Mass General Brigham angiogenesis inhibitors Coverage Update

Coverage Criteria for Indications

Initial coverage criteria — example: Cervical Cancer

Covered when ALL of the following are met (example: cervical cancer; applies similarly for other indication-specific sets):

Cervical Cancer - general

Combination regimens: a Paclitaxel and carboplatin (if PD-L1-positive tumors, pembrolizumab can be added); b Paclitaxel and cisplatin; c Paclitaxel and topotecan

mCRC

Metastatic colorectal cancer (mCRC) coverage when ALL criteria are met:

mCRC: 1 Diagnosis of metastatic colorectal cancer; 2 Prescriber is an oncologist; 3 Appropriate dosing (weight required); 4 Requested agent will be used in combination with ONE of the following: a fluoropyrimidine-containing therapy; b capecitabine-containing therapy; c oxaliplatin-containing therapy; d irinotecan-containing therapy

NSCLC (multiple criteria sets)

Non-Small Cell Lung Cancer (NSCLC) coverage variations — criteria depend on histology, biomarkers, performance status, and combination regimens:

Non-squamous NSCLC: 1 Diagnosis of unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC; 2 Prescriber is an oncologist; 3 Appropriate dosing (weight required); 4 Requested agent will be used in combination with BOTH carboplatin and paclitaxel

NSCLC with EGFR mutation: 1 Diagnosis of non-squamous NSCLC with EGFR mutation positive (e.g., Exon 19 deletion or L858R); 2 Prescriber is an oncologist; 3 Requested agent will be used in combination with erlotinib

Advanced/metastatic adenocarcinoma or large cell NSCLC with PD-L1+: 1 Diagnosis of advanced/metastatic adenocarcinoma, large cell, NSCLC NOS with PD-L1 expression positive; 2 Prescriber is an oncologist; 3 Requested agent will be used in combination with ALL of the following: carboplatin, paclitaxel, and atezolizumab (or atezolizumab + hyaluronidase)

Initial therapy when PD-1/PD-L1 contraindicated (PS 0-2):

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) coverage conditions:

HCC (bevacizumab in combination): Diagnosis of unresectable or metastatic HCC; Prescriber is an oncologist; Requested agent will be used in combination with atezolizumab (or atezolizumab + hyaluronidase); Appropriate dosing (weight required)

HCC (ramucirumab single-agent): Diagnosis of HCC; Prescriber is an oncologist; AFP >= 2400 ng/mL; Inadequate response or prior treatment with sorafenib is referenced in ramucirumab indicationAFP >= 2400 ng/mL

Per ramucirumab indication, prior sorafenib treatment and AFP threshold required

Ophthalmologic conditions

Ophthalmologic indications coverage conditions:

Intravitreal bevacizumab indications: Diagnosis of wet age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), or myopic choroidal neovascularization (mCNV); Requested dosing 1.25 mg intravitreally every four or eight weeks or as needed1.25 mg q4-8 weeks

Prescriber and administration details to be documented

Zaltrap (ziv-aflibercept)

mCRC and Zaltrap (ziv-aflibercept) coverage conditions:

Zaltrap for mCRC: 1 Diagnosis of metastatic colorectal cancer; 2 Prescriber is an oncologist; 3 Appropriate dosing (weight required); 4 Requested agent will be used in combination with irinotecan or FOLFIRI; 5 Inadequate response or adverse reaction to ONE of the listed regimens or contraindication to ALL of the listed regimens (CAPEOX, FOLFOX, fluoropyrimidine [capecitabine or 5-FU], oxaliplatin-based therapy); 6 Inadequate response, adverse reaction, or contraindication to a bevacizumab product

mCRC — FOLFIRI context

mCRC (bevacizumab-containing regimens for combination with FOLFIRI):

mCRC with FOLFIRI: Requested agent will be used in combination with ONE of the following: FOLFIRI or irinotecan; Appropriate dosing (weight required); Inadequate response, adverse reaction, or contraindication to capecitabine-based regimen or 5-FU/leucovorin

NSCLC

Covered for Non-Small Cell Lung Cancer when specified conditions are met

NSCLC general requirements: 1 Diagnosis of NSCLC; 2 Prescriber is an oncologist; 3 Appropriate dosing (weight required)

NSCLC agent-specific pathways: One of the following agent-specific criteria must be met

Cyramza in combination with docetaxel: Requested agent will be used in combination with docetaxel AND there is inadequate response, adverse reaction, or contraindication to a platinum-containing chemotherapy regimen

