Last Review Date: 12/01/2020

Date of Origin: 10/17/2008

Dates Reviewed: 06/2009, 12/2009, 03/2010, 06/2010, 09/2010, 12/2010, 02/2011, 03/2011, 06/2011, 09/2011, 12/2011, 03/2011, 06/2012, 09/2012, 12/2012, 02/2013, 03/2013, 06/2013, 08/2013, 09/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 05/2015, 08/2015, 11/2015, 02/2016, 05/2016, 08/2016, 11/2016, 12/2016, 02/2017, 05/2017, 08/2017, 11/2017, 02/2018, 05/2018, 09/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020, 06/2020, 09/2020, 12/2020

I. Length of Authorization 

Coverage will be provided for six months and may be renewed (unless otherwise specified).

• For CNS cancers (symptom management), coverage will be provided for 12 weeks and may NOT be renewed.

II. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

• 100 mg/4 mL vial: 3 vials 21 days
• 400 mg/16 mL vial: 4 vials per 21 days

2. Max Units (per dose and over time) [HCPCS Unit]:

Oncology indications (J9035/Q5107/Q5118):

• Small Bowel Adenocarcinoma:
  • 60 billable units per 14 days
• CRC, CNS & RCC:
  • 120 billable units per 14 days
• All other indications:
  • 170 billable units per 21 days
  • 120 billable units per 14 days

III. Initial Approval Criteria

Coverage is provided in the following conditions:

• Patient is at least 18 years of age; AND

Universal Criteria 

• Patient has no recent history of hemoptysis (i.e., the presence of ≥2.5 mL of blood in sputum) OR any grade 3-4 hemorrhage; AND
• Patient must not have had a surgical procedure within the preceding 28 days or have a surgical wound that has not fully healed; AND

Colorectal Cancer (CRC) † 

• Will not be used as part of adjuvant treatment; AND
  • Patient has metastatic, unresectable, or advanced disease; AND

• Used as first- or second-line therapy in combination with a fluoropyrimidine- (e.g., 5-fluorouracil/5-FU or capecitabine) or irinotecan-based regimen; OR

• Used in combination with a fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based regimen (if not used first line) as subsequent therapy for advanced or metastatic disease that has progressed on a first-line bevacizumab containing regimen

Non-Squamous Non-Small Cell Lung Cancer (NSCLC) † 

• Used as first-line therapy for recurrent, locally advanced, unresectable, or metastatic disease in combination with carboplatin and paclitaxel †; OR
• Used for recurrent, advanced, or metastatic disease (excluding locoregional recurrence or symptomatic local disease with no evidence of disseminated disease) or mediastinal lymph node recurrence with prior radiation therapy; AND

• • Used as first-line therapy; AND
    • Used for one of the following:
• EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET rearrangement negative tumors* and PD-L1 < 1% in patients with PS ≤ 1; OR
• EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET rearrangement negative tumors* and PD-L1 ≥ 1% in patients with PS ≤ 2; OR
• BRAF V600E-mutation, NTRK gene fusion, MET exon 14 skipping mutation, or RET rearrangement positive tumors in patients with PS ≤ 1; AND
  • • Used in combination with:
• Pemetrexed and either carboplatin or cisplatin (excluding use in PD-L1 ≥ 1%); OR
• Atezolizumab, carboplatin, and paclitaxel; OR
  • Used as subsequent therapy in patients with PS ≤ 1; AND
    • Used for one of the following:
• EGFR, ALK, or ROS1 positive tumors and prior targeted therapy§; OR
• BRAF V600E-mutation, NTRK gene fusion, MET exon 14 skipping mutation, or RET rearrangement positive tumors; OR
• PD-L1 expression-positive (PD-L1 ≥ 1%) tumors that are EGFR, ALK, ROS1, BRAF, MET exon 14 skipping mutation, and RET negative* with prior PD-1/PD-L1 inhibitor therapy but no prior platinum-doublet chemotherapy; AND
  • • Used in combination with:
      • •  
        • Carboplatin and paclitaxel; OR
        • Pemetrexed and either carboplatin or cisplatin; OR
        • Atezolizumab, carboplatin, and paclitaxel (excluding use in patients who have received prior PD-1/PD-L1 inhibitor therapy); OR

• Used as continuation maintenance therapy (bevacizumab must have been included in patient’s first-line chemotherapy regimen) in patients who achieved a tumor response or stable disease after first-line systemic therapy; AND
  • • Used as a single agent; OR
    • Used in combination with pemetrexed following a first-line bevacizumab/pemetrexed/platinum chemotherapy regimen; OR
    • Used in combination with atezolizumab following a first-line atezolizumab/carboplatin/paclitaxel/bevacizumab regimen; OR
• Used in combination with erlotinib for sensitizing EGFR mutation positive disease as continuation of therapy following disease progression on erlotinib with bevacizumab for asymptomatic disease, symptomatic brain lesions, or isolated symptomatic systemic lesions

Cervical Cancer † 

• Patient has persistent, recurrent, or metastatic disease; AND
• Used in combination with paclitaxel AND either cisplatin, carboplatin, or topotecan

Breast Cancer ‡ 

• Patient has recurrent or metastatic disease; AND
• Patient has a high tumor burden, rapidly progressive disease, or visceral crisis; AND
• Used in combination with paclitaxel; AND
• Patient has human epidermal growth factor receptor 2 (HER2)-negative disease; AND

• Disease is hormone receptor-negative; OR
• Disease is hormone receptor-positive with visceral crisis or refractory to endocrine therapy

Renal Cell Carcinoma (RCC) † Ф

• Used in combination with interferon alfa for metastatic disease †; OR

• Patient has metastatic or relapsed disease; AND

• Used as a single agent in patients with non-clear cell histology ‡; OR
• Used in combination with everolimus in patients with non-clear cell histology ‡; OR
• Used in combination with erlotinib in patients with non-clear cell histology papillary disease including hereditary leiomyomatosis and renal cell cancer (HLRCC) ‡

Central Nervous System (CNS) Cancer  

• Used for symptom management related to radiation necrosis, poorly controlled vasogenic edema, or mass effect as single-agent short-course therapy; AND
  • Patient has a diagnosis of one of the following other CNS cancers ‡:

• • Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (Low-Grade, WHO Grade II); OR
  • Primary CNS Lymphoma; OR
  • Meningiomas; OR
  • Brain or Spine metastases; OR
  • Medulloblastoma; OR
  • Glioblastoma or Anaplastic Gliomas; OR
  • Intracranial or Spinal Ependymoma (excluding subependymoma); OR
• Used as a single agent OR in combination with one of the following: carmustine, lomustine, or temozolomide in patients with recurrent Anaplastic Gliomas ‡ Ф or recurrent Glioblastoma † ‡; OR
• Used as a single agent for progressive or recurrent Intracranial and Spinal Ependymoma (excluding subependymoma) after prior radiation therapy ‡; OR
• Used as a single agent for patients with surgically inaccessible recurrent or progressive Meningioma when radiation is not possible ‡

Ovarian Cancer † ‡ Ф 

• Patient has malignant stage II-IV sex cord-stromal tumors ‡; AND
  • Used as single agent therapy for clinically relapsed disease; OR
• Patient has epithelial ovarian or fallopian tube or primary peritoneal cancer †; AND
  • Patient has persistent or recurrent disease; AND

• Bevacizumab has not been used previously; AND
• Patient is not experiencing an immediate biochemical relapse (i.e., rising CA-125 without radiographic evidence of disease); AND
  • If platinum sensitive, used as a single agent or in combination niraparib or in combination with carboplatin AND either gemcitabine, paclitaxel † or PEGylated liposomal-doxorubicin; OR
  • If platinum resistant, used as a single agent or in combination with one of the following: oral cyclophosphamide, PEGylated liposomal doxorubicin, paclitaxel, or topotecan †; OR
    • • Used for rising CA-125 levels or clinical relapse in patients who have received no prior chemotherapy in combination with paclitaxel and carboplatin; OR

• • Used as maintenance therapy; AND
    • Used as a single agent or in combination with olaparib following primary therapy including bevacizumab; OR
    • Used as a single agent following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease; OR
    • Used in combination with paclitaxel and carboplatin for stable disease following neoadjuvant therapy as continued maintenance therapy; OR
  • Used as neoadjuvant therapy for endometrioid or serous histology in combination with paclitaxel and carboplatin; AND
• Patient is a poor surgical candidate or has a low likelihood of optimal cytoreduction; OR
  • Used as adjuvant therapy in combination with paclitaxel and carboplatin; AND
• Patient has pathologic stage II-IV disease; OR
• Patient is a poor surgical candidate or has a low likelihood of optimal cytoreduction; AND
  • Patient has endometrioid or serous histology; AND
  • Used after interval debulking surgery (IDS) in patients with a response or stable disease to neoadjuvant therapy

Soft Tissue Sarcoma ‡ ⁴

• Used as a single agent for angiosarcoma; OR
• Used in combination with temozolomide for solitary fibrous tumor

Endometrial Carcinoma (Uterine Neoplasms) ‡ ⁴

• Used as a single agent therapy for disease that has progressed on prior cytotoxic chemotherapy; OR
• Used in combination with carboplatin and paclitaxel for advanced and recurrent disease

Malignant Pleural Mesothelioma (MPM)* ‡ ⁴

• Patient has unresectable disease OR clinical stage IIIB or IV disease, sarcomatoid, or medically inoperable tumors; AND

• Used in combination with pemetrexed and cisplatin or carboplatin as initial therapy, followed by single-agent maintenance bevacizumab

*peritoneal, pericardial, and tunica vaginalis testis mesothelioma will be evaluated on a case-by-case basis

Vulvar Cancer ‡ 

• Used in combination with paclitaxel and cisplatin for squamous cell carcinoma; AND
• Patient has unresectable locally advanced, metastatic, or recurrent disease

Small Bowel Adenocarcinoma ‡ 

• Used as initial therapy; AND
• Patient has advanced or metastatic disease; AND
• Used in combination with a fluoropyrimidine-based regimen

Hepatocellular Carcinoma (HCC) † Ф ^1-4,14,15  

• Used as first-line therapy in combination with atezolizumab; AND
• Patient has Child-Pugh Class A disease; AND
• Patient has locally advanced, unresectable, inoperable, or metastatic disease

† FDA-labeled indication(s); ‡ Compendia recommended indication(s); Ф Orphan Drug

IV. Renewal Criteria 

Coverage can be renewed based upon the following criteria:

• Patient continues to meet universal and other indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Disease response with treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: gastrointestinal perforations and fistulae, surgical/wound healing complications, hemorrhage, arterial and venous thromboembolic events (ATE & VTE), uncontrolled hypertension, posterior reversible encephalopathy syndrome (PRES), nephrotic syndrome, proteinuria, severe infusion reactions, ovarian failure, congestive heart failure (CHF), etc.; AND

CNS Cancers – symptom management (short-course therapy):

• May NOT be renewed

Colorectal Cancer (after first-line bevacizumab-containing regimen):

• Refer to Section III for criteria

Malignant Mesothelioma (maintenance therapy):

• Refer to Section III for criteria

Ovarian Cancer (in combination with gemcitabine):

• May NOT exceed 10 cycles of therapy

Ovarian Cancer (maintenance therapy):

• Refer to Section III for criteria

Non-Squamous Non-Small Cell Lung Cancer (continuation therapy in combination with erlotinib):

• Refer to Section III for criteria

V. Dosage/Administration 

VI. Billing Code/Availability Information

HCPCS Code:

• J9035 – Injection, bevacizumab, 10 mg; 1 billable unit = 10 mg
• Q5107 – Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg: 1 billable unit = 10 mg
• Q5118 – Injection, bevacizumab-bvzr, biosimilar, (zirabev), 10 mg; 1 billable unit = 10 mg

NDC(s):

• Avastin single-use vial, 100 mg/4 mL solution for injection: 50242-0060-xx
• Avastin single-use vial, 400 mg/16 mL solution for injection: 50242-0061-xx
• Mvasi single-use vial, 100 mg/4 mL solution for injection: 55513-0206-xx
• Mvasi single-use vial, 400 mg/16 mL solution for injection: 55513-0207-xx
• Zirabev single-use vial, 100 mg/4 mL solution for injection: 00069-0315-xx
• Zirabev single-use vial, 400 mg/16 mL solution for injection: 00069-0342-xx

VII. References

1. Avastin [package insert]. South San Francisco, CA; Genentech; October 2020. 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, 2020. 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 November 2020.
5. Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer. 2013 Aug 6; 109(3): 552–558
6. Delishaj D, Ursino S, Pasqualetti F, et al. Bevacizumab for the Treatment of Radiation-Induced Cerebral Necrosis: A Systematic Review of the Literature. J Clin Med Res. 2017 Apr; 9(4): 273–280.
7. Fahrenbruch R, Kintzel P, Bott AM, et al. Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. J Oncol Pract. 2018 Mar;14(3):e130-e136.
8. Hematology/Oncology Pharmacy Association (2019). Intravenous Cancer Drug Waste Issue Brief. Retrieved from http://www.hoparx.org/images/hopa/advocacy/Issue-Briefs/Drug_Waste_2019.pdf
9. Bach PB, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016 Feb 29;352:i788.
10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer 8.2020. National Comprehensive Cancer Network, 2020. 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 Guidelines, go online to NCCN.org. Accessed November 2020.
11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer 1.2020. National Comprehensive Cancer Network, 2020. 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 Guidelines, go online to NCCN.org. Accessed November 2020.
12. Thatcher N, Goldschmidt JH, Thomas M, et al. Efficacy and safety of biosimilar ABP 215 compared with bevacizumab in patients with advanced nonsquamous non-small cell lung cancer (MAPLE): a randomized, double-blind, phase III study. Clin Cancer Res. 2019;25:2088-2095.
13. Reinmuth N, Bryl M, Bondarenko I, et al. PF-06439535 (a Bevacizumab Biosimilar) Compared with Reference Bevacizumab (Avastin®), Both Plus Paclitaxel and Carboplatin, as First-Line Treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Study. BioDrugs. 2019 Oct;33(5):555-570. doi: 10.1007/s40259-019-00363-4.
14. Cheng AL, Qin S, Ikeda M, et al. LBA3-IMBrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019 Nov;30 Suppl 9:ix186-ix187.
15. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers 5.2020. National Comprehensive Cancer Network, 2020. 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 Guidelines, go online to NCCN.org. Accessed November 2020.
16. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Bowel Adenocarcinoma 2.2020. National Comprehensive Cancer Network, 2020. 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 Guidelines, go online to NCCN.org. Accessed November 2020.
17. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.
18. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539-1544.
19. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006;24(21):3354-3360. doi:10.1200/JCO.2005.05.1573.
20. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37.
21. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13(12):1225-1233. doi:10.1016/S1470-2045(12)70509-0.
22. Allegra CJ, Yothers G, O'Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29(1):11-16. doi:10.1200/JCO.2010.30.0855.
23. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50.
24. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34.
25. Wick W, Gorlia T, Bendszus M, et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med 2017; 377:1954-1963.
26. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40.
27. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111. doi:10.1016/S0140-6736(07)61904-7.
28. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654-1663. doi:10.1016/S0140-6736(17)31607-0.
29. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011 Dec 29;365(26):2473-83.
30. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial. Journal of Clinical Oncology 2014 32:13, 1302-1308.
31. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–2045.
32. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779–791.
33. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60.
34. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1):257-263. doi:10.1093/annonc/mds237.
35. Lorusso D, Ferrandina G, Colombo N, et al. Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer: The MITO END-2 trial. Journal of Clinical Oncology 2015 33:15_suppl, 5502-5502.

36. National Government Services, Inc. Local Coverage Article for Billing and Coding: Bevacizumab and biosimilars (A52370). Centers for Medicare & Medicaid Services, Inc. Updated on 9/25/2020 with effective date 10/01/2020. Accessed November 2020.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA):