Medical Policy

Policy Num:       M5.001.005
Policy Name:     Bevacizumab
Policy ID:          [M5.001.005] [Ac / MA / M+ / P+]  [NCD 110.17 ]

Last Review: May 14, 2025
Next Review: May 20, 2026

Medicare Policies: NCD 110.17

Bevacizumab - Bevacizumab Biologics for Oncologic Uses

Population Reference No.	Populations	Interventions
1	Individuals: with colorectal cancer (CRC)	Interventions of interest are: Treatment with bevacizumab
2	Individuals: with non-squamous non-small cell lung cancer (NSCLC)	Interventions of interest are: Treatment with bevacizumab
3	Individuals: with cervical cancer	Interventions of interest are: Treatment with bevacizumab
4	Individuals: with renal cell carcinoma	Interventions of interest are: Treatment with bevacizumab
5	Individuals: with central nervous system (CNS) cancer	Interventions of interest are: Treatment with bevacizumab
6	Individuals: with ovarian cancer	Interventions of interest are: Treatment with bevacizumab
7	Individuals: with soft tissue sarcoma	Interventions of interest are: Treatment with bevacizumab
8	Individuals: with endometrial carcinoma (Uterine Neoplasms)	Interventions of interest are: Treatment with bevacizumab
9	Individuals: with malignant pleural mesothelioma	Interventions of interest are: Treatment with bevacizumab
10	Individuals: with vulvar cancer	Interventions of interest are: Treatment with bevacizumab
11	Individuals: with small bowel adenocarcinoma	Interventions of interest are: Treatment with bevacizumab
12	Individuals: with hepatocellular carcinoma (HCC)	Interventions of interest are: Treatment with bevacizumab

Summary

Bevacizumab is a humanized monoclonal antibody directed against Vascular Endothelial Growth Factor A (VEGF-A). Vascular Endothelial Growth Factors (VEGF) and their receptors (VEGF-R) contribute to the tumor growth and to the metastasis through the promotion of the angiogenesis.

Off-label non-oncologic uses of Bevacizumab are not discussed in this medical policy.

Objective

The objective of this evidence review is to determine whether bevacizumab improves the net health outcome in patients with need of oncologic treatment.

Coverage Indications, Limitations, and/or Medical Necessity

Indications:

As published in CMS Program Integrity Manual, Section 13.5.4, in order to be covered under Medicare, a service shall be reasonable and necessary.

Medicare Benefit Policy Manual – Pub. 100-02, Chapter 15, Section 50, describes national policy regarding Medicare guidelines for coverage of drugs and biologicals.

Generally, drugs and biologicals are covered only if all of the following requirements are met:

They meet the definition of drugs or biologicals;
They are of the type that are not usually self-administered by the patients who take them;
They meet all the general requirements for coverage of items as incident to a physician's services;
They are reasonable and necessary for the diagnosis or treatment of the illness or injury for which they are administered according to accepted standards of medical practice;
They are not excluded as immunizations; and
They are not excluded as immunizations; and
They have not been determined by the FDA to be less than effective.

A medically accepted indication, which is covered by Triple-S is one of the following:

An FDA approved, labeled indication; or
A use supported in:
- the American Hospital Formulary Service Drug Information (AHFS-DI),
- NCCN Drugs and Biologics Compendium,
- Truven Health Analytics Micromedex DrugDex®,
- Elsevier/Gold Standard Clinical Pharmacology; and
- Wolters Kluwer Lexi-Drugs® ; or
Articles or Local Coverage Determinations (LCDs) published by First Coast Service Options, Inc.; or
Triple-S Advantage medical policies.

Medical Necessity Summary:

The use of bevacizumab is medically necessary when all of the following are true:

Patient is at least 18 years of age, and
Patient must have no recent history of hemorrhage or hemoptysis (the presence of blood in sputum); and
Patient must not have had a surgical procedure within the preceding 28 days or have a surgical wound that has not fully healed

The use of bevacizumab is considered medically necessary for the following conditions:

Bevacizumab is FDA-approved for the following indications :