Cyramza in combination with erlotinib: Requested agent will be used in combination with erlotinib

Metastatic colorectal cancer (Zaltrap)

Covered for metastatic colorectal cancer when the following are met

CRC general requirements: 1 Diagnosis of metastatic colorectal cancer; 2 Prescriber is an oncologist; 3 Appropriate dosing (weight required)

Zaltrap combination requirement: Requested agent will be used in combination with irinotecan or FOLFIRI

Prior regimen failure: Inadequate response or adverse reaction to ONE of the following regimens or contraindication to ALL of the following regimens: CAPEOX, FOLFOX, fluoropyrimidine (capecitabine or 5-FU), oxaliplatin-based therapy

Bevacizumab prior exposure: Inadequate response, adverse reaction, or a contraindication to a bevacizumab product

Biosimilar bevacizumab products are not uniformly interchangeable for every FDA-approved Avastin indication. The policy notes that Alymsys (bevacizumab-maly) lacks several ovarian cancer indications and hepatocellular carcinoma (HCC), and that Mvasi (bevacizumab-awwb), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) do not carry the HCC indication. When requesting coverage, confirm that the specific biosimilar being used includes the FDA-approved indication for the member’s diagnosis; if the biosimilar’s label does not include the indication, coverage should follow the applicable criteria for that diagnosis and product labeling.

Requests that do not include required clinical details may be implicitly excluded from coverage review. For oncology indications this includes missing documentation of required prior therapy or prior regimen failure (for example, the Zaltrap pathway requires documentation of inadequate response/adverse reaction to listed regimens or contraindication to those regimens), absence of biomarker or mutation status when specified (eg, EGFR exon 19 deletion or exon 21 L858R for certain NSCLC pathways), omission of prescriber specialty (an oncologist is required for the oncology pathways), or lack of appropriate weight-based dosing information. If these elements are not provided, the request may be denied or held pending submission of the missing documentation.

A request is considered not medically necessary when the documented clinical record does not meet the diagnosis-specific criteria outlined in this policy. Examples include absence of required prior therapy or documentation of prior inadequate response/adverse reaction where such step-therapy is specified, lack of prescriber specialty designation (oncologist for oncology indications), failure to document required dosing (including weight when weight-based dosing is specified), or continuation requests that do not provide evidence of ongoing benefit or response. Such requests should be denied as not medically necessary unless the missing information is supplied and demonstrates that the member meets the policy criteria.

Allowed Drug Combinations and Required Prior Regimens

Regimen	NSCLC setting / notes
Carboplatin + paclitaxel
Carboplatin or cisplatin + pemetrexed
Carboplatin + paclitaxel + atezolizumab (Tecentriq) or atezolizumab + hyaluronidase (Tecentriq Hybreza)
Erlotinib in combination with requested agent for EGFR‑mutant NSCLC (EGFR exon 19 deletion or exon 21 L858R)

Regimen	mCRC setting / prior therapy requirement
Bevacizumab combined with FOLFIRI (irinotecan, leucovorin, 5‑FU) or irinotecan
Ziv‑aflibercept (Zaltrap) combined with FOLFIRI or irinotecan
Requirement: inadequate response, adverse reaction to, or contraindication to fluoropyrimidine‑based regimens (eg, capecitabine or 5‑FU/leucovorin) or oxaliplatin‑based therapy may be required

Example combination	Tumor type / required prior regimen
Ramucirumab (Cyramza) + docetaxel
Ramucirumab (Cyramza) + erlotinib
Ziv‑aflibercept (Zaltrap) + irinotecan or FOLFIRI
Bevacizumab products combined with listed chemotherapy or immunotherapy per NCCN and package insert guidance
Note: Cyramza combinations are used in NSCLC with requirement for prior platinum‑containing chemotherapy for some pathways; Zaltrap is for mCRC after oxaliplatin‑based therapy, and bevacizumab combinations follow NCCN and PI recommendations

Referenced Agents, Biomarkers, Dosing, and Approval Durations

Referenced agents (drug names/package inserts)mixed

Cyramza	ramucirumab (drug name referenced)
Zaltrap	ziv-aflibercept (drug name referenced)
Avastin / Alymsys / Vegzelma	bevacizumab products (including biosimilars bevacizumab-maly, bevacizumab-adcd)

Alpha fetoprotein (AFP)

