Commercial

Medical Policy

Notification

Bevacizumab (Avastin®) and Related Biosimilars For Oncologic Use

Notification Issue Date:

This version of the policy will become effective 05/15/2020.

This policy has been updated to communicate the Company's designation of two biosimilars as its preferred products: bevacizumab-awwb (Mvasi™) and bevacizumab-bvzr (Zirabev™).

Coverage for vascular diseases of the eye have been moved to Medical Policy: Intravitreal Injection of Vascular Endothelial Growth Factor (VEGF) Antagonists and Related Biosimilars 08.00.74m.

On February 20, 2020, the following language was added to the Company-Designated Preferred Products section of the Policy section: Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

Title:

Bevacizumab (Avastin®) and Related Biosimilars For Oncologic Use

Policy #:

08.00.66v

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

This policy addresses numerous medically necessary indications* for the use of bevacizumab (Avastin®), bevacizumab-maly (Alymsys®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™) in the following cancers (listed in order of appearance within the Policy section):

Ampullary Adenocarcinoma	Kidney cancer
Central nervous system tumors	Malignant pleural// peritoneal mesothelioma
Cervical carcinoma	Non-squamous non-small cell lung cancer
Colon carcinoma, appendiceal adenocarcinoma	Ovarian (epithelial), fallopian tube, primary peritoneal cancers
Rectal carcinoma	Soft tissue sarcoma: Angiosarcoma/ Solitary Fibrous Tumor
Small bowel adenocarcinoma	Uterine/ endometrial cancers
Hepatocellular carcinoma	Vulvar cancer
*Indications for single-agent therapy, preferred second-line therapy, subsequent therapy, relapsed or refractory therapy, pediatric and adult treatment, and limitations of use are all addressed within each section of specific cancer.

MEDICALLY NECESSARY

COMPANY-DESIGNATED PREFERRED PRODUCTS
Although there are many bevacizumab products on the market (e.g., bevacizumab [Avastin®], bevacizumab-maly (Alymsys®), bevacizumab-awwb [Mvasi™], bevacizumab-bvzr [Zirabev™]), there is no reliable evidence of the superiority of any one product of bevacizumab compared to other products. The Company has designated the following bevacizumab biosimilar products as its preferred products: bevacizumab-awwb (Mvasi™) and bevacizumab-bvzr (Zirabev™).

These products are less costly and at least as likely to produce equivalent therapeutic results as the non-preferred products, which includes, but are not limited to bevacizumab (Avastin®) and any other non-preferred bevacizumab biosimilars.

According to the United States Food and Drug Administration (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.” Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

NON-PREFERRED PRODUCTS
Use of non-preferred products, bevacizumab (Avastin®) or any non-preferred biosimilar, is considered medically necessary and, therefore, covered only for individuals who are currently receiving or have previously received a non-preferred product for the specified bevacizumab indication.

If the individual has not previously received a non-preferred product to treat the specified indication, these non-preferred products are eligible for coverage when the individual has documented contraindication(s) or intolerance(s) to the Company designated preferred products.

BEVACIZUMAB AND RELATED BIOSIMILARS
Bevacizumab and related biosimilars are considered medically necessary and, therefore, covered for the following indications when the dosing and frequency requirements listed in Attachment A and the requirements listed in the COMPANY-DESIGNATED PREFERRED PRODUCTS and NON-PREFERRED PRODUCTS Sections above are met:

AMPULLARY ADENOCARCINOMA

First-line therapy in individuals with good performance status (ECOG 0-1, with good biliary drainage and adequate nutritional intake)‡ in combination with

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

CapeOx (capecitabine and oxaliplatin) regimen

The above regimens are used for intestinal type

unresectable localized disease

stage IV resected ampullary cancer

metastatic disease at initial presentation

‡may be followed by chemoradiation for palliative indications

First-line therapy for intestinal type in select individuals with poor performance status (PS) and ECOG PS 2 for unresectable localized disease, stage IV resected ampullary cancer, metastatic disease at initial presentation
in combination with

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Fluorouracil

Capecitabine

CapeOx (capecitabine and oxaliplatin) regimen

Subsequent therapy for disease progression in individuals with good performance status (ECOG 0-1, with good biliary drainage and adequate nutritional intake) and intestinal type if previously treated with oxaliplatin-based therapy in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Subsequent therapy to be considered for disease progression in select individuals with poor performance status (PS) and ECOG PS 2 with intestinal type in combination with any of the fpllowing:

Capecitabine

Fluorouracil

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen

CapeOx (capecitabine and oxaliplatin) regimen

CENTRAL NERVOUS SYSTEM TUMORS

Treatment of recurrent anaplastic glioma or recurrent glioblastoma disease as a single agent (National Comprehensive Cancer Network [NCCN]-preferred) or in combination with carmustine, lomustine, or temozolomide if bevacizumab monotherapy fails and it is desirable to continue the steroid sparing effects of bevacizumab
As short-course single agent therapy for management of symptoms driven by radiation therapy (RT) necrosis, poorly controlled vasogenic edema, or mass effect for any of the following conditions:

Adult low-grade (WHO grade I) glioma
Adult Glioma: Oligodendroglioma (IDH-mutant, 1p19q codeleted)
Adult Glioma: IDH-mutant Astrocytoma
Adult Glioma: Glioblastoma
Adult intracranial and spinal ependymoma (excludes subependymoma)
Adult medulloblastoma
Primary central nervous system lymphoma
Meningiomas
Brain metastases (limited or extensive)
Metastatic spine tumors

