALL of the following are met:

ALL of the following

Drug is one of Alymsys (bevacizumab-maly) IV, Avastin (bevacizumab), Avzivi (bevacizumab-tnjn) IV, Jobevne (bevacizumab-nwgd) IV, or Vegzelma (bevacizumab-adcd) IV
Major surgery timing: Initiation is no earlier than 28 days following major surgery and until surgical wound is fully healed
Step requirement: Individual has inadequate response or intolerance to Mvasi (bevacizumab-awwb) OR Zirabev (bevacizumab-bvzr)
Indication (ONE of)
- Metastatic colorectal cancer, in combination with an intravenous 5-fluorouracil or equivalent 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) after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy
- Unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer, 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: combination regimens for stage III/IV post-resection, platinum-resistant recurrent disease, and platinum-sensitive recurrent disease as detailed in policy
- Hepatocellular carcinoma (HCC) in combination with Tecentriq (atezolizumab) for unresectable or metastatic HCC who have not received prior systemic therapy AND the individual has had an inadequate response or intolerance to Mvasi OR Zirabev

ref_original

title_original

ref": "b1_1

title": "Injectable Bevacizumab Second-line (Alymsys, Avastin, Avzivi, Jobevne, Vegzelma)

Limits and Investigational Uses for Certain Bevacizumab Products

Coverage and investigational status:

ALL of the following

Biosimilar status: Alymsys, Avzivi, Jobevne, and Vegzelma are biosimilars to Avastin
Investigational uses: Alymsys, Avzivi, Jobevne, and Vegzelma are considered investigational for all other uses not listed, including advanced adenocarcinoma of the pancreas

ref_original

title_original

ref": "b1_2

title": "Limits and Investigational Uses for Certain Bevacizumab Products

Cyramza (ramucirumab) Injectable

May be considered medically necessary when ONE of the following indication-specific criteria are met:

ANY of the following

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 aberrations must have progressed on FDA-approved therapy for these aberrations prior to receiving Cyramza
Metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine when used in combination with FOLFIRI (irinotecan, folinic acid, fluorouracil)
Hepatocellular carcinoma (HCC) in individuals with alpha fetoprotein ≥ 400 ng/mL who have been treated with sorafenib when used as a single agent

ref_original

title_original

ref": "b1_3

title": "Cyramza (ramucirumab) Injectable

Zaltrap (ziv-aflibercept) Injectable

May be considered medically necessary when ALL of the following are met:

ALL of the following

Individual has metastatic colorectal cancer (mCRC) resistant to or progressed following an oxaliplatin-containing regimen
Zaltrap is used in combination with 5-fluorouracil or equivalent (e.g., capecitabine, floxuridine), leucovorin, and irinotecan (FOLFIRI)

ref_original

title_original

ref": "b1_4

title": "Zaltrap (ziv-aflibercept) Injectable

Fruzaqla (fruquintinib) Oral

May be considered medically necessary when ALL of the following are met:

ALL of the following

Age: Individual is aged 18 years or older>= 18
Prior chemotherapy: Previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
Prior anti-VEGF: Previously treated with an anti-VEGF therapy
Prior anti-EGFR if RAS WT: Previously treated with an anti-EGFR therapy if RAS wild-type

ref_original

title_original

ref": "b1_5

title": "Fruzaqla (fruquintinib) Oral

Lenalidomide (generic) and Revlimid (lenalidomide)

May be considered medically necessary for specific hematologic indications when ALL criteria are met:

ref_original

title_original

ref": "b1_6

title": "Lenalidomide (generic) and Revlimid (lenalidomide)

Pomalyst (pomalidomide)

May be considered medically necessary when ALL of the following are met:

ALL of the following

Age: Individual is aged 18 years or older>= 18
Multiple myeloma regimen-specific requirements (ONE of)
- MM - poma + dex after 2 prior therapies: Received at least two prior therapies including Revlimid (lenalidomide) and a proteasome inhibitor (PI) AND demonstrated disease progression within 60 days of completion of last prior therapy AND dose ≤ 4 mg per dayDose <= 4 mg/day; Progression within 60 days
- MM - poma + darzalex regimen: In combination with Darzalex Faspro and dexamethasone when received at least one prior line of therapy including Revlimid and a PI AND dose ≤ 4 mg per dayDose <= 4 mg/day
Kaposi sarcoma indication (ONE of)
- KS - AIDS-related: Dose ≤ 5 mg per day may be considered medically necessary for adult individuals with AIDS-related Kaposi sarcoma after failure of HAARTDose <= 5 mg/day
- KS - HIV-negative: Dose ≤ 5 mg per day may be considered for individuals with KS who are HIV-negativeDose <= 5 mg/day

ref_original

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ref": "b1_7

title": "Pomalyst (pomalidomide)" } ] }

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General Policy Statements

ALL of the following

FDA dosing: All medications listed are subject to FDA dosage and administration prescribing information
Investigational uses: All other uses of the medications listed in this policy are considered investigational

Length of Approval and Re-authorization

ALL of the following

Initial approval durations: Non-formulary exception reviews for all oral and injectable drugs listed may be approved up to 12 months
Oral other reviews: All other reviews for oral drugs listed may be approved up to 3 months
Re-authorization: non-formulary exception reviews and all other reviews for oral and injectable drugs may be approved up to 12 months if drug-specific coverage criteria are met and chart notes demonstrate continued positive clinical response

General policy recognition of NCCN categories

The Company recognizes NCCN Drugs & Biologics Compendium indications as follows:

ALL of the following

Proven categories: NCCN Categories of Evidence and Consensus of 1 and 2A are considered proven (may be covered).
Unproven categories: NCCN Categories of Evidence and Consensus of 2B and 3 are considered unproven; Category 2B may be considered for coverage if provider submits significant peer-reviewed phase 2 or phase 3 studies demonstrating treatment effectiveness.

Bevacizumab (Avastin) and indications with specific coverage positions

Coverage positions described historically and revised over time; specific indications cited as medically necessary or investigational in literature summaries.

ref_original

title_original

ref": "b1_11

title": "Bevacizumab (Avastin) and indications with specific coverage positions

Documentation Required

Surgery timing for bevacizumab products

Do not initiate bevacizumab products earlier than 28 days following major surgery and until the surgical wound is fully healed. Include documentation of the date of major surgery and evidence that the surgical wound is healed.

Step Therapy

Bevacizumab biosimilar to reference step requirement

For the listed bevacizumab biosimilars, coverage of certain second-line biosimilars requires demonstration of an inadequate response or intolerance to Mvasi (bevacizumab-awwb) OR Zirabev (bevacizumab-bvzr) prior to approval for the biosimilar product.

Affected codes: Q5107, Q5118
Applies to biosimilars including Alymsys, Avastin, Avzivi, Jobevne, Vegzelma as described in policy

Documentation Required

Prior therapies required

Document prior lines of therapy as applicable to the drug-specific criteria. Examples include prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; prior anti-VEGF biological therapy; prior anti-EGFR therapy when RAS wild-type; prior Revlimid (lenalidomide) and a proteasome inhibitor for multiple myeloma; prior sorafenib for certain HCC criteria; and other prior agents as specified in the individual drug sections.

Prior Authorization

Product sequencing and preferred product requirements

Providers must follow plan product-preference and sequencing requirements per policy history and effective dates. Certain HCPCS/J codes are affected and sequencing or step requirements apply; some biosimilars require prior inadequate response or intolerance to specified reference products before coverage.

Affected codes: J1725, Q5107, Q5118, J9999, Q5126, Q5129, Q5160, C9399
Follow product-preference and sequencing changes noted in policy history (effective dates) when requesting coverage

Documentation Required

Submission of evidence for Category 2B NCCN indications

For NCCN Category 2B indications, submit significant peer-reviewed phase 2 or phase 3 studies demonstrating treatment effectiveness to be considered for coverage.

Billing Rule

Adherence to FDA dosing and administration

Medications listed are subject to the product's FDA dosage and administration prescribing information. Non-formulary exception authorizations may be approved up to 12 months.

28 days after major surgery and until wound healed

Other thresholds compiledAFP >= 400 ng/mL; Age >= 18 years; Lenalidomide dose limits (MDS 10 mg, MCL 25 mg, FL/MZL 20 mg); Pomalyst progression window: progression within 60 days

03/01/2024removed

Removed the requirement that bevacizumab products must try two prior chemotherapy regimens for platinum‑resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (annual review effective 03/01/24).

03/01/2024added

Avzivi (bevacizumab-tnjn) added as a non-preferred bevacizumab product and HCPCS code J9999 added for Avzivi.

12/01/2022added

Alymsys (bevacizumab-maly) and Vegzelma (bevacizumab-adcd) added to policy with requirement that individual have an inadequate response or intolerance to Avastin or Zirabev first; HCPCS coding updates (C9142 added then later removed; Q5126/Q5129 added in 2023 coding updates).

04/01/2023revised

Coding updates: new HCPCS codes Q5129 added; earlier temporary codes (J3590, C9142) removed per coding update.

10/01/2024 (effective 01/03/2025)revised

Provider notification issued: Mvasi (bevacizumab-awwb) designated preferred and Avastin (bevacizumab) designated non-preferred effective 2025-01-03; updated coverage criteria for Alymsys, Avastin, Avzivi and Vegzelma to require an adequate trial and failure with Mvasi or Zirabev prior to coverage.

09/01/2025added

Jobevne (bevacizumab-nwgd) added as a non-preferred bevacizumab product; HCPCS code C9399 added for Jobevne and Jobevne included in J9999 parenthetical.

01/01/2026addedLatest

New HCPCS code Q5160 (bevacizumab-nwgd Jobevne) effective 01/01/26 added to coding; policy effective date updated to Jan 1, 2026 reflecting latest coding and product-preference positions.

05/01/2025clarified

Annual review clarification: medications in policy are subject to FDA dosing and administration and non-formulary exception reviews for all drugs may be approved up to 12 months (clarification only).