| Coverage Policy Manual | |
| Policy #: | 2017006 |
| Category: | Pharmacy |
| Initiated: | February 2017 |
| Last Review: | September 2023 |
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| Bevacizumab (e.g., Avastin™) for Oncologic Indications | |
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| Description: |
Bevacizumab is a recombinant humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents binding to endothelial receptors VEGFR-1 and VEGFR-2. VEGF is a signal protein that stimulates angiogenesis and introduces anti-apoptotic proteins bcl-2 and A1. Increased expression of VEGF is associated with worse outcomes, including tumor growth, metastatic disease progression, and poor prognosis. Bevacizumab is given via IV infusion. (Genetic Inc., 2016)
Regulatory Status
Bevacizumab (e.g., Avastin™) was approved by the U.S. Food and Drug Administration (FDA) in February 2004 for the first line treatment of metastatic colorectal cancer in combination with 5-fluorouracil chemotherapy; FDA-approval for second-line therapy of colorectal cancer was given in June 2006. In October 2006, bevacizumab, with carboplatin and paclitaxel, was FDA-approved for first-line treatment of locally advanced, recurrent, or metastatic non-squamous, non-small cell lung cancer based on an improvement in survival time when bevacizumab is added to a standard chemotherapy regimen. In February 2008, bevacizumab with paclitaxel was granted FDA-approval for previously untreated metastatic HER2-negative breast cancer based on an improvement in progression-free survival; however, an improvement in overall survival was not demonstrated. The FDA rescinded this approval in November 2011 after reviewing the results of 4 clinical studies of bevacizumab in breast cancer and determining a lack of prolonged overall survival and a lack of sufficient benefit in slowing disease progression relative to the significant risks of the drug. Other FDA-approved indications include progressive glioblastoma (2009), metastatic renal cell carcinoma (2009), persistent, recurrent, or metastatic cervical cancer (2014), and platinum-resistant (2014) or platinum-sensitive (2016) ovarian cancer (U.S. Food and Drug Administration, 2004, 2006, 2008, 2011, 2009, 2014, 2016).
In September 2017, the FDA approved bevacizumab-awwb (e.g., Mvasi), the first biosimilar to bevacizumab (e.g., Avastin).
In June 2019, the FDA approved bevacizumab-bvzr (e.g., Zirabev), biosimilar to bevacizumab (e.g., Avastin).
In April 2022, the FDA approved bevacizumab-maly (e.g., Alymsys), a biosimilar to bevacizumab (e.g., Avastin).
In September 2022, the FDA approved bevacizumab-adcd (e.g., Vegzelma), a biosimilar to bevacizumab (e.g., Avastin).
Coding
See CPT/HCPCS Code section below..
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Policy/ Coverage: |
For members of plans that utilize a prescription drug program vendor (i.e., Arkansas State Employees and Public School Employees, Arkansas State Police and Arkansas State University) for preferred products under the medical benefit, the preferred products contained in this policy are NOT applicable. Please contact the member’s prescription drug program vendor.
Effective January 1, 2024, Prior Approval is required for bevacizumab for oncologic indications.
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Effective January 1, 2024
Select products (e.g., Mvasi and Zirabev) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5107 Mvasi Bevacizumab awwb
Q5118 Zirabev Bevacizumab bvzr
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9035 Avastin Bevacizumab
Q5126 Alymsys Bevacizumab-maly
Q5129 Vegzelma Bevacizumab-adcd
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Bevacizumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
CONTINUED APPROVAL for up to 12 months:
OFF-LABEL INDICATIONS for Bevacizumab (e.g., Avastin) and Biosimilars; Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI), Bevacizumab-maly (e.g., Alymsys), and Bevacizumab-adcd (e.g., Vegzelma).
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications.
Dosing and Administration
Dosing per FDA Guidelines
Authorization will not exceed a maximum dose of 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. Providers must dose in accordance with the FDA label for FDA-approved indications.
The recommended dose of bevacizumab is based on indication.
Bevacizumab is available in a 100mg/4mL or 400mg/16 mL solution for injection.
Bevacizumab should be administered as an intravenous infusion by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Bevacizumab, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, Bevacizumab, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2023 to December 31, 2023
Select products (e.g., Mvasi and Zirabev) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the refer ⬚ ence product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5107 Mvasi Bevacizumab awwb
Q5118 Zirabev Bevacizumab bvzr
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9035 Avastin Bevacizumab
Q5126 Alymsys Bevacizumab-maly
Q5129 Vegzelma Bevacizumab-adcd
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Avastin™ (e.g., Bevacizumab)
The use of Bevacizumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness for the following indications:
Limitations of Use: Bevacizumab (e.g., Avastin™) are not indicated for adjuvant treatment of colon cancer
Dosing and Administration
Dosing per FDA Guidelines
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI), Bevacizumab-maly (e.g., Alymsys), and Bevacizumab-adcd (e.g., Vegzelma)
The use of Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Limitations of Use: Bevacizumab-bvzr (e.g., ZIRABEV), bevacizumab-awwb (e.g., MVASI), bevacizumab-maly (e.g., Alymsys), and bevacizumab-adcd (e.g., Vegzelma) are not indicated for adjuvant treatment of colon cancer.
Dosing and Administration
Dosing per FDA Guidelines
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
OFF-LABEL INDICATIONS for Bevacizumab (e.g., Avastin™) and Biosimilars; Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI), Bevacizumab-maly (e.g., Alymsys), and Bevacizumab-adcd (e.g., Vegzelma
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosing and Administration
Dosing per FDA Guidelines
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 1, 2022 to February 2023
Biosimilar products (e.g., Mvasi and Zirabev) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5107 Mvasi Bevacizumab awwb
Q5118 Zirabev Bevacizumab bvzr
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9035 Avastin Bevacizumab
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Avastin™ (e.g., Bevacizumab)
The use of Bevacizumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness for the following indications:
Limitations of Use: Bevacizumab (e.g., Avastin™) are not indicated for adjuvant treatment of colon cancer
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI)
The use of Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness for the following indications:
Limitations of Use: Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI) are not indicated for adjuvant treatment of colon cancer.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
OFF-LABEL INDICATIONS for Bevacizumab (e.g., Avastin™) and Biosimilars; Bevacizumab-bvzr (e.g., ZIRABEV) and Bevacizumab-awwb (e.g., MVASI)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 1, 2022
Biosimilar products (Mvasi and Zirabev) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5107 Mvasi Bevacizumab awwb
Q5118 Zirabev Bevacizumab bvzr
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9035 Avastin Bevacizumab
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
(FDA labeled)
Avastin™ (Bevacizumab) is FDA approved for the treatment of:
Off-label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
ZIRABEV (bevacizumab-bvzr) and MVASI (bevacizumab-awwb) are FDA approved for the treatment of:
Off-label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 1, 2021 to October 31, 2021
Biosimilar products (Mvasi and Zirabev) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5107 Mvasi Bevacizumab awwb
Q5118 Zirabev Bevacizumab bvzr
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9035 Avastin Bevacizumab
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
(FDA labeled)
Avastin™ (Bevacizumab) is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
ZIRABEV (bevacizumab-bvzr) and MVASI (bevacizumab-awwb) are FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 2021 to July 31, 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Avastin™ (Bevacizumab) is FDA approved for the treatment of:
1. Metastatic colorectal cancer, with intravenous 5-fluorouracil–based chemotherapy for first- or
second-line treatment.
2. Metastatic colorectal cancer, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatinbased
chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin- containing regimen.
3. Non-squamous non-small cell lung cancer, either
4. Glioblastoma, as a single agent for adult patients with progressive disease following prior
therapy.
5. Metastatic renal cell carcinoma with interferon alfa
6. Cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in
persistent, recurrent, or metastatic disease; or second-line therapy as a single agent.
7. Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is either
8. Hepatocellular Carcinoma (HCC
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
ZIRABEV (bevacizumab-bvzr) and MVASI (bevacizumab-awwb) are FDA approved for the
treatment of:
9. Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment.
10. Recurrent glioblastoma in adults.
11. Metastatic renal cell carcinoma in combination with interferon alfa.
12. Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
Limitations of Use: ZIRABEV and MVASI are not indicated for adjuvant treatment of colon
cancer.
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the
treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective July 2020 January 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Avastin™ (Bevacizumab) is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
ZIRABEV (bevacizumab-bvzr) and MVASI (bevacizumab-awwb) are FDA approved for the
treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the
treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective March 2020 to June 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Avastin™ (Bevacizumab) is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
ZIRABEV (bevacizumab-bvzr) is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the
treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective February 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Bevacizumab is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Dosing
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 2019 to January 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Bevacizumab is FDA approved for the treatment of:
Off-label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.
Dosing
Per FDA label guidelines.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the
treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational. Investigational services are specific contract
exclusions in most member benefit certificates of coverage.
Effective 2/10/2017 to January 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
(FDA labeled)
Bevacizumab is FDA approved for the treatment of:
Off-label
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of
less than either
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of Bevacizumab for the treatment of any other oncologic indications or any other oncologic
circumstances than those outlined above does not meet member benefit certificate primary coverage
criteria.
For members with contracts without primary coverage criteria, the use of Bevacizumab for the
treatment of any other oncologic indications or any other oncologic circumstances than those
outlined above is considered investigational. Investigational services are specific contract
exclusions in most member benefit certificates of coverage.
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| Rationale: |
Colorectal cancer
Fluoropyrimidines
Two randomized controlled trials have reported benefits for adding Bevacizumab (BV) to 5-fluorouracil–based chemotherapy. In both studies, the patients had been previously untreated with BV.
Vincenzi et al (2009) published the results of a single-center phase 2 trial that investigated the value of bevacizumab + 5-fluorouracil(5-FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options. The authors included 48 patients that had been heavily pretreated with oxaliplatin-based, irinotecan-based or cetuximab plus weekly irinotecan chemotherapy whose disease had progressed. Bevacizumab was added at a dose of 5 mg/kg. 5-FU/folinic acid was administered according to the de Gramont schedule. The response rate was 6.25%, and 30.4% of patients that demonstrated stable disease as the best response. The median time to disease progression was 3.5 months, and the median survival time was 7.7 months. The authors concluded that a bevacizumab + de Gramont schedule in heavily pretreated colorectal cancer patients yields a modest but significant clinical benefit.
Kabbinavar et al (2005) published results from a randomized control trial that compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. This trial enrolled 209 patients who had metastatic CRC and one of the following characteristics: age>or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin<or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. The results were that median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group . Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo). The authors concluded that the addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
Masi et al (2015) published results of randomized control trial BEBYP trial that studied continuation or reintroduction of BV beyond progression to first-line therapy in metastatic colorectal cancer. This study randomly assigned 185 patients undergoing first-line fluoropyrimidine-based chemotherapy with bevacizumab to receive second line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival (PFS). Median PFS was significantly improved by continuation of bevacizumab with the second-line regimen (median 6.8 versus 5 months), although the differences in objective response rates to the second-line regimen (17 versus 21 percent) and disease control rates overall (58 versus 70 percent) were not statistically significant. The authors concluded that that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC.
Irinotecan regimens
The benefit of adding bevacizumab to irinotecan was initially shown in a 2004 study by Hurwitz et al. In this trial, 813 patients with previously untreated metastatic colorectal cancer, were randomly assigned to irinotecan/fluorouracil (FU)/leucovorin (LV; IFL) with or without bevacizumab. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. Results from the study showed improved objective response rate (45 versus 35 percent), significantly improved time to tumor progression (TTP; 11 versus 6 months) and median survival (20 versus 16 months). The authors concluded that the addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
Other Second Line Combination Therapy
Bennouna et al (2013) published results of the randomized control European TML (ML18147) study that studied continuation of bevacizumab after first progression in metastatic colorectal cancer. 820 patients with unresectable mCRC progressing within three months of receiving first-line chemotherapy with bevacizumab were randomly assigned to fluoropyrimidine-based chemotherapy with or without bevacizumab (2.5 mg/kg/week). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). The primary endpoint was overall survival, analyzed by intention to treat. Continuation of bevacizumab with the second line chemotherapy regimen was associated with a significant improvement in progression-free (median 5.7 versus 4.1 months) and overall survival (median 11.2 versus 9.8 months), and bevacizumab-related adverse events were not increased. Although significantly more patients achieved disease control in the bevacizumab group (68 versus 54 percent), objective response rates in both arms were low (5.4 versus 3.9 percent for bevacizumab and no bevacizumab, respectively). The authors concluded that maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer.
Non-small cell lung cancer:
Soria et al (2013) published the results of a systematic review and meta-analysis of a randomized trial that added bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. The authors analyzed summary data of 2194 patients (1313 bevacizumab; 881 controls) from four randomized trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analyzed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss≤5% versus>5% (P = 0.03). Bevacizumab significantly increased the risk of grade≥3 proteinuria, hypertension, hemorrhagic events, neutropenia, and febrile neutropenia. The authors concluded that Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.
Sandler et al (2006) published the results from the Eastern Cooperative Oncology Group trial E4599. In this study, 878 previously untreated patients with advanced, nonsquamous NSCLC were randomly assigned to chemotherapy with paclitaxel and carboplatin alone (444 patients) or paclitaxel and carboplatin plus bevacizumab (434 patients), (15 mg/kg) on day 1 of each cycle. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status,>1) were excluded. The primary end point was overall survival. Patients receiving chemotherapy plus bevacizumab showed increases in the objective response rate (35 versus 15 percent with paclitaxel plus carboplatin alone), overall survival (median 12.3 versus 10.3 months), one-year and two-year survival rates (51 versus 44 and 23 versus 15 percent, respectively), and progression-free survival (6.2 versus 4.5 months). The authors concluded that the addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths.
Glioblastomas
Friedman (2009) published the results of a non-comparative phase II trial, in which 167 patients with recurrent glioblastoma were randomly assigned to bevacizumab (10 mg/kg), either as a single agent or at the same dose in conjunction with irinotecan. Treatment cycles were repeated every two weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. All patients had received prior chemotherapy with temozolomide. In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, The objective response rates were 28 and 38% respectively, estimated 6-month progression-free survival rates were 43% and 50%, respectively; and median overall survival was 9.2 and 8.7 months, respectively. The authors concluded that Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
Treatment with bevacizumab or bevacizumab plus irinotecan was generally well tolerated, and toxicity was limited to that expected with these agents. Steroid dosages were stable or reduced in almost all patients. With longer follow up, the 12 and 24-month survival rates were 38 and 16 to 17 percent on both treatment arms, which appeared to be better than historical control series (Cloughesy et al, 2010).
Taal et al (2014) reported on the noncomparative BELOB trial. In this trial, 153 patients with a first recurrence of glioblastoma after standard temozolomide plus radiation were randomly assigned to receive intravenous bevacizumab, oral lomustine (110 mg/m2), or combined bevacizumab plus lomustine. Randomization of patients was stratified with a minimization procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analyzed by intention to treat. The median overall survival was 8 months in both single-agent arms and 12 months in patients treated with bevacizumab plus lomustine.
Renal cell cancer
Reni et al (2008 and 2010) conducted two prospective, randomized, phase III trials of bevacizumab plus IFN-alpha versus IFN-alpha monotherapy. In these trials (collectively referred to as the CALGB 90206 trial), 732 previously untreated patients with metastatic RCC were randomly assigned to either IFNa plus bevacizumab or IFNa plus placebo.The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. Treatment with bevacizumab plus IFNa resulted in improvement in progression-free survival (median, 8.5 versus 5.2 months) and a trend toward improved overall survival (median, 18.3 versus 17.4 months). The authors concluded that OS favored the bevacizumab plus IFN-alpha arm but did not meet the predefined criteria for significance. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-alpha.
Cervical cancer
Tewari et al (2014) published the results from the GOG 240 trial. This study randomly assigned 452 women with metastatic cervical cancer to cisplatin plus paclitaxel or to paclitaxel plus topotecan with a second randomization to treatment with or without bevacizumab. The primary end point was overall survival. Treatment with paclitaxel plus topotecan (with or without bevacizumab) resulted in a significantly higher risk of progression compared with cisplatin plus paclitaxel median PFS, 5.7 versus 7.6 months, respectively). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; 98% confidence interval, P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%). The authors concluded that the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.
Monk et al (2009) reported the results of the GOG 204 trial. This study enrolled 513 patients with metastatic or advanced cervical cancer and randomly assigned them to treatment with cisplatin plus paclitaxel (the reference control arm) or one of three experimental regimens (cisplatin plus vinorelbine, cisplatin plus gemcitabine, or cisplatin plus topotecan). The results were that there was no difference in response rates; and cisplatin plus paclitaxel resulted in less serious thrombocytopenia compared with the other arms. The authors concluded that paclitaxel/ cisplatin should remain the doublet of choice in the treatment of advanced or recurrent cervical cancer. The authors also observed non-statistically significant trends in improved overall survival, tumor response, and quality of life with Paclitaxel + cisplatin versus other doublets examined in the study.
Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal cancer
Epithelial cancers of ovarian, fallopian tube, and peritoneal origin exhibit similar clinical characteristics and behavior. As such, these are often combined and define epithelial ovarian cancer (EOC) in clinical trials and clinical practice.
Platinum-Sensitive Recurrent EOC
The data regarding bevacizumab specifically for women with platinum-sensitive recurrent EOC come from two key randomized control trials.
Aghajanian et al (2012, 2014 and 2016) published three articles on the results of the of a phase III study of carboplatin and gemcitabine plus bevacizumab in EOC. In this trial, commonly referred to as the OCEANS trial, 484 women with platinum-sensitive EOC were randomly assigned to carboplatin (area under the curve [AUC] 4 on day 1) and gemcitabine (1000 mg/m2 on days 1 and 8) with cycles repeated every 21 days with or without bevacizumab (15 mg/kg on day 1 every three weeks concurrent with chemotherapy for 10 cycles maximum, followed by bevacizumab alone until disease progression or toxicity). The primary endpoint was improved progression-free survival.
Bevacizumab with chemotherapy when compared with chemotherapy plus placebo resulted in an improvement in progression-free survival (PFS)(12 versus 8 months). However, overall survival (OS) was not different between the two arms (34 versus 33 months). There was also a higher objective response rate (79 versus 57 percent). However, bevacizumab+chemotherapy also exhibited a higher rate of treatment discontinuation for adverse events (23 versus 5 percent), including higher rates of serious hypertension (17 versus <1 percent), proteinuria >grade 3 (9 versus 1 percent), and non-central nervous system bleeding (6 versus 1 percent).
Coleman et al (2015) published the results of the randomized controlled Gynecologic Oncology Group 213 (GOG 213) trial. In this trial, 700 women with platinum-sensitive recurrent ovarian, peritoneal primary and fallopian tube cancer were randomly assigned to surgical treatment (secondary cytoreduction versus no secondary cytoreduction) and separately, to medical treatment (carboplatin plus paclitaxel with or without bevacizumab). The bevacizumab treatment arm of patients received combination bevacizumab + chemotherapy followed by single agent bevacizumab until disease progression.
The results of the study were presented at the 2015 Annual Meeting for Women’s Cancers. Compared with treatment with chemotherapy alone, the administration of bevacizumab resulted in a significant improvement in PFS (14 versus 10 months, respectively), a trend towards a significant improvement in OS, which was not statistically significant (42 versus 37 months), and higher rates of serious (grade 3/4) gastrointestinal complications, such as perforation, necrosis or fistula (6 versus 3 percent) and infections (13 versus 6 percent).
Platinum-Resistent Recurrent EOC
Pujade-Lauraine (2014) published results from AURELIA study which was the first randomized control trial to combining bevacizumab with chemotherapy in platinum-resistant epithelial ovarian cancer. The study enrolled 361 patients who were randomly assigned treatment with chemotherapy plus or minus bevacizumab (15 mg/kg every three weeks). All patients met specific eligibility criteria, which included no evidence of disease progression during platinum-based chemotherapy, no more than two prior lines of chemotherapy, no history of bowel obstruction and no prior treatment with bevacizumab. Chemotherapy options were based on the investigator's choice of either paclitaxel (n = 115), topotecan (n = 120) or pegylated liposomal doxorubicin (PLD) (n = 126). Patients who received chemotherapy alone were allowed to cross over to single-agent bevacizumab at the time of disease progression.
Compared with chemotherapy alone, chemotherapy plus bevacizumab resulted in a statistically significant improvement in the overall response rate (ORR, 31 versus 13 percent, respectively), a reduction in the risk of disease progression (median duration 6.7 versus 3.4 months), but no statistically significant improvement in overall survival (OS)(16.6 versus 13.3 months), an increase in the rate of grade 2 or greater adverse events, including hypertension and proteinuria. In addition, four patients (2.2 percent) treated with bevacizumab experienced a gastrointestinal perforation.
Poveda et al (2015) published the results of a planned subset analysis of the AURELIA study which evaluated the outcomes associated with the individual regimens. The addition of bevacizumab to chemotherapy consistently resulted in better outcomes compared with treatment with chemotherapy alone. For those patients receiving paclitaxel, the ORR was 53 versus 30 percent with or without bevacizumab, respectively; median progression-free survival (PFS) was 10 versus 4 months (HR 0.46, 95% CI 0.30-0.71). For those patients receiving topotecan, the ORR was 17 versus 0 percent and the median PFS was 6 versus 2 months. For those patients receiving PLD, the ORR was 14 versus 8 percent; and the median PFS was 5 versus 4 months.
Malignant Mesothelioma
Zalcman et al (2016) published results of the MAPS trial in which 448 patients were randomly assigned to pemetrexed-cisplatin plus bevacizumab or to pemetrexed-cisplatin alone. The trial was limited to patients with pleural mesothelioma, and only patients who were not eligible for radical surgery were included. Cisplatin (75 mg/m2) and pemetrexed (500 mg/kg) were given on day 1 of each of six 21-day cycles. Bevacizumab was given at a dose of 15 mg/kg on day 1, and was continued as maintenance every three weeks following completion of six cycles of chemotherapy. No crossover was allowed. The results of the study were that with a median follow-up of 39 months, progression-free survival was significantly increased with the bevacizumab combination compared with cisplatin-pemetrexed alone (median, 9.2 versus 7.3 months) and overall survival was significantly increased with the combination as well (median, 18.8 versus 16.1 months).
Furthermore, National Comprehensive Cancer Network (NCCN, v.2.2015) guidelines have included this regimen as an option for standard front-line therapy for malignant pleural mesothelioma. However, US Food and Drug Administration (FDA) approval has not be given for this indication.
Breast Cancer
Dickler et al (2016) published the results of a randomized trial to investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer. In this trial, 343 women (median age of 58) were randomly assigned 1:1 to letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks). The trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension. The authors concluded that the addition of bevacizumab to letrozole improved PFS in hormone receptor-positive metastatic breast cancer, but this benefit was associated with a marked increased risk of grade 3 to 4 toxicities.
Miller et al (2007) published the results of a randomized trial to compare the efficacy and safety of paclitaxel with that of paclitaxel plus bevacizumab. In this trial, 722 patients were randomly assigned to receive 90 mg of paclitaxel per square meter of body-surface area on days 1, 8, and 15 every 4 weeks, either alone or with 10 mg of bevacizumab per kilogram of body weight on days 1 and 15. The primary end point was progression-free survival; overall survival was a secondary end point. Paclitaxel plus bevacizumab significantly prolonged progression-free survival as compared with paclitaxel alone (median, 11.8 vs. 5.9 months) and increased the objective response rate (36.9% vs. 21.2%). However, the overall survival rate was similar in the two groups (median, 26.7 vs. 25.2 months). Grade 3 or 4 hypertension was the most common adverse effect (14.8%). The authors concluded that initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone.
Cameron et al (2013) published the results of the BEATRICE trial that assessed whether the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer improves progression-free survival. In this trial, 1290 patients (aged 18 or older) were randomly assigned to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). Chemotherapy included with an anthracycline, taxane, or both. The primary endpoint was invasive disease-free survival (IDFS). At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group. 3-year IDFS was 82·7% with chemotherapy alone and 83·7% with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups. The authors concluded that Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer.
Angiosarcoma, Solitary Fibrous Tumor, Hemangiopercytoma
Agulnik et al (2013) published the results of a single-arm trial to determine the efficacy and safety of bevacizumab in the treatment of metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas. Selection criteria included patients with surgically unresectable disease, Eastern Cooperative Oncology Group (ECOG) performance status of ≤1, adequate organ function and no radiation treatment in the past 28 days. The study enrolled 32 patients to received bevacizumab 15 mg/kg IV infusion in 21-day cycles. Of the 30 patients evaluated for efficacy and toxic effect, four (two angiosarcoma and two epithelioid hemangioendothelioma; 17%) had a partial response. Fifteen patients (11 angiosarcoma and 4 epithelioid hemangioendothelioma; 50%) showed stable disease with a mean time to progression of 26 weeks. Bevacizumab was well tolerated with only one grade 4 adverse event. Expected known toxic effects of the drug were manageable. The authors concluded Bevacizumab to be an effective and well-tolerated treatment for metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas.
Constantinidou et al (2012) reported on a study of 24 patients with locally advanced unresectable or metastatic solitary fibrous tumor (SFT) , 17 of whom received systemic cytotoxic chemotherapy (17 anthracycline-based, 2 temozolomide plus bevacizumab, and 1 trabectedin, an experimental drug). Three others received axitinib. There was one objective partial response, and 20 patients with stable disease. Median PFS in the entire cohort was 4.2 months.
The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016) list the following indications for temozolomide: Solitary Fibrous Tumor/Hemangiopericytoma in combination with bevacizumab for the treatment of solitary fibrous tumor and hemangiopericytoma.
Endometrial carcinoma
Aghajanian et al (2011) reported on the Gynecologic Oncology Group (GOG) trial that assessed the activity and tolerability of single-agent bevacizumab in recurrent or persistent endometrial cancer (EMC) after receiving one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of ≤ 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and overall response rate. The study enrolled 53 women. The ORR was 15 percent with 36 percent progression-free at six months. The median PFS and OS were 4 and 11 months, respectively. The authors concluded that Bevacizumab is well tolerated and active based on PFS at 6 months in recurrent or persistent EMC.
In addition, Lorusso et al (2015) published results of the randomized, multicenter Italian Trials in Ovarian Cancer (MITO) Group END-2 trial. In the study, 108 patients who had received ≤1 prior platinum-based regimens and progressed >6 months after completion of first-line therapy were treated with carboplatin plus paclitaxel and randomly assigned to treatment with or without bevacizumab. Compared with carboplatin plus paclitaxel, the addition of bevacizumab resulted in higher ORR (71.7 versus 54.3 percent), significant improvement in PFS (median, 13 versus 8.7 months), and no significant difference in OS (median, 23.5 versus 18 months). These results suggest that bevacizumab has activity in combination with chemotherapy as second line treatment for women with recurrent or metastatic endometrial cancer. However, definitive data from phase III randomized trials are needed before adopting it as a standard treatment option.
2018 Update
A literature search conducted through February 2018 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Aparicio et al (2018) published the results of an open-label, phase III, RCT that compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during chemotherapy-free intervals (CFI) subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. The researchers randomly assigned 491 patients between March 2010 to July 2013 to one of the two control groups. Disease progression or death occurred during induction chemotherapy in 85 patients (17%), 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups, and the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. The researchers concluded that bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.
Yamada et al (2017) published the results of the TRICOLORE trial which was a randomized, open-label, phase 3, non-inferiority trial comparing S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). In the study, between June 2012 and September 2014, patients from 53 institutions who had previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen. 487 patients underwent randomization. 243 patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI) in the control group and 14.0 months (95% CI) in the experimental group (HR 0.84, 95% CI). 157 patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher. The researchers concluded that S-1 and irinotecan plus bevacizumab is non-inferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment for mCRC and could be a new standard treatment.
Walter et al (2018) published an article describing an ongoing clinical trial (NCT02820857) referred to as the PRODIGE 41-BEVANEC randomized phase II study which will be evaluating bevacizumab in combination with FOLFIRI after the failure of platinum-etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma. Planned enrollment is 124 patients and eligibility criteria is age 18 years or older, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy.
2019 Update
The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851 (Coleman,R L, et al, 2017).
The primary endpoint for both the bevacizumab objective and the surgical objective was overall survival, measured from randomisation to death from any cause. Secondary endpoints were investigator-assessed progression-free survival, defined as the time from randomisation to disease progression or death due to any cause; the incidence of carboplatin and paclitaxel hypersensitivity; and the effect of treatment on patient-reported outcomes and quality of life. As additional exploratory outcomes, we investigated several translational science outcomes— namely, molecular omics and biochemical profiles associated with the duration of overall survival, progression-free survival, and adverse effects, as well as determinants of sensitivity or resistance to carboplatin and paclitaxel with or without bevacizumab (which will be reported at a later date). A further exploratory outcome was to bank DNA from whole blood to evaluate the association between single nucleotide polymorphisms and clinical outcomes (Coleman,R L, et al, 2017).
In summary, this phase 3 trial showed that bevacizumab added to paclitaxel and carboplatin might favourably affect overall survival in women with platinum-sensitive recurrent ovarian cancer. Additionally, it significantly improves progression-free survival and objective response. There was no observation of any new safety signals nor toxicity that differentially increased treatment discontinuation (Coleman,R L, et al, 2017).
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population.
The intention-to-treat population included 336 patients in the atezolizumab–bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab–bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab–bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab–bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab–bevacizumab group; however, other high-grade toxic effects were infrequent.
In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. ( Finn RS, Qin S, Ikeda M, et. al., 2020)
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023.
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.(2022) Avastin [package insert] San Francisco, CA. Genentech, Inc.; 2022. Aghajanian C, Blank SV, Goff BA, et al.(2012) 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; 30:2039. Aghajanian C, Goff B, Nycum LR, et al.(2014) Independent radiologic review: bevacizumab in combination with gemcitabine and carboplatin in recurrent ovarian cancer. Gynecol Oncol 2014; 133:105. Aghajanian C, Goff B, Nycum LR, et al.(2015) Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 2015; 139:10. Aghajanian C, Sill MW, Darcy KM, et al.(2011) Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. 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