Treatment for recurrent WHO grade 3 oligodendroglioma (IDH-mutant, 1p19q codeleted) in individuals with Karnofsky Performance Status (KPS) ≥ 60, recurrent or progressive WHO grade 3 or 4 IDH-mutant astrocytoma for individuals with Karnofsky Performance Status (KPS) ≥ 60// Glioblastoma, recurrent or progressive adult glioblastoma for the following:

as a single agent (preferred)
may be considered in combination with carmustine, lomustine, or temozolomide if bevacizumab monotherapy fails and it is desirable to continue the steroid sparing effects of bevacizumab

Treatment as a single-agent for disease progression or recurrent intracranial and spinal ependymoma (excludes subependymoma) in individuals who are refractory to surgery or RT, if received prior RT and individuals has any of the following:

gross total or subtotal resection with negative cerebrospinal fluid (CSF) cytology
subtotal resection and evidence of metastasis (brain, spine, or CSF)
unresectable disease

Treatment as a single agent for surgically inaccessible recurrent or progressive meningiomas when radiation is not possible.
Treatment for palliation of recurrent or progressive disease for pediatric diffuse high-grade glioma*

*Except oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant (see NCCN Guidelines for Central Nervous System Cancers in Adults)

CERVICAL CARCINOMA

Preferred first-line, second-line, or subsequent therapy as clinically appropriate (if not used previously as first-line) in combination with pembrolizumab, paclitaxel, and cisplatin or carboplatin for PD-L1 positive (combined positive score [CPS] ≥1) as determined by an FDA-approved test for:

local/regional recurrence

stage IVB or distant metastases

First-line, second-line, or subsequent therapy as clinically appropriate (if not used previously as first-line) in combination with paclitaxel and cisplatin or carboplatin (preferred regimens), or in combination with paclitaxel and topotecan for the following:

local/regional recurrence

stage IVB or distant metastases

Second-line or subsequent therapy as a single agent for

local/regional recurrence

stage IVB or distant metastases

First-line, second-line, or subsequent therapy as clinically appropriate (if not used previously as first-line) for persistent, recurrent, or metastatic small cell neuroendocrine carcinoma of the cervix (NECC) in combination with topotecan and paclitaxel

Second-line or subsequent therapy for persistent, recurrent, or metastatic small cell neuroendocrine carcinoma of the cervix (NECC) as a single agent

COLON OR RECTAL CANCERS:

Colorectal cancer

For the treatment of individuals with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test

Colon cancer

In combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOX (capecitabine and oxaliplatin), or FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen, in individuals appropriate for intensive therapy for any of the following indications:

as primary treatment for locally unresectable or medically inoperable disease

as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction

for synchronous unresectable metastases of other sites

as primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

and progressed on non-intensive therapy, except if received previous fluoropyrimidine, with improvement in functional status

As subsequent therapy for progression of advanced or metastatic disease in combination with trifluridine and tipiracil in individuals who have progressed through all available regimens and previously received for any of the following indications:

oxaliplatin-based therapy without irinotecan

irinotecan-based therapy without oxaliplatin

treatment with oxaliplatin and irinotecan

therapy without irinotecan or oxaliplatin

without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

In combination with capecitabine or with 5-FU/leucovorin (fluorouracil and leucovorin) regimen, in individuals not appropriate for intensive therapy for any of the following indications:

as primary treatment for locally unresectable or medically inoperable disease

as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction

for synchronous unresectable metastases of other sites

As NCCN preferred anti-angiogenic therapy as primary treatment for individuals with unresectable metachronous metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS] only or deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] and patient is not a candidate for immunotherapy) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months for any of the following indications:

in combination with irinotecan

in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Therapy in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin and irinotecan), CapeOX (capecitabine and oxaliplatin), or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) regimen (strongly consider FOLFIRINOX for individuals with excellent performance status) if intensive therapy recommended for any of the folowing:

as adjuvant treatment 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. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy.

as adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous chemotherapy

as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy.

Therapy in combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen, if intensive therapy not recommended, for advanced or metastatic disease for any of the following:

adjuvant treatment 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. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy. (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progression on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H])

adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous chemotherapy. (pMMR/MSS or ineligible for or progression on checkpoint inhibitor immunotherapy for dMMR/MSI-H)

adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous immunotherapy (dMMR/MSI-H)

adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy. (pMMR/MSS or ineligible for or progression on checkpoint inhibitor immunotherapy for dMMR/MSI-H)

Subsequent therapy for progression of advanced or metastatic disease for any of the following:

NCCN preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen if previously treated with oxaliplatin-based therapy without irinotecan

in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen or CapeOX (capecitabine and oxaliplatin) regimen if previously treated with irinotecan-based therapy without oxaliplatin

NCCN preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI if previously treated without irinotecan or oxaliplatin

in combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin if previously treated without irinotecan or oxaliplatin

Appendiceal Adenocarcinoma

Initial systemic therapy for advanced or metastatic disease in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen, CapeOX (capecitabine and oxaliplatin) regimen, FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) regimen (strongly NCCN recomended for individuals with excellent performance status) for one of the following:

if intensive therapy recommended

if intensive therapy recommended and progressed on non-intensive therapy, except if received previous fluoropyrimidine, with improvement in functional status

Initial systemic therapy for advanced or metastatic disease in combination with capecitabine or with 5-FU/leucovorin (fluorouracil and leucovorin) regimen if intensive therapy not recommended

Subsequent therapy for progression of advanced or metastatic disease for any of the following:

as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen if previously treated with oxaliplatin-based therapy without irinotecan

in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen or CapeOX (capecitabine and oxaliplatin) regimen if previously treated with irinotecan-based therapy without oxaliplatin

as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI if previously treated without irinotecan or oxaliplatin

in combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin if previously treated without irinotecan or oxaliplatin