Cervical cancer - in combination with paclitaxel and cisplatin or topotecan for persistent, recurrent, or metastatic disease
Cervical cancer - in combination with pembrolizumab and chemotherapy for persistent, metastatic, or recurrent disease with PD-L1 combined positive score ≥ 1
CNS - Brain cancer (glioblastoma) - as a single agent or in combination with carmustine, temozolomide, or lomustine in patients with recurrent disease
Colon cancer - in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment of metastatic disease
Colon cancer - in combination with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment of metastatic disease in patients who have progressed on a first-line bevacizumab-containing regimen
Hepatocellular carcinoma - in combination with atezolizumab in patients with unresectable or metastatic disease who have not received prior systemic therapy
Non-small cell lung cancer - in combination with carboplatin and paclitaxel for first-line treatment of non-squamous, unresectable, locally advanced, recurrent, or metastatic disease
Ovarian cancer - for the treatment of recurrent epithelial disease in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant disease or in combination with carboplatin and paclitaxel or carboplatin and gemcitabine followed by single agent bevacizumab for platinum-sensitive disease
Ovarian cancer - in combination with carboplatin and paclitaxel followed by single agent bevacizumab for stage III-IV disease following initial surgical resection
Rectal cancer - in combination with intravenous 5-FU-based chemotherapy for first- or second-line treatment of metastatic disease
Rectal cancer - in combination with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen

Bevacizumab is recommended by the NCCN Drugs and Biologics Compendium^® for off-label use for the following indications:

Ampullary adenocarcinoma - as first-line therapy for intestinal type disease in combination with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), or CapeOx (capecitabine and oxaliplatin) for unresectable localized disease, stage IV resected disease, or metastatic disease at initial presentation in patients with performance status 0 - 1; and in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOx (capecitabine and oxaliplatin), capecitabine, or fluorouracil and leucovorin in patients with performance status 2
Ampullary adenocarcinoma - as subsequent therapy for disease progression for intestinal type disease in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) for patients with performance status 0 - 1, and in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOx (capecitabine and oxaliplatin), capecitabine, or fluorouracil and leucovorin in patients with performance status 2
Appendiceal adenocarcinoma - as initial systemic therapy for advanced or metastatic disease in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), FOLFIRI (fluorouracil, leucovorin and irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), 5-FU/LV (fluorouracil and leucovorin), or capecitabine
Appendiceal adenocarcinoma - as subsequent therapy for progression of advanced or metastatic disease in combination with irinotecan with or without oxaliplatin, FOLFIRI (fluorouracil, leucovorin and irinotecan), FOLFOX (fluorouracil, leucovorin, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), or trifluridine and tipiracil
Cervical cancer - as first-line therapy in combination with paclitaxel and carboplatin for squamous cell carcinoma, adenosquamous, or adenocarcinoma with local/regional recurrence or stage IVB disease or disease with distant metastases
Cervical cancer - as second-line or subsequent therapy in combination with paclitaxel and carboplatin for squamous cell carcinoma, adenosquamous, or adenocarcinoma with local/regional recurrence or stage IVB disease or disease with distant metastases, if not used previously as first-line therapy
Cervical cancer - as single agent second-line or subsequent therapy for squamous cell carcinoma, adenosquamous, or adenocarcinoma with local/regional recurrence or stage IVB disease or disease with distant metastases
Cervical cancer - as single agent second-line or subsequent therapy for persistent, recurrent, or metastatic small cell neuroendocrine carcinoma of the cervix (NECC)
CNS - Brain cancer (astrocytoma or oligodendroglioma) - as a single agent or in combination with carmustine, temozolomide, or lomustine for recurrent disease; or as short course, single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
CNS - Brain cancer (glioblastoma) - as short course, single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
CNS - Brain cancer (glioma, medulloblastoma, or metastatic spine tumors) - as short course, single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
CNS - Brain cancer (meningioma) - as short course, single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect, or as a single agent or in combination with everolimus for patients with surgically inaccessible recurrent or progressive disease when radiation therapy is not possible
CNS - Brain metastases (limited or extensive) - as short-course single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
CNS - Intracranial and spinal ependymoma (excluding subependymoma) - as a single agent for progression or recurrent disease in patients who are refractory to surgery or radiation therapy, if received prior radiation therapy and had gross total or subtotal resection with negative cerebrospinal fluid (CSF) cytology, subtotal resection and evidence of metastases (brain, spine, or CSF), or unresectable disease
CNS - Intracranial and spinal ependymoma (excluding subependymoma) - as short-course, single agent therapy for the management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
CNS - Primary CNS lymphoma - as short-course, single agent therapy for management of symptoms driven by radiation therapy necrosis, poorly controlled vasogenic edema, or mass effect
Colon cancer - as primary treatment in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin and irinotecan), CapeOx (capecitabine and oxaliplatin), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), 5-FU/LV (fluorouracil and leucovorin), or capecitabine for locally unresectable or medically inoperable disease
Colon cancer - as adjuvant treatment in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOx (capecitabine and oxaliplatin), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), 5-FU/LV (fluorouracil and leucovorin), or capecitabine following synchronized or staged resection and/or local therapy for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment, following resection and/or local therapy for resectable metachronous metastases in patients who have received previous chemotherapy, or for unresectable metachronous metastases that converted to resectable disease after primary treatment
Colon cancer - as adjuvant treatment in combination with irinotecan for unresectable metachronous metastases that converted to resectable disease after primary treatment
Colon cancer - as primary treatment in combination with CapeOx (capecitabine and oxaliplatin) or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) for unresectable synchronous liver and/or lung metastases
Colon cancer - as primary treatment in combination with CapeOx (capecitabine and oxaliplatin), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), or capecitabine for synchronous abdominal/peritoneal metastases, unresectable synchronous metastases of other sites, unresectable metachronous metastases that remain unresectable after primary treatment, or for unresectable metachronous metastases in patients who have not received adjuvant FOLFOX or CapeOx therapy within the past 12 months and have had previous 5-FU/LV (fluorouracil and leucovorin) or capecitabine therapy or who have not had previous chemotherapy
Colon cancer - as primary treatment in combination with irinotecan for unresectable metachronous metastases in patients who have had adjuvant FOLFOX or CapeOx therapy within the past 12 months
Colon cancer - as subsequent treatment for disease progression in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), irinotecan with or without oxaliplatin, or trifluridine and tipiracil
Diffuse high-grade glioma (Pediatric) - single agent, palliative treatment for recurrent or progressive disease in patients who do NOT have a diagnosis of oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant
Endometrial cancer (serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma) - in combination with carboplatin and paclitaxel as first-line therapy for advanced and recurrent disease or as second-line and subsequent therapy for advanced and recurrent disease when bevacizumab or a bevacizumab biosimilar in combination with paclitaxel was not previously used
Endometrial cancer (serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma) - as a single agent, second-line or subsequent therapy for disease that progressed on prior cytotoxic chemotherapy
Hepatocellular carcinoma - first-line therapy in combination with atezolizumab for patients with Child-Pugh class A only unresectable disease who are not a transplant candidate; have liver-confined disease, disease that is inoperable by performance status, comorbidity, or with minimal or uncertain extrahepatic disease; or metastatic disease or with extensive liver tumor burden
Mesothelioma: Peritoneal - as first-line systemic therapy in combination with pemetrexed and cisplatin or, for non-candidates for cisplatin, pemetrexed and carboplatin for diffuse disease with unicavitary, epithelioid histology; for diffuse disease with biphasic/sarcomatoid histology or bicavitary disease; or for recurrence of benign multicystic or well-differentiated papillary disease after prior cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy
Mesothelioma: Peritoneal - as subsequent systemic therapy in combination with atezolizumab, pemetrexed and cisplatin, or (in non-candidates for cisplatin) pemetrexed and carboplatin
Mesothelioma: Pleural - as first-line systemic therapy or induction chemotherapy in combination with pemetrexed and cisplatin or pemetrexed and carboplatin (if not a candidate for cisplatin) for clinical stage I-IIIA disease with epithelioid histology or for clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors
Mesothelioma: Pleural - as subsequent therapy in combination with pemetrexed and cisplatin or pemetrexed and carboplatin (if not a candidate for cisplatin) when immunotherapy was administered as first-line treatment or when given as a rechallenge if good response to front-line pemetrexed-based treatment
Non-small cell lung cancer (NSCLC) - as first-line therapy for the treatment of stage IV or recurrent disease in combination with carboplatin and pemetrexed; cisplatin and pemetrexed; or atezolizumab, carboplatin, and paclitaxel
Non-small cell lung cancer (NSCLC) - as a single agent or in combination with pemetrexed or atezolizumab as continuation maintenance therapy for non-squamous, stage IV metastatic or recurrent disease
Non-small cell lung cancer (NSCLC) - as subsequent therapy for the treatment of stage IV or recurrent disease in combination with carboplatin and paclitaxel; carboplatin and pemetrexed; cisplatin and pemetrexed; or atezolizumab, carboplatin, and paclitaxel
Non-small cell lung cancer - in combination with erlotinib as first-line or initial therapy for EGFR mutation positive Stage IV, recurrent or advanced disease
Non-small cell lung cancer - as single agent therapy or in combination with pemetrexed or atezolizumab for continuation maintenance therapy when negative for actionable molecular markers and PD-L1 expression ‹ 1%
Ovarian cancer (epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer) – in combination with carboplatin and paclitaxel as neoadjuvant therapy; or in combination with carboplatin and paclitaxel or carboplatin and docetaxel as continued treatment for stable disease following neoadjuvant therapy in patients who are poor surgical candidates and have low likelihood of optimal cytoreduction
Ovarian cancer (malignant sex cord-stromal tumors) – as a single agent for persistent or recurrent disease in patients with clinical relapse and stage II-IV disease
Ovarian cancer (epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, mucinous carcinoma, grade 1 endometrioid carcinoma, low-grade serous carcinoma, carcinosarcoma, clear cell carcinoma) – as adjuvant therapy in combination with carboplatin and paclitaxel; carboplatin and docetaxel; fluorouracil, leucovorin, and oxaliplatin; or capecitabine and oxaliplatin in patients with pathologic stage II-IV disease
Ovarian cancer (epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, mucinous carcinoma, grade 1 endometrioid carcinoma, low-grade serous carcinoma, carcinosarcoma, clear cell carcinoma) – as a single agent or in combination with capecitabine and oxaliplatin; carboplatin and gemcitabine; carboplatin and liposomal doxorubicin; carboplatin and paclitaxel; fluorouracil, leucovorin, and oxaliplatin; ixabepilone; liposomal doxorubicin; mirvetuximab soravtansine-gynx; niraparib; oral cyclophosphamide; paclitaxel and carboplatin; topotecan; or weekly paclitaxel for persistent or recurrent disease
Ovarian cancer (epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, mucinous carcinoma, grade 1 endometrioid carcinoma, low-grade serous carcinoma, carcinosarcoma, clear cell carcinoma) – as single agent maintenance therapy in patients with partial or complete response following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease; or as maintenance therapy in combination with olaparib in patients with stage II-IV disease with complete or partial response to primary therapy including bevacizumab or a bevacizumab biosimilar
Rectal cancer - as primary treatment in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOx (capecitabine and oxaliplatin), capecitabine, or 5FU-LV (fluorouracil and leucovorin) in patients with T3, N Any; T1-2, N1-2; T4, N Any disease; or locally unresectable or medically inoperable disease when resection is contraindicated following neoadjuvant therapy or total neoadjuvant therapy
Rectal cancer - as adjuvant treatment in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), 5FU-LV (fluorouracil and leucovorin), or capecitabine following resection and/or local therapy for resectable metachronous metastases
Rectal cancer - as adjuvant treatment in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), 5FU-LV (fluorouracil and leucovorin), capecitabine, or irinotecan for unresectable metachronous metastases that converted to resectable disease after primary treatment
Rectal cancer - as primary treatment in combination with CapeOx (capecitabine and oxaliplatin), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), or capecitabine for synchronous abdominal/peritoneal metastases, unresectable synchronous metastases of other sites, or unresectable isolated pelvic/anastomotic recurrence; or for unresectable metachronous metastases in patients who have not received adjuvant FOLFOX or CapeOx therapy within the past 12 months and have had previous 5FU-LV (fluorouracil and leucovorin) or capecitabine therapy or who have not had previous chemotherapy
Rectal cancer - as primary treatment in combination with CapeOx (capecitabine and oxaliplatin) or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable
Rectal cancer - as primary treatment in combination with irinotecan for unresectable metachronous metastases in patients who have had adjuvant FOLFOX or CapeOx therapy within the past 12 months
Rectal cancer - as subsequent treatment for disease progression in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), irinotecan with or without oxaliplatin, or trifluridine and tipiracil
Renal cell cancer – in combination with erlotinib for relapsed or stage IV, advanced papillary renal cell carcinoma (RCC), including hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated RCC
Renal cell cancer – as subsequent, single agent therapy for relapsed or stage IV, clear cell disease
Renal cell cancer – as a single agent or in combination with everolimus for relapsed or stage IV, non-clear cell disease
Small bowel adenocarcinoma - for advanced metastatic disease in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), CapeOx (capecitabine and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) when intensive therapy is recommended and in combination with capecitabine, 5-FU/leucovorin (fluorouracil and leucovorin), or FOLFIRI (fluorouracil, leucovorin, and irinotecan) when intensive therapy is not recommended
Soft tissue sarcoma - as a single agent for the treatment of angiosarcoma
Soft tissue sarcoma - in combination with temozolomide for the treatment of solitary fibrous tumor
Vulvar cancer – as first-line therapy in combination with cisplatin and paclitaxel or carboplatin and paclitaxel for locally advanced unresectable disease (larger T2, T3) or initially unresectable nodes regardless of T stage that is clinically positive for residual tumor at the primary site and/or nodes or for locally advanced disease (larger T2, T3) or initially unresectable nodes regardless of T stage with positive margins following resection
Vulvar cancer – as second-line or subsequent therapy in combination with cisplatin and paclitaxel or carboplatin and paclitaxel as additional treatment following primary therapy with concurrent chemoradiation; as primary treatment for metastatic disease beyond the pelvis (any T, any N, M1 beyond pelvis); for isolated inguinofemoral/pelvic lymph node recurrence if prior external beam radiation therapy (EBRT); or for clinical nodal or distant recurrence with multiple pelvic nodes, distant metastasis, or prior pelvic EBRT when bevacizumab or a bevacizumab biosimilar in combination with cisplatin and paclitaxel or carboplatin and paclitaxel was not used previously

Limitations:

If a use is identified as not indicated by CMS or the FDA, or if a use is specifically identified as not indicated in the American Hospital Formulary Services (AHFS), Elsevier/Gold Standard Clinical Pharmacology, NCCN Drugs and Biologics Compendium, Truven Health Analytics Micromedex DrugDex® and/or Wolters Kluwer Lexi-Drugs® compendium, the off-label use is not supported and the drug will not be covered.

Regardless of the evidence supporting coverage for a particular off-label use, payment may only be made if the use is reasonable and necessary for the treatment of illness or injury of the specific patient receiving the drug.

Services related to non-covered services or drugs are also not covered (e.g., administration services).

Upon review, if the drug use is not on the FDA label, does not appear on the American Hospital Formulary Services (AHFS), Elsevier/Gold Standard Clinical Pharmacology, NCCN Drugs and Biologics Compendium, Truven Health Analytics Micromedex DrugDex® and/or Wolters Kluwer Lexi-Drugs® compendium or Triple-S has not published a Medical Policy covering the off-label use as listed below, then the drug use is not approved and the use of the drug may be denied. However, determinations as to whether medication is reasonable and necessary for an individual patient may be made on appeal on the same basis as all other such determinations (i.e., with support from the peer-reviewed literature, with the advice of medical consultants, with reference to accepted standards of medical practice, and in consideration of the medical circumstance of the individual case).

The route of administration must be reasonable and necessary as well as the drug. (Pub 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.2 - Determining Self-Administration of Drug or Biological (Rev. 91; Issued: 06-20-08; Effective/Implementation Date: 07-21-08)). Triple-S will use evidence-based clinical guidelines to determine medical necessity of the route of administration.

Benefit Application

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Triple-S Salud Preferred Drugs Determination

Triple-S Salud will consider the following agents as preferred: Zirabev & Mvasi for shared FDA approved conditions.

Non-Preferred Agents Step Therapy Criteria

Other Non Preferred Agents may be covered when the criteria listed under Sections A., B., or C.
are satisfied:

A. Trial and failure of all of the following: Zirabev & Mvasi, resulting in minimal clinical response to therapy OR

B. History of intolerance or adverse event to all of the following: Zirabev & Mvasi OR

C. Continuation of prior therapy within the past 365 days.

Triple-S Salud has defined that Medicare Part B coverage may include non-preferred therapies. These non-preferred therapies will require prior authorization. Prior authorization for a non-preferred therapy will require history of therapeutic failure of a preferred therapy among other criteria. If a provider administers a non-preferred therapy without obtaining prior authorization, Triple-S Salud may deny claims for the non-preferred therapy.

FDA- Approved Indication	Avastin	Zirabev	Mvasi
Metastatic colorectal cancer, in combination with intravenous fluorouracil based chemotherapy for first- or second-line treatment	X	X	X
Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen	X	X	X
Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment.	X	X	X
Recurrent glioblastoma in adults.	X	X	X
Metastatic renal cell carcinoma in combination with interferon alfa.	X	X	X
Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan.	X	X	X
Epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection	X	X
Epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens	X	X
Epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum sensitive recurrent disease	X	X
Hepatocellular Carcinoma (HCC) in combination with atezolizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy	X

Regulatory Status

AVASTIN (bevacizumab) injection, for intravenous use FDA Initial U.S. Approval: 2004.

MVASI™ (bevacizumab-awwb) injection, for intravenous use Initial U.S. Approval: 2017

ZIRABEVTM (bevacizumab-bvzr) injection, for intravenous use Initial U.S. Approval: 2019

ALYMSYS® (bevacizumab-maly) injection, for intravenous use Initial U.S. Approval: 2022

VEGZELMA (bevacizumab-adcd) injection, for intravenous use Initial U.S. Approval: 2022

Medicare National Coverage

NCD 110.17 Anti-Cancer Chemotherapy for Colorectal Cancer

bevacizumab (Avastin™) is an anti-cancer chemotherapeutic agent approved by the Food and Drug Administration (FDA) for the treatment of colorectal cancer. Anti-cancer chemotherapeutic agents are eligible for coverage when used in accordance with FDA-approved labeling (see section 1861(t)(2)(B) of the Social Security Act (the Act)), when the off-label use is supported in one of the authoritative drug compendia listed in section 1861(t)(2)(B)(ii)(I) of the Act, or when the Medicare Administrative Contractor (MAC) determines an off-label use is medically accepted based on guidance provided by the Secretary (section 1861(t)(2)(B)(ii)(II).

This policy supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for Bevacizumab. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this Medical Policy. Neither Medicare payment policy rules nor this Medical Policy replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for Bevacizumab and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the Internet-Only Manuals (IOMs) published on the CMS Web site.

References

1. Avastin [package insert]. South San Francisco, CA; Genentech; June 2019. Accessed November 2020.

2. Mvasi [package insert]. Thousand Oaks, CA; Amgen, Inc.; June 2019. Accessed November 2020.

3. Zirabev [package insert]. New York, NY; Pfizer, Inc.; January 2020. Accessed November 2020.

4. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) bevacizumab. National Comprehensive Cancer Network, 2021. The NCCN. Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc.” To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed June 2021.

5. Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) for Anti-Cancer Chemotherapy for Colorectal Cancer (110.17) Accessed June 2021

6. Triple-S Medical Policy 05.001.017

7. National Government Services, Inc. Local Coverage Determination (LCD): Drugs and Biologicals, Coverage of, for Label and Off-Label Uses (L33394)

8. First Coast Service Options, Inc. Local Coverage Determination (LCD): Label and Off-label Coverage of Outpatient DRUGS AND BIOLOGICALS (L33915)

Codes

Codes list is for reference purposes only and might not be all-inclusive.

Codes	Number	Description
HCPCS	J9035	Injection Bevacizumab 10 MG
	Q5107*	Injection, bevacizumab-awwb, biosimilar, (Mvasi), 10 mg
	Q5118*	Injection, bevacizumab-bvcr, biosimilar, (Zirabev), 10 mg
	Q5126	Injection, bevacizumab-maly, biosimilar, (Alymsys), 10 mg
	Q5129	Injection, bevacizumab-adcd (Vegzelma), biosimilar, 10 mg
ICD-10-CM	C17.0	Malignant neoplasm of duodenum
	C17.1	Malignant neoplasm of jejunum
	C17.2	Malignant neoplasm of ileum
	C17.3	Meckel's diverticulum, malignant
	C17.8	Malignant neoplasm of overlapping sites of small intestine
	C17.9	Malignant neoplasm of small intestine, unspecified
	C18.0	Malignant neoplasm of cecum
	C18.1	Malignant neoplasm of appendix
	C18.2	Malignant neoplasm of ascending colon
	C18.3	Malignant neoplasm of hepatic flexure
	C18.4	Malignant neoplasm of transverse colon
	C18.5	Malignant neoplasm of splenic flexure
	C18.6	Malignant neoplasm of descending colon
	C18.7	Malignant neoplasm of sigmoid colon
	C18.8	Malignant neoplasm of overlapping sites of colon
	C18.9	Malignant neoplasm of colon, unspecified
	C19	Malignant neoplasm of rectosigmoid junction
	C20	Malignant neoplasm of rectum
	C21.2	Malignant neoplasm of cloacogenic zone
	C21.8	Malignant neoplasm of overlapping sites of rectum, anus and anal canal
	C22.0	Liver cell carcinoma
	C22.3	Angiosarcoma of liver
	C22.8	Malignant neoplasm of liver, primary, unspecified as to type
	C22.9	Malignant neoplasm of liver, not specified as primary or secondary
	C24.1	Malignant neoplasm of ampulla of Vater
	C33	Malignant neoplasm of trachea
	C34.00-C34.92	Malignant neoplasm of unspecified main bronchus - Malignant neoplasm of unspecified part of left bronchus or lung
	C38.4	Malignant neoplasm of pleura
	C45.0	Mesothelioma of pleura
	C45.1	Mesothelioma of peritoneum
	C45.2	Mesothelioma of pericardium
	C45.7	Mesothelioma of other sites
	C45.9	Mesothelioma, unspecified
	C46.0-C46.4	Kaposi's sarcoma of skin - Kaposi's sarcoma of gastrointestinal sites
	C46.51	Kaposi's sarcoma of right lung
	C46.52	Kaposi's sarcoma of left lung
	C46.7	Kaposi's sarcoma of other sites
	C48.0	Malignant neoplasm of retroperitoneum
	C48.1	Malignant neoplasm of specified parts of peritoneum
	C48.2	Malignant neoplasm of peritoneum, unspecified
	C48.8	Malignant neoplasm of overlapping sites of retroperitoneum and peritoneum
	C49.0	Malignant neoplasm of connective and soft tissue of head, face and neck
	C49.10	Malignant neoplasm of connective and soft tissue of unspecified upper limb, including shoulder
	C49.11	Malignant neoplasm of connective and soft tissue of right upper limb, including shoulder
	C49.12	Malignant neoplasm of connective and soft tissue of left upper limb, including shoulder
	C49.20	Malignant neoplasm of connective and soft tissue of unspecified lower limb, including hip
	C49.21	Malignant neoplasm of connective and soft tissue of right lower limb, including hip
	C49.22	Malignant neoplasm of connective and soft tissue of left lower limb, including hip
	C49.3	Malignant neoplasm of connective and soft tissue of thorax
	C49.4	Malignant neoplasm of connective and soft tissue of abdomen
	C49.5	Malignant neoplasm of connective and soft tissue of pelvis
	C49.6	Malignant neoplasm of connective and soft tissue of trunk, unspecified
	C49.8	Malignant neoplasm of overlapping sites of connective and soft tissue
	C49.9	Malignant neoplasm of connective and soft tissue, unspecified
	C51.0	Malignant neoplasm of labium majus
	C51.1	Malignant neoplasm of labium minus
	C51.2	Malignant neoplasm of clitoris
	C51.8	Malignant neoplasm of overlapping sites of vulva
	C52	Malignant neoplasm of vagina
	C53.0	Malignant neoplasm of endocervix
	C53.1	Malignant neoplasm of exocervix
	C53.8	Malignant neoplasm of overlapping sites of cervix uteri
	C53.9	Malignant neoplasm of cervix uteri, unspecified
	C54.0	Malignant neoplasm of isthmus uteri
	C54.1	Malignant neoplasm of endometrium
	C54.2	Malignant neoplasm of myometrium
	C54.3	Malignant neoplasm of fundus uteri
	C54.8	Malignant neoplasm of overlapping sites of corpus uteri
	C54.9	Malignant neoplasm of corpus uteri, unspecified
	C56.1	Malignant neoplasm of right ovary
	C56.2	Malignant neoplasm of left ovary
	C56.9	Malignant neoplasm of unspecified ovary
	C57.00-C57.22	Malignant neoplasm of unspecified fallopian tube - Malignant neoplasm of left round ligament
	C57.3	Malignant neoplasm of parametrium
	C57.4	Malignant neoplasm of uterine adnexa, unspecified
	C57.7	Malignant neoplasm of other specified female genital organs
	C57.8	Malignant neoplasm of overlapping sites of female genital organs
	C57.9	Malignant neoplasm of female genital organ, unspecified
	C64.1	Malignant neoplasm of right kidney, except renal pelvis
	C64.2	Malignant neoplasm of left kidney, except renal pelvis
	C64.9	Malignant neoplasm of unspecified kidney, except renal pelvis
	C65.1	Malignant neoplasm of right renal pelvis
	C65.2	Malignant neoplasm of left renal pelvis
	C65.9	Malignant neoplasm of unspecified renal pelvis
	C70.0	Malignant neoplasm of cerebral meninges
	C70.1	Malignant neoplasm of spinal meninges
	C71.0	Malignant neoplasm of cerebrum, except lobes and ventricles
	C71.1	Malignant neoplasm of frontal lobe
	C71.2	Malignant neoplasm of temporal lobe
	C71.3	Malignant neoplasm of parietal lobe
	C71.4	Malignant neoplasm of occipital lobe
	C71.5	Malignant neoplasm of cerebral ventricle
	C71.6	Malignant neoplasm of cerebellum
	C71.7	Malignant neoplasm of brain stem
	C71.8	Malignant neoplasm of overlapping sites of brain
	C71.9	Malignant neoplasm of brain, unspecified
	C72.0	Malignant neoplasm of spinal cord
	C72.1	Malignant neoplasm of cauda equina
	C72.9	Malignant neoplasm of central nervous system, unspecified
	C83.30	Diffuse large B-cell lymphoma, unspecified site
	C83.31	Diffuse large B-cell lymphoma, lymph nodes of head, face, and neck
	C83.39	Diffuse large B-cell lymphoma, extranodal and solid organ sites
	C83.390	Primary central nervous system lymphoma
	C83.398	Diffuse large B-cell lymphoma of other extranodal and solid organ sites
	C83.59	Lymphoblastic (diffuse) lymphoma, extranodal and solid organ sites
	C83.79	Burkitt lymphoma, extranodal and solid organ sites
	C83.80	Other non-follicular lymphoma, unspecified site
	C83.81	Other non-follicular lymphoma, lymph nodes of head, face, and neck
	C83.89	Other non-follicular lymphoma, extranodal and solid organ sites
	C84.49	Peripheral T-cell lymphoma, not elsewhere classified, extranodal and solid organ sites
	C85.89	Other specified types of non-Hodgkin lymphoma, extranodal and solid organ sites
	C85.99	Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites
	D32.0	Benign neoplasm of cerebral meninges
	D32.1	Benign neoplasm of spinal meninges
	D42.0	Neoplasm of uncertain behavior of cerebral meninges
	D42.1	Neoplasm of uncertain behavior of spinal meninges
	D43.0	Neoplasm of uncertain behavior of brain, supratentorial
	D43.1	Neoplasm of uncertain behavior of brain, infratentorial
	D43.2	Neoplasm of uncertain behavior of brain, unspecified
	D43.4	Neoplasm of uncertain behavior of spinal cord
	D43.9	Neoplasm of uncertain behavior of central nervous system, unspecified
	D49.2	Neoplasm of unspecified behavior of bone, soft tissue, and skin
	G96.89	Other specified disorders of central nervous system
	I67.89	Other cerebrovascular disease
	I78.0	Hereditary hemorrhagic telangiectasia
	Q85.02	Neurofibromatosis, type 2
	Q85.03	Schwannomatosis
	Q85.83	Von Hippel-Lindau syndrome
	T66.XXXA	Radiation sickness, unspecified, initial encounter
	T66.XXXD	Radiation sickness, unspecified, subsequent encounter
	T66.XXXS	Radiation sickness, unspecified, sequela
	Z85.09	Personal history of malignant neoplasm of other digestive organs
	Z85.038	Personal history of other malignant neoplasm of large intestine
	Z85.42	Personal history of malignant neoplasm of other parts of uterus
	Z85.048	Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus
	Z85.118	Personal history of other malignant neoplasm of bronchus and lung
	Z85.43	Personal history of malignant neoplasm of ovary
	Z85.44	Personal history of malignant neoplasm of other female genital organs
	Z85.528	Personal history of other malignant neoplasm of kidney
	Z85.53	Personal history of malignant neoplasm of renal pelvis

*Preferred drugs

Policy History

Date	Action	Description
5/14/2025	Policy Review	ICD-10-CM Diagnosis codes reviewed (Added: C22.0 C22.8 C22.9 C24.1 C45.1 C45.2 C45.7 C45.9 C52 C72.1 C83.390 C83.398 C83.59 C83.79 C84.49 C85.99 D43.9 Q85.02 Q85.03 Q85.83 Z85.09 Z85.42). No changes to policy statement. Policy presented at the Utilization Management Committee MA
5/10/2024	Policy Review	Medicare NCD references were clarified. Applicable NCD 110.17. Policy presented at the Utilization Management Committee MA
10/26/2023	Annual Review	Added biosimilars bevacizumab-maly (Alymsys) HCPCS Q5126, bevacizumab-adcd (Vegzelma) HCPCS Q5129. Breast cancer indication removed References updated.
8/28/2023	Policy Review	Update policy with deletion of reference to naive patients in Benefit Application section.
11/09/2022	Annual review	Reviewed by the Providers Advisory Committee. Added FDA indication for Cervical cancer - in combination with pembrolizumab and chemotherapy for persistent, metastatic, or recurrent disease with a PD-L1 combined positive score ≥ 1%. Added Off Label indications for Ampullary Adenocarcinoma and Appendiceal Adenocarcinoma.
11/10/2021	Revision	Policy statement format changed and updated. Revision with latest guidelines by recommendation of the Physician Advisory Board.
07/13/2021	New Policy	New Triple-S Advantage medical policy with preferred drug determination for Bevacizumab agents.