Alpha fetoprotein (AFP) threshold2400 ng/mL

Use caseRequired for ramucirumab (Cyramza) single-agent HCC indication post-sorafenib

Context in policyReferenced in HCC coverage criteria as AFP >= 2400 ng/mL

Intravitreal bevacizumab dosing

Intravitreal bevacizumab dose1.25 mg intravitreally

Dosing intervalEvery 4 or 8 weeks, or as needed

Indications referenced

Prior Authorization and Documentation Requirements

Prior Authorization

Prior Authorization Required

Prior authorization required — medical benefit prior authorization is required for these agents. Authorization may be reviewed on a case‑by‑case basis for members who are new to the plan currently receiving treatment with the requested medication (excluding products obtained as samples or via manufacturer patient assistance programs). Initial approvals will generally be granted for 6 months (Avastin for certain ophthalmic indications: 12 months).

Medical benefit prior authorization required
Case‑by‑case review for members new to plan; lack of documentation may result in denial
Initial approvals: 6 months (Avastin for Wet AMD/macular edema following RVO, DME, DR, or mCNV: 12 months)
Reauthorizations: other agents: 6 months

Documentation Required

Required Clinical Documentation

Provider must submit documentation supporting the requested use. Required documentation includes: diagnosis, prescriber specialty (oncologist when specified), appropriate dosing with weight when applicable, and evidence of clinical response for continuation requests. For members new to the plan, include prior treatment history and source of product if obtained via samples or patient assistance.

Line of Therapy Designations

second-line

Second-line: Gastric/GEJ adenocarcinoma after prior chemo: Diagnosis of gastric or GEJ adenocarcinoma; Prescriber is an oncologist; Inadequate response or adverse reaction to ONE or contraindication to BOTH fluoropyrimidine- and platinum-containing regimens; Appropriate dosing

Aligns with Cyramza indication after progression on prior fluoropyrimidine- or platinum-containing chemotherapy

salvage

Salvage: HCC post-sorafenib (ramucirumab single-agent): Advanced/metastatic HCC with prior sorafenib treatment and AFP >= 2400 ng/mLAFP >= 2400 ng/mL

Per ramucirumab FDA indication

second-line

Biomarker and Mutation Requirements

PD-L1

PD-L1 requirementPD-L1 expression positive is required for certain combinations (e.g., pembrolizumab may be added to bevacizumab regimens in PD-L1–positive cervical cancer and guides selection of bevacizumab + atezolizumab combinations in NSCLC)

Use case in cervical cancerPembrolizumab can be added to paclitaxel + carboplatin regimens when tumors are PD-L1 positive

Use case in NSCLCPD-L1 positivity used to select bevacizumab + atezolizumab-containing regimens for advanced/metastatic adenocarcinoma/large cell NSCLC

AFP (Alpha fetoprotein)

AFP threshold value2400 ng/mL

Specific requirementRequired for ramucirumab single-agent HCC indication in members previously treated with sorafenib

Background, Definitions, and Agent Descriptions

Bevacizumab and related angiogenesis inhibitors are monoclonal antibodies or fusion proteins that inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis and are used across multiple solid tumor types and certain ophthalmologic conditions. Avastin (bevacizumab) is a humanized recombinant monoclonal antibody with approved indications including cervical cancer, metastatic colorectal cancer, non-squamous NSCLC, glioblastoma, metastatic renal cell carcinoma, select ovarian cancer settings, and hepatocellular carcinoma; these agents are commonly used in combination regimens. Related products and biosimilars (for example, Mvasi, Zirabev, Vegzelma, and Alymsys) have labels that variably align with Avastin’s indications, and other angiogenesis-targeting agents (eg, ramucirumab, ziv-aflibercept) have distinct, indication-specific uses described in their labeling.

Biosimilar / reference

Listed bevacizumab biosimilarsMvasi (bevacizumab-awwb), Zirabev (bevacizumab-bvzr), Alymsys (bevacizumab-maly), Vegzelma (bevacizumab-adcd)

Indication alignment noteIndicational alignment varies: Alymsys lacks several ovarian and HCC indications; Mvasi, Vegzelma and Zirabev lack the HCC indication

Policy implicationSome biosimilars do not carry all Avastin indications; check product-specific FDA indications when authorizing

OpenPayer

Angiogenesis Inhibitor Biologics (bevacizumab, ramucirumab, ziv-aflibercept and biosimilars) — Coverage and Prior Authorization Criteria