Subsequent therapy for progression of advanced or metastatic disease in combination with trifluridine and tipiracil in individuals who have progressed through all available regimens and previously received for any of the following:

oxaliplatin-based therapy without irinotecan

irinotecan-based therapy without oxaliplatin

treatment with oxaliplatin and irinotecan

therapy without irinotecan or oxaliplatin

therapy without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

Rectal carcinoma

In combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen as primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant therapy, or total neoadjuvant therapy if intensive therapy recommended.
As primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant therapy, or total neoadjuvant therapy if intensive therapy recommended with any of the following:

CapeOX (capecitabine and oxaliplatin) regimen
FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Therapy in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOX (capecitabine and oxaliplatin), or FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) regimen (strongly consider FOLFIRINOX for individuals with excellent performance status) if intensive therapy recommended (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progression on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H]) for any of the following:
- primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
- primary treatment for synchronous unresectable metastases of other sites
- primary treatment for unresectable isolated pelvic/anastomotic recurrence
- initial treatment for unresectable metachronous metastases in individuals who have not received previous FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy
- and progressed on non-intensive therapy, except if received previous fluoropyrimidine, with improvement in functional status
Therapy in combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen if intensive therapy not recommended (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progression on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H]) for any of the following:
- primary treatment for synchronous unresectable metastases of other sites
- primary treatment for unresectable isolated pelvic/anastomotic recurrence
- primary treatment for unresectable metachronous metastases inindividuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy and progressed on non-intensive therapy, except if received previous fluoropyrimidine, with improvement in functional status
- as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
In combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen in individuals not appropriate for intensive therapy

as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
as primary treatment for synchronous unresectable metastases of other sites
as primary treatment for unresectable isolated pelvic/anastomotic recurrence
as primary treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

Primary treatment for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable in combination with one of the following:

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
CapeOX (capecitabine and oxaliplatin) regimen
FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen

Preferred anti-angiogenic therapy as primary treatment for individuals with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months for any of the following:

in combination with irinotecan
in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Subsequent therapy for progression of advanced or metastatic disease for the following indications:

as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen if previously treated with oxaliplatin-based therapy without irinotecan
in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) regimen if previously treated with irinotecan-based therapy without oxaliplatin
as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI if previously treated without irinotecan or oxaliplatin
in combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin if previously treated without irinotecan or oxaliplatin

Subsequent therapy for progression of advanced or metastatic disease in combination with trifluridine and tipiracil in individuals who have progressed through all available regimens and previously received any of the following regiments:

oxaliplatin-based therapy without irinotecan
irinotecan-based therapy without oxaliplatin
treatment with oxaliplatin and irinotecan
therapy without irinotecan or oxaliplatin
therapy without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

SMALL BOWEL ADENOCARCINOMA

In combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), CapeOX (capecitabine and oxaliplatin), or FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen for advanced or metastatic disease if intensive therapy is appropriate as:

as initial therapy
as subsequent therapy

In combination with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) regimen for advanced or metastatic disease if intensive therapy is appropriate as:

as initial therapy
as subsequent therapy in individuals who previously received initial therapy with nivolumab with or without ipilimumab, or pembrolizumab

In combination with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen for advanced or metastatic disease and individuals with prior oxaliplatin exposure in the adjuvant setting or contraindication to oxaliplatin

as initial therapy
as subsequent therapy in individuals who previously received initial therapy with nivolumab with or without ipilimumab, or pembrolizumab, or dostarlimab-gxly

In combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen for advanced or metastatic disease in individuals not appropriate for intensive therapy

as initial therapy
as subsequent therapy in individuals who previously received initial therapy with nivolumab with or without ipilimumab, or pembrolizumab

HEPATOCELLULAR CARCINOMA

In individuals with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib
As NCCN preferred first-line treatment in combination with atezolizumab for individuals (Child-Pugh Class A only) for individuals who have any of the following indications:

unresectable disease and are not a transplant candidate
liver-confined disease, inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease
metastatic disease or extensive liver tumor burden

KIDNEY CARCINOMA

Treatment for relapse or stage IV disease for the following regiments:

as single-agent systemic therapy for non-clear cell histology
in combination with everolimus as systemic therapy for non-clear cell histology

In individuals with relapsed or stage IV hereditary renal cell carcinoma in combination with erlotinib for non-clear cell histology in selected individuals with advanced papillary renal cell carcinoma including hereditary leiomyomatosis and renal cell carcinoma (HLRCC) associated RCC

MALIGNANT PLEURAL MESOTHELIOMA

In combination with pemetrexed and cisplatin (NCCN preferred for epithelioid histology) as first-line systemic therapy for any of the following:

unresectable clinical stage I-IIIA disease after surgical exploration (if induction chemotherapy was not given) and epithelioid histology
clinical stage I-IIIA disease and epithelioid histology who have not undergone surgical exploration (if induction chemotherapy was not given)
clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in individuals with performance status (PS) 0-2

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma

Treatment in those who are not candidates for cisplatin in combination with pemetrexed and carboplatin (preferred for epithelioid histology) as first-line systemic therapy for the following indications:

unresectable clinical stage I-IIIA disease after surgical exploration (if induction chemotherapy was not given) and epithelioid histology
clinical stage I-IIIA disease and epithelioid histology who have not undergone surgical exploration (if induction chemotherapy was not given)
clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in individuals with performance status (PS) 0-2

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma

Preferred subsequent systemic therapy, if immunotherapy was administered as first-line treatment or to be considered as a rechallenge if good response to front-line pemetrexed-based treatment for the following regiments:

in combination with pemetrexed and cisplatin
in combination with pemetrexed and carboplatin in those who are not candidates for cisplatin

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma

MALIGNANT PERITONEAL MESOTHELIOMA

In combination with pemetrexed and cisplatin (preferred for epithelioid histology) as first-line systemic therapy for unresectable:

diffuse peritoneal mesothelioma (PeM) with unicavitary, epithelioid histology that is medically inoperable and/or complete cytoreduction not achievable (including high-risk features**) and ECOG performance status (PS) 0-2
diffuse PeM with biphasic/sarcomatoid histology or bicavitary disease and ECOG PS 0-2
recurrence of diffuse PeM with unicavitary, epithelioid histology after prior cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), if no previous adjuvant systemic therapy given and ECOG PS 0-2
recurrence of benign multicystic or well-differentiated papillary PeM after prior CRS ± HIPEC for ECOG PS 0-2

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma
**High-risk features include Ki-67 >9%, nodal metastasis, high tumor burden (Peritoneal Cancer Index [PCI] >17), completeness of cytoreduction (CC) score >1, biphasic disease, or bicavitary disease

Treatment in individuals who are not candidates for cisplatin in combination with pemetrexed and carboplatin (preferred for epithelioid histology) as first-line systemic therapy for unresectable:

diffuse peritoneal mesothelioma (PeM) with unicavitary, epithelioid histology that is medically inoperable and/or complete cytoreduction not achievable (including high-risk features**) and ECOG performance status (PS) 0-2

diffuse PeM with biphasic/sarcomatoid histology or bicavitary disease and ECOG PS 0-2

recurrence of diffuse PeM with unicavitary, epithelioid histology after prior cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), if no previous adjuvant systemic therapy given and ECOG PS 0-2

recurrence of benign multicystic or well-differentiated papillary PeM after prior CRS ± HIPEC for ECOG PS 0-2

Subsequent systemic therapy for ECOG performance status (PS) 0-2 in combination with atezolizumab if not previously treated with immune checkpoint inhibitors

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma

NCCN preferred subsequent systemic therapy, if immunotherapy was administered as first-line treatment or to be considered as a rechallenge if good response to front-line pemetrexed-based treatment and ECOG performance status (PS) 0-2

in combination with pemetrexed and cisplatin

in combination with pemetrexed and carboplatin in those who are not candidates for cisplatin

*May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma

NON-SQUAMOUS NON-SMALL CELL LUNG CANCER (NSCLC): ADENOCARCINOMA AND LARGE CELL CARCINOMA

In individuals who have unresectable, locally advanced, recurrent, or metastatic NSCLC, as first-line treatment in combination with paclitaxel (Taxol®) and carboplatin (Paraplatin®)
In combination with erlotinib for EGFR mutation-positive (eg, exon 19 deletion or L858R) nonsquamous cell histology, recurrent, advanced, or metastatic disease with no history of hemoptysis as (except for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease) either first-line therapy or continuation of therapy following disease progression on combination of erlotinib with bevacizumab for asymptomatic disease, symptomatic brain lesions, or symptomatic systemic limited progression (if T790M negative)
As first-line therapy Treatment for recurrent, advanced, or metastatic disease** as first-line therapy for PD-L1 expression positive (≥1%) tumors that are negative for actionable molecular biomarkers*
and no contraindications to PD-1 or PD-L1 inhibitors and performance status (PS) 0-2 in combination with atezolizumab, carboplatin and paclitaxel for nonsquamous cell histology
Treatment for recurrent, advanced, or metastatic disease in individuals with performance status 0-1, tumors of nonsquamous cell histology, and no history of recent hemoptysis (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease in combination with:

carboplatin and either paclitaxel or pemetrexed (useful in certain circumstances, if contraindications** to PD-1 or PD-L1 inhibitors)
cisplatin and pemetrexed (useful in certain circumstances, if contraindications** to PD-1 or PD-L1 inhibitors)

The above regimens are used as:
- initial systemic therapy for PD-L1 expression positive (≥1%) and negative for actionable molecular markers* with contraindications to PD-1 or PD-L1 inhibitors
- initial systemic therapy for PD-L1 <1% and negative for actionable molecular markers*
- first-line therapy for EGFR exon 20 mutation positive tumors
- first-line therapy for KRAS G12C mutation positive tumors
- first-line or subsequent therapy for BRAF V600E mutation positive tumors
- first-line or subsequent therapy for NTRK1/2/3 gene fusion positive tumors
- first-line or subsequent therapy for MET exon 14 skipping mutation positive tumors
- first-line or subsequent therapy for RET rearrangement positive tumors
- first-line therapy for ERBB2 (HER2) mutation positive tumors
- subsequent therapy for EGFR mutation positive (eg, exon 19 deletion or L858R) tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib therapy
- subsequent therapy for EGFR S768I, L861Q, and/or G719X mutation positive tumors and prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib therapy
- subsequent therapy for ALK rearrangement positive tumors and prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib therapy
- subsequent therapy for ROS1 rearrangement positive tumors and prior crizotinib, entrectinib, or ceritinib therapy
- subsequent therapy for PD-L1 expression positive (≥1%) tumors and negative for actionable molecular markers* after prior PD-1/PD-L1 inhibitor but no prior platinum-containing chemotherapy
Treatment for recurrent, advanced, or metastatic disease in individuals with performance status 0-1, tumors of nonsquamous cell histology, and no history of recent hemoptysis in combination with atezolizumab, carboplatin and paclitaxel (if no contraindications** to PD-1 or PD-L1 inhibitors) with no evidence of disseminated disease for any of the following indications:
- initial systemic therapy for PD-L1 <1% and negative for actionable molecular markers*
- first-line therapy for EGFR exon 20 mutation-positive tumors
- first-line therapy for KRAS G12C mutation-positive tumors
- first-line or subsequent therapy for BRAF V600E mutation-positive tumors
- first-line or subsequent therapy for NTRK1/2/3 gene fusion-positive tumors
- first-line or subsequent therapy for MET exon 14 skipping mutation-positive tumors
- first-line or subsequent therapy for RET rearrangement positive tumors
- first-line therapy for ERBB2 (HER2) mutation positive tumors
- subsequent therapy for EGFR exon 19 deletion or exon 21 L858R tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib therapy
- subsequent therapy for EGFR S768I, L861Q, and/or G719X mutation positive tumors and prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib therapy
- subsequent therapy for ALK rearrangement positive tumors and prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib therapy
- subsequent therapy for ROS1 rearrangement positive tumors and prior crizotinib, entrectinib, or ceritinib therapy
Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (≥1%) tumors that are negative for actionable molecular markers* and no contraindications** to PD-1 or PD-L1 inhibitors and performance status 0-2 in combination with atezolizumab, carboplatin and paclitaxel for nonsquamous cell histology (except for locoregional recurrence or symptomatic local disease [with the exception of mediastinal lymph node recurrence with prior radiation therapy] with no evidence of disseminated disease)
Continuation maintenance therapy in combination with atezolizumab for recurrent, advanced, or metastatic disease for PD-L1 expression positive (≥1%) tumors that are negative for actionable molecular markers* and no contraindications** to PD-1 or PD-L1 inhibitors in individuals with performance status 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology (except for locoregional recurrence or symptomatic local disease [with the exception of mediastinal lymph node recurrence with prior radiation therapy] with no evidence of disseminated disease)
Continuation maintenance therapy for recurrent, advanced, or metastatic disease (except for locoregional recurrence or symptomatic local disease [with the exception of mediastinal lymph node recurrence with prior radiation therapy] with no evidence of disseminated disease) with PD-L1 expression <1% in individuals with performance status 0 to 2, tumors of nonsquamous cell histology, and no history of recent hemoptysis who achieve tumor response or stable disease following initial systemic therapy, with one of the following regimens:

as single-agent
in combination with pemetrexed (if previously used with a first-line pemetrexed/platinum chemotherapy regimen)
in combination with atezolizumab (if previously used first-line as part of an atezolizumab/carboplatin/paclitaxel/bevacizumab regimen) for nonsquamous cell histology and no contraindications** to PD-1 or PD-L1 inhibitors

*If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these individuals are treated as though they do not have driver oncogenes
**Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents, or presence of an oncogene (eg, EGFR [exon 19 deletions, p.L858R point mutation in exon 21], ALK rearrangements, RET rearrangements), which would predict lack of benefit

OVARIAN CANCER (EPITHELIAL), FALLOPIAN TUBE CANCER, OR PRIMARY PERITONEAL CANCER

Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

In combination with carboplatin and paclitaxel, followed by bevacizumab or related biosimilar as a single agent, for stage III or IV disease following initial surgical resection

In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens

In combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by bevacizumab as a single agent, for platinum-sensitive recurrent disease

Maintenance therapy as a single agent if used previously as part of combination therapy for individuals with partial or complete response following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease

As an NCCN-preferred therapy for rising CA-125 levels or clinical relapse in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

As an NCCN-preferred targeted therapy as a single agent for persistent disease or recurrence (except for immediate treatment of biochemical relapse )

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant disease)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant disease)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease)

for radiographic and/or clinical relapse in individuals with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)

completing prior chemotherapy

As an NCCN preferred primary adjuvant therapy in combination with carboplatin and paclitaxel (NCCN preferred with paclitaxel) or docetaxel for pathologic stage II-IV disease

Maintenance therapy for stage II-IV high-grade serous or grade 2/3 endometrioid carcinoma if a complete response (CR) or partial response (PR) to primary therapy including bevacizumab

as a single agent in individuals BRCA1/2 wild-type or unknown and HR proficient or status unknown

in combination with olaparib in individuals BRCA1/2 wild-type or unknown and HR deficient

as a single agent in individuals BRCA1/2 wild-type or unknown and HR deficient

in combination with olaparib in individuals with a germline or somatic BRCA1/2 mutation

For platinum-sensitive persistent disease or recurrence (except for immediate treatment of biochemical relapse) for the following indications in combination with:

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy (platinum-sensitive or platinum-resistant)

for progression on primary, maintenance, or recurrence therapy (platinum-resistant)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant)

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-resistant) in combination with:

carboplatin and gemcitabine (preferred in platinum-sensitive disease)

carboplatin and paclitaxel (preferred in platinum-sensitive disease)

carboplatin and liposomal doxorubicin (preferred in platinum-sensitive disease)

As NCCN preferred therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide, liposomal doxorubicin , weekly paclitaxel, or topotecan (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

As NCCN preferred therapy in combination with paclitaxel or docetaxel (preferred with paclitaxel) and carboplatin for individuals who are poor surgical candidates or have a low likelihood of optimal cytoreduction as:

neoadjuvant therapy

continued treatment for stable disease following neoadjuvant therapy

adjuvant therapy following interval debulking surgery (IDS) in individuals with response or stable disease to neoadjuvant therapy

Maintenance therapy as a single agent (useful in certain circumstances) if used previously as part of a combination therapy for individuals with partial or complete response following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease

Carcinosarcoma (Malignant Mixed Müllerian Tumors)

Adjuvant treatment in combination with carboplatin and paclitaxel or docetaxel for pathologic stage II-IV disease (preferred with paclitaxel)

Maintenance therapy in combination with olaparib for stage II-IV carcinosarcoma with a germline or somatic BRCA1/2 mutation if complete response (CR) or partial response (PR) to primary therapy including bevacizumab

NCCN preferred treatment for rising CA-125 levels or clinical relapse in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

NCCN preferred targeted therapy as a single agent for persistent disease or recurrence 2B for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant disease)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant disease)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease)

for radiographic and/or clinical relapse in individuals with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)

Treatment for persistent disease or recurrence (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy (platinum-sensitive or platinum-resistant)

for progression on primary, maintenance, or recurrence therapy (platinum-resistant)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant)

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive)

in combination with any of the following:

carboplatin and gemcitabine (preferred in platinum-sensitive disease)

carboplatin and paclitaxel (preferred in platinum-sensitive disease)

carboplatin and liposomal doxorubicin (preferred in platinum-sensitive disease)

Therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide (preferred), liposomal doxorubicin (preferred), weekly paclitaxel (preferred), topotecan (preferred), mirvetuximab soravtansine-gynx (in folate receptor-alpha expressing tumors; useful in certain circumstances), or ixabepilone (if previously treated with taxane; other recommended option) 2B for immediate treatment of biochemical relapse, or for combination with mirvetuximab soravtansine-gynx or ixabepilone

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

for stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

Maintenance therapy as a single agent if used previously as part of a combination therapy for individuals with partial or complete response following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease

Malignant Sex Cord-Stromal Tumors

As a single agent for clinical relapse in individuals with stage II-IV disease

Clear Cell Carcinoma of the Ovary

Maintenance therapy in combination with olaparib for stage II-IV clear cell carcinoma with a germline or somatic BRCA1/2 mutation if complete response (CR) or partial response (PR) to primary therapy including bevacizumab

As an NCCN preferred therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide, liposomal doxorubicin, weekly paclitaxel, or topotecan except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

For persistent disease or recurrence (except for immediate treatment of biochemical relapse )

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant)

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-resistant)

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive)

in combination with:

carboplatin and gemcitabine (NCCN-preferred)

carboplatin and paclitaxel (NCCN-preferred)

carboplatin and liposomal doxorubicin (preferred)

As NCCN preferred targeted therapy as a single agent for persistent disease or recurrence (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant disease)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant disease)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease)

for radiographic and/or clinical relapse in individuals with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)

As an NCCN preferred therapy for rising CA-125 levels or clinical relapse in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

Grade 1 Endometrioid Carcinoma

As an NCCN preferred therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide, liposomal doxorubicin, weekly paclitaxel, or topotecan except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

As an NCCN preferred targeted therapy as a single agent for persistent disease or recurrence except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant disease)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant disease)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease)

for radiographic and/or clinical relapse in individuals with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)

Preferred treatment for rising CA-125 levels or clinical relapse in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

As adjuvant therapy in combination with carboplatin and paclitaxel (NCCN preferred) for pathologic stage II-IV, grade 1 endometrioid carcinoma

As NCCN-preferred for platinum-sensitive persistent disease or recurrence (except for immediate treatment of biochemical relapse) for the following indications:

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy (platinum-sensitive or platinum-resistant)

for progression on primary, maintenance, or recurrence therapy (platinum-resistant)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant)*

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant)

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive)

in combination with:

carboplatin and gemcitabine

carboplatin and paclitaxel

carboplatin and liposomal doxorubicin

Low-Grade Serous Carcinoma

As NCCN preferred treatment for recurrence in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

As NCCN preferred targeted therapy as a single agent for platinum-sensitive or platinum-resistant recurrence

As NCCN preferred therapy for platinum-resistant recurrence in combination with oral cyclophosphamide, liposomal doxorubicin, weekly paclitaxel, or topotecan

As NCCN preferred for platinum-sensitive or platinum-resistant persistent disease or recurrence (except for immediate treatment of biochemical relapse) as immediate treatment for serially rising CA-125 or in individuals that previously received chemotherapy in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy in combination with:

carboplatin and gemcitabine

carboplatin and paclitaxel

carboplatin and liposomal doxorubicin

As NCCN preferred Adjuvant therapy in combination with carboplatin and paclitaxel (NCCN preferred) for pathologic stage II-IV low-grade serous carcinoma

Mucinous Carcinoma

As NCCN preferred therapy for rising CA-125 levels or clinical relapse in individuals who have received no prior chemotherapy in combination with paclitaxel and carboplatin

NCCN preferred therapy for platinum-sensitive persistent disease or recurrence (except for immediate treatment of biochemical relapse )

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy

in combination with

carboplatin and gemcitabine (NCCN-preferred)

carboplatin and paclitaxel (NCCN-preferred)

carboplatin and liposomal doxorubicin (NCCN-preferred)

Therapy for platinum-resistant persistent disease or recurrence (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

for stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

in combination with any of the following

As NCCN preferred adjuvant treatment for pathologic stage II-IV disease in combination with carboplatin and paclitaxel

As NCCN preferred targeted therapy as a single agent for persistent disease or recurrence except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy (platinum-resistant disease)

for stable or persistent disease (if not on maintenance therapy) (platinum-resistant disease)

for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease)

for radiographic and/or clinical relapse in individuals with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)

As NCCN preferred therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide, liposomal doxorubicin, weekly paclitaxel, or topotecan except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy

for progression on primary, maintenance, or recurrence therapy

stable or persistent disease (if not on maintenance therapy)

for complete remission and relapse <6 months after completing chemotherapy

SOFT TISSUE SARCOMA

In individuals with angiosarcoma as a single agent
In individuals with solitary fibrous tumor or hemangiopericytoma in combination with temozolomide, as NCCN-preferred therapy.

UTERINE CANCER/ENDOMETRIAL CANCER

First-line therapy (or second-line or subsequent therapy as clinically appropriate if not used previously) in combination with carboplatin and paclitaxel for advanced and recurrent disease only for any of the following:

for disseminated metastases with or without sequential palliative external beam radiation therapy (EBRT)
with sequential external beam radiation therapy (EBRT) and with or without brachytherapy for locoregional recurrence in individuals with no prior RT to site of recurrence, or previous brachytherapy only
after surgical exploration, with sequential EBRT for locoregional recurrence in individuals with disease confined to the vagina or paravaginal soft tissue, or in pelvic, para-aortic or common iliac lymph nodes
after surgical exploration, with or without sequential EBRT for locoregional recurrence in individuals with upper abdominal or peritoneal disease
with or without sequential palliative EBRT or brachytherapy for locoregional recurrence in individuals who have received prior EBRT to site of recurrence

Second-line or subsequent therapy as a single agent for recurrent disease that has progressed on prior cytotoxic chemotherapy for any of the following indications:
- may be considered for isolated metastases
- for disseminated metastases with or without sequential palliative external beam radiation therapy (EBRT)
- with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with no prior RT to site of recurrence, or previous brachytherapy only
- after surgical exploration, with sequential EBRT for locoregional recurrence in individuals with disease confined to the vagina or paravaginal soft tissue, or in pelvic, para-aortic or common iliac lymph nodes
- after surgical exploration, with or without sequential EBRT for locoregional recurrence in individuals with upper abdominal or peritoneal disease
- with or without sequential palliative EBRT or brachytherapy for locoregional recurrence in individuals who have received prior EBRT to site of recurrence

VULVAR CANCER

First-line therapy for advanced or recurrent/metastatic disease (or second-line or subsequent therapy as clinically appropriate if not used previously) in combination with cisplatin and paclitaxel (NCCN preferred regimen) for any of the following:

consider as additional treatment following primary therapy with concurrent chemoradiation 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

consider as additional treatment following primary therapy with concurrent chemoradiation for locally advanced disease (larger T2, T3) or initially unresectable nodes regardless of T stage with positive margins following resection

as primary treatment for metastatic disease beyond the pelvis (any T, any N, M1 beyond pelvis)

consider for isolated inguinofemoral/pelvic lymph node recurrence if prior external beam radiation therapy (EBRT)

for clinical nodal or distant recurrence with multiple pelvic nodes, distant metastasis, or prior pelvic EBRT

NOT MEDICALLY NECESSARY

For individuals receiving their first course of bevacizumab, use of the non-preferred reference product bevacizumab (Avastin®) or any non-preferred biosimilar, is considered not medically necessary and, therefore, not covered unless the individual has documented contraindication(s) or intolerance(s) to the Company designated preferred products, since they are more costly than the preferred products that are at least as likely to produce equivalent therapeutic results for that individual's illness.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of bevacizumab and related biosimilars are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the medical policy on off-label coverage for prescription drugs and biologics.

MANDATES

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive agents (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

DOSING AND FREQUENCY REQUIREMENTS

Refer to Attachment A for dosing and frequency requirements for bevacizumab and related biosimilars.

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this Policy to ensure consistency with the most recently published recommendations for the use of bevacizumab and related biosimilars. Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of bevacizumab and related biosimilars outside of the Dosing and Frequency Requirements listed in this Policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the precertification process. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for bevacizumab and related biosimilars.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of bevacizumab and related biosimilars is requested outside of the Dosing and Frequency Guidelines listed in this Policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

The World Health Organization (WHO) grading system is contained in the volume Histological Typing of Tumours of the Central Nervous System. The WHO grade has four categories of tumors:

Grade I tumors are slow-growing, nonmalignant, and associated with long-term survival.
Grade II tumors are relatively slow-growing but sometimes recur as higher grade tumors. They can be nonmalignant or malignant.
Grade III tumors are malignant and often recur as higher grade tumors.
Grade IV tumors reproduce rapidly and are very aggressive malignant tumors.

From the histological point of view the WHO system is based on the same criteria as the St Anne-Mayo system.

THE EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS

The ECOG has developed the ECOG Performance Status; it was originally published in 1982 in the American Journal of Clinical Oncology*. ECOG states, "These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. They are included here for health care professionals to access."

ECOG Performance Status
Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2	Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50 percent of waking hours
3	Capable of only limited self care, confined to bed or chair more than 50 percent of waking hours
4	Completely disabled. Cannot carry on any self care: Totally confined to bed or chair
5	Dead

*Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

PD-L1 IHC 22C3 pharmDx TEST

PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay using monoclonal mouse anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma (ESCC), cervical cancer, urothelial carcinoma and head and neck squamous cell carcinoma (HNSCC) tissues using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression in NSCLC is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. PD-L1 protein expression in gastric or GEJ adenocarcinoma, ESCC, cervical cancer, urothelial carcinoma and HNSCC is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, bevacizumab and related biosimilars are covered under the medical benefits of the Company’s products when the medical necessity criteria, dosing and frequency requirements, and the precertification/preapproval requirements listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

The initial approval for the use of bevacizumab was granted by the FDA on February 26, 2004. Supplemental approvals have since been issued. The safety, effectiveness, and pharmacokinetic profile of bevacizumab in the pediatric population have not been established.

The FDA has issued subsequent approvals for biosimilar products.

Description

Bevacizumab and related biosimilars are recombinant humanized monoclonal IgG1 antibodies that work by binding to and inhibiting the action of vascular endothelial growth factor (VEGF). VEGF is a substance that binds to certain cells to stimulate new blood vessel formation (angiogenesis). When VEGF is bound to bevacizumab and related biosimilars, it cannot stimulate the formation and growth of new blood vessels. Bevacizumab and related biosimilars are thought to enhance the effects of chemotherapy.

The US Food and Drug Administration (FDA) has granted approval for the use of bevacizumab and related biosimilars for the following indications:

In individuals who have metastatic carcinoma of the colon or rectum, as first- or second-line treatment, in combination with intravenous 5-fluorouracil--based chemotherapy
In individuals who have metastatic carcinoma of the colon or rectum, as a second-line treatment in patients who have progressed on a first-line bevacizumab regimen, in combination with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin--based chemotherapy
In individuals who have unresectable, locally advanced, recurrent, or metastatic non-squamous non-small cell lung cancer, as first-line treatment in combination with paclitaxel (Taxol®) and carboplatin (Paraplatin®)
In individuals who have recurrent glioblastoma, as a single agent
In individuals who have metastatic renal cell carcinoma, in combination with interferon alfa
In individuals who have persistent, recurrent, or metastatic carcinoma of the cervix, in combination with paclitaxel and cisplatin or paclitaxel and topotecan
In individuals who have stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent.
In individuals who have platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.
In individuals who have platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer when given either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by bevacizumab as a single agent.
In individuals with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy, in combination with atezolizumab (Tecentriq)

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

In 2008, the FDA gave accelerated approval for the treatment of metastatic breast cancer. However in 2011, the FDA withdrew this indication, since further studies showed only a small delay in tumor growth compared to earlier trials, no increase in overall survival, and an increase in the incidence of serious adverse events. Considering all information from these studies, the FDA concluded that the risks of this drug outweighed its benefits in the treatment of patients with metastatic breast cancer. Although this indication was withdrawn from the FDA, drug compendia still support the use of bevacizumab for the treatment of metastatic breast cancer.

References

American Hospital Formulary Service (AHFS). Bevacizumab (Avastin®). Drug Information 2022. [Lexicomp Online Web site]. 07/12/22. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 23, 2023.

Bevacizumab (Avastin®) labeling. Genentech, Inc., South San Francisco, CA. 09/2022. Available at: https://www.avastin-hcp.com/. Accessed March 23, 2023.

Eastern Cooperative Oncology Group (ECOG). ECOG performance status. Available at: http://ecog-acrin.org/resources/ecog-performance-status. Accessed March 23, 2023.

Elsevier’s Clinical Pharmacology Compendium. Bevacizumab (Avastin®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™). 05/09/2022. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/monograph/2709?n=Avastin [via subscription only]. Accessed March 23, 2023.

Lexi-Drugs Compendium. bevacizumab (Avastin). 03/15/2023. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 23, 2023.

Mvasi (bevacizumab-awwb) labeling. Amgen Inc., Thousand Oaks, CA. 02/2023. Available at: https://www.mvasi.com/hcp. Accessed March 23, 2023.

National Cancer Institute (NCI). Ovarian epithelial, fallopian tube, and primary peritoneal cancer treatment (PDQ®). Health professional version. 05/20/2021. [NCI Web site]. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional/page1. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Pediatric Central Nervous System Cancers. v.2.2023. [NCCN Web site]. 10/31/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Ampullary Adenocarcinoma. v.2.2022. [NCCN Web site]. 12/06/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ampullary.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Central nervous system cancers. v.1.2023. [NCCN Web site]. 03/24/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Cervical cancer. v.1.2023. [NCCN Web site]. 01/06/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Colon cancer. v.1.2023. [NCCN Web site]. 03/29/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Hepatobiliary cancers. v.5.2021. [NCCN Web site]. 09/21/2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Kidney cancer. v.4.2023. [NCCN Web site]. 01/18/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Malignant Pleural Mesothelioma. v.1.2023. [NCCN Web site]. 12/15/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer. v.2.2023. [NCCN Web site]. 02/17/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. v.1.2023. [NCCN Web site]. 12/22/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf . Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Rectal cancer. v.1.2023. [NCCN Web site]. 03/29/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Small bowel adenocarcinoma. v.1.2023. [NCCN Web site]. 01/09/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Soft Tissue Sarcoma. v.1.2023. [NCCN Web site]. 03/13/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms. v.1.2023. [NCCN Web site]. 12/22/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf . Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Vulvar cancer (Squamous cell carcinoma). v.1.2023. [NCCN Web site]. 12/22/2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf. Accessed March 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™. Bevacizumab (Avastin®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™). 2021. [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed March 23, 2023.

Pope WB, Lai A, Nghiemphu P, et al. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology. 2006;66(8):1258-1260.

Salah Uddin ABM, Jarmi T. Neurologic Manifestations of Glioblastoma multiforme. [eMedicine Web site]. 11/07/2021. Available at: http://emedicine.medscape.com/article/1156220-overview. Accessed March 23, 2023.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Bevacizumab (Avastin®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™). 03/07/2023. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ [via subscription only]. Accessed March 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Avastin (bevacizumab). Package insert. [FDA Web site]. 09/18/2022. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed March 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Mvasi™(bevacizumab-awwb). Package insert. [FDA Web site]. 02/17/2023. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761028. Accessed March 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. bevacizumab-bvzr (Zirabev™). Package insert. [FDA Web site]. 02/17/2023. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed March 23, 2023

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Postmarket drug safety information for patients and providers. Questions and answers about avastin. 12/16/2010. Available at: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm237095.htm. Accessed March 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. PD-L1 IHC 22C3 pharmDx. 07/29/2019. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150013b.pdf. Accessed March 23, 2023.

Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253-1259.

Zirabev (bevacizumab-bvzr) labeling. Pfizer Inc., NY, NY. 02/2023. Available at: https://www.zirabev.com/. Accessed March 23, 2023.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment B.

HCPCS Level II Code Number(s)

C9257 Injection, bevacizumab, 0.25 mg

J9035 Injection, bevacizumab, 10 mg

Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

Q5118 Injection, bevacizumab-bvzr, biosimilar, (Zirabev), 10 mg

Q5126 Injection, bevacizumab-maly, biosimilar, (alymsys), 10 mg

Q5129 Injection, bevacizumab-adcd (vegzelma), biosimilar, 10mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross Reference

Policy History

Version Effective Date:

10/1/2024

Version Issued Date:

10/1/2024

Version Reissued Date: