Medicare Advantage

Medical Policy

Notification

Bevacizumab (Avastin®) and Related Biosimilars For Oncologic Use

Notification Issued 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 MA08.073f.

Title:

Bevacizumab (Avastin®) and Related Biosimilars For Oncologic Use

Policy #:

MA08.072o

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-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™) in the following cancers (listed in order of appearance within the Policy section):

Ampullary Adenocarcinoma	Non-squamous non-small cell lung cancer
Central nervous system tumors	Ovarian (epithelial), fallopian tube, primary peritoneal cancers
Cervical carcinoma	Rectal carcinoma
Colon cancer, appendiceal adenocarcinoma	Small bowel adenocarcinoma
Hepatocellular carcinoma	Soft tissue sarcoma: angiosarcoma/solitary fibrous tumor
Kidney cancer	Uterine/endometrial carcinoma
Malignant pleural/peritoneal mesothelioma	Vaginal cancer
Malignant Sex Cord-Stromal Tumors	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 and at least as likely to produce equivalent therapeutic results as the non-preferred products, which include, but are not limited to bevacizumab (Avastin®) and any other non-preferred bevacizumab biosimilars.

According to the U.S. 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 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

FOLFIRINOX (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

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 any of the following:

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

Capecitabine and fluorouracil

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 following:

Capecitabine

Fluorouracil

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

CapeOx (capecitabine and oxaliplatin) regimen

CENTRAL NERVOUS SYSTEM TUMORS

Pediatric Central Nervous System Cancers

Pediatric Diffuse High-Grade Gliomas

Treatment for palliation of recurrent or progressive disease for pediatric diffuse high-grade glioma*

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

Treatment for recurrent or progressive disease for all risk categories as part of TEMR (temozolomide, irinotecan, bevacizumab) regimen

Treatment for recurrent or progressive disease for all risk categories as part of MEMMAT (thalidomide, celecoxib, fenofibrate, etoposide, cyclophosphamide, bevacizumab) regimen

Adult Central Nervous System Cancers

For symptomatic mass effect, brain edema, radiation necrosis:

Extensive Brain Metastases

Metastatic Spine Tumors

Limited Brain Metastases

Meningiomas

Primary Spinal Cord Tumors

Primary CNS Lymphoma

Adult Medulloblastoma

Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma)

High-Grade Glioma: Other

Adult Glioma: Glioblastoma

Adult Glioma: Circumscribed Glioma

Adult Glioma: IDH-mutant Astrocytoma

Adult Glioma: Oligodendroglioma (IDH-mutant, 1p19q codeleted)

Treatment for recurrent or progressive disease for adult glioma (glioblastoma, high-grade glioma)

as a single agent (NCCN preferred)

in combination with carmustine, lomustine, or temozolomide if disease progression on bevacizumab monotherapy and it is desirable to continue the steroid-sparing effects of bevacizumab

Treatment for recurrent or progressive disease of high-grade glioma or glioblastoma as a single agent (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

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

gross total or subtotal resection with negative cerebrospinal fluid (CSF) cytology

subtotal resection and evidence of metastasis (brain, spine, or CSF)

unresectable disease

Adult medulloblastoma:

treatment for recurrence in combination with temozolomide and irinotecan

Primary central nervous system lymphoma

Meningiomas:

treatment to be considered as single agent for surgically inaccessible recurrent or progressive disease when radiation is not possible

Brain metastases (limited or extensive)

Primary Spinal Cord Tumors:

as single-agent treatment for neurofibromatosis type 2 vestibular schwannomas with hearing loss

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 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

CERVICAL CANCER

Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan.

NCCN 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 assay or test validated test performed in a CLIA-certified laboratory 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 and continued for maintenance therapy for the following:

local/regional recurrence

stage IVB or recurrence with distant metastases

Second-line or subsequent therapy as a single agent for:

local/regional recurrence

stage IVB or or recurrence with 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 and continued for maintenance therapy

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

RECTAL CANCER

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 total neoadjuvant therapy (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) or neoadjuvant/definitive immunotherapy (dMMR/MSI-H) if intensive therapy recommended

in CapeOX (capecitabine and oxaliplatin) regimen

in FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

in FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

in combination with capecitabine

in 5-FU/leucovorin (fluorouracil and leucovorin) 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 progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation)

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 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 progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation)

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

Primary treatment for synchronous liver only and/or lung only metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS]; deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation and not a candidate for immunotherapy) that are unresectable or medically inoperable in combination with

FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen

CapeOX (capecitabine and oxaliplatin) regimen

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

Preferred anti-angiogenic therapy as initial treatment for individuals with unresectable metachronous metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS]) and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months

in combination with irinotecan

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

Second-line and subsequent therapy for progression of advanced or metastatic disease (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation)

as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, if not previously given and if previously treated with oxaliplatin-based therapy without irinotecan

in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) regimen, if not previously given and if previously treated with irinotecan-based therapy without oxaliplatin

in combination with FOLFOX, CapeOX, FOLFIRI (preferred), irinotecan and oxaliplatin, irinotecan (preferred), or FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin), if not previously given and if previously treated without irinotecan or oxaliplatin

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 FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen, in individuals appropriate for intensive therapy (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation), if intensive therapy recommended 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 initial 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

Primary treatment for unresectable synchronous liver and/or lung metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS]; deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation and individual is not a candidate for immunotherapy) in combination with any of the following regimens:

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

Second-line and subsequent therapy, if not previously given, for progression of advanced or metastatic disease (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) in combination with trifluridine and tipiracil (preferred), if not previously given, in individuals who have progressed through all available regimens

In combination with capecitabine or with 5-FU/leucovorin (fluorouracil and leucovorin) regimen (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation), 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 initial 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

As NCCN-preferred antiangiogenic therapy as initial 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 previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months for any of the following regimens:

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 following:

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 (pMMR/MSS or ineligible for or progression on checkpoint inhibitor immunotherapy for dMMR/MSI-H)

As second-line and subsequent therapy for progression of advanced or metastatic disease (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) 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, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) or irinotecan and oxaliplatin, if not previously given and if previously treated without irinotecan or oxaliplatin

Appendiceal Adenocarcinoma

Initial systemic therapy for advanced or metastatic disease (proficient mismatch repair/microsatellite-stable (pMMR/MSS) or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) 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 recommended 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 (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) in combination with capecitabine or with 5-FU/leucovorin (fluorouracil and leucovorin) regimen if intensive therapy not recommended

Second line and subsequent therapy for progression of advanced or metastatic disease (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation) for any of the following:

as 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

as NCCN preferred antiangiogenic 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

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 initial therapy

as second-line and subsequent therapy

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

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 if intensive therapy recommended

as initial therapy

as second-line and subsequent therapy (if not previously given)

Initial therapy in combination with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) for advanced or metastatic disease if intensive therapy is recommended

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

Initial therapy in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) for advanced or metastatic disease and if individuals received previous FOLFOX/CAPEOX in the adjuvant setting within the past 12 months or contraindication

HEPATOCELLULAR CARCINOMA

In individuals with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

As adjuvant therapy in combination with atezolizumab following resection or ablation for those whose initial clinical presentation is operable by performance status or comorbidity and meet resection criteria, and are at high risk of recurrence (defined as size > 5 cm, >3 tumors, macrovascular invasion or microvessel invasion on histology or grade 3/4 histology)

As NCCN-preferred first-line treatment in combination with atezolizumab for individuals who have any of the following indications:

liver-confined, unresectable disease and are deemed ineligible for transplant

extrahepatic/metastatic disease and are deemed ineligible for resection, transplant, or locoregional therapy

KIDNEY CARCINOMA

In individuals with metastatic renal cell carcinoma in combination with interferon alfa.

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

in combination with everolimus as systemic therapy for non-clear cell histology (if first-line therapy and stage IV, then M1 or unresectable T4, M0 only)

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 (cisplatin or carboplatin) pemetrexed (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

NCCN note: *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)

for individuals with performance status (PS) 0-2 and: clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in individuals with performance status (PS) 0-2

NCCN note: *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 for the following regiments:

in combination with pemetrexed and cisplatin

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

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

MALIGNANT PERITONEAL MESOTHELIOMA

Used in combination with pemetrexed and (cisplatin or carboplatin) (NCCN preferred for epithelioid histology) as first-line systemic therapy for

adjuvant treatment of peritoneal mesothelioma (PeM) with unicavitary, epithelioid histology that is medically operable and complete cytoreduction achievable, following cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), if surgical/pathologic high-risk features** and no neoadjuvant therapy given

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

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

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

ECOG PS 0-2 and: recurrence of PeM with biphasic/sarcomatoid histology after prior CRS + HIPEC

NCCN notes:*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

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

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

NCCN notes: *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 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 in those who have not undergone surgical exploration (if induction chemotherapy was not given)

those with performance status (PS) 0-2 and: clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or if medically inoperable

NCCN notes: *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

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

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

NCCN preferred subsequent systemic therapy, in combination with pemetrexed and cisplatin or carboplatin, 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

NCCN note: *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 (e.g., 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 (if contraindications** to PD-1 or PD-L1 inhibitors)

cisplatin and pemetrexed (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* (may be KRAS G12C mutation positive) with contraindications to PD-1 or PD-L1 inhibitors

initial systemic therapy for PD-L1 <1% and negative for actionable molecular markers* (may be KRAS G12C mutation positive)

first-line therapy for EGFR exon 20 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 (e.g., exon 19 deletion or L858R) tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, amivantamab-vmjw + lazertinib 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) for any of the following indications:

initial systemic therapy for PD-L1 <1% and negative for actionable molecular markers* (may be KRAS G12C mutation positive)

first-line therapy for EGFR exon 20 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, amivantamab-vmjw + lazertinib 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* (may be KRAS G12C mutation positive) 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% that are negative for actionable molecular biomarkers* (may be KRAS G12C mutation positive) 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

NCCN notes:* Complete genotyping for 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 (e.g., 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 two 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 response (PR) or complete response (CR) 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 who 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 primary adjuvant therapy for pathologic stage II-IV disease in combination with oxaliplatin and docetaxel

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 CR or 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 (or niraparib if unable to tolerate 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 who 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 therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide (NCCN preferred), cyclophosphamide and pembrolizumab, liposomal doxorubicin (NCCN preferred) , weekly paclitaxel (NCCN preferred), or topotecan (NCCN preferred), mirvetuximab soravtansine-gynx (in folate receptor-alpha expressing tumors; useful in certain circumstances), or gemcitabine (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals who 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 (NCCN 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 CR following recurrence therapy with chemotherapy plus bevacizumab for platinum-sensitive disease

Carcinosarcoma (Malignant Mixed Müllerian Tumors)

Adjuvant treatment with any of the following:

in combination with oxaliplatin and docetaxel for pathologic stage II-IV disease

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

Maintenance therapy in combination with olaparib or niraparib (if unable to tolerate olaparib) for stage II-IV carcinosarcoma with a germline or somatic BRCA1/2 mutation if CR or 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 (except for immediate treatment of biochemical relapse)

as immediate treatment for serially rising CA-125 in individuals who 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 who 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 (NCCN preferred), oral cyclophosphamide and pembrolizumab liposomal doxorubicin (NCCN preferred), weekly paclitaxel (NCCN preferred), topotecan (NCCN preferred), gemcitabine, mirvetuximab soravtansine-gynx (in folate receptor-alpha–expressing tumors), or ixabepilone (if previously treated with taxane) 2B for immediate treatment of biochemical relapse, or for combination with ixabepilone

as immediate treatment for serially rising CA-125 in individuals who 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 PR or CR 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 or niraparib (if unable to tolerate olaparib) for stage II-IV clear cell carcinoma with a germline or somatic BRCA1/2 mutation if CR or PR to primary therapy including bevacizumab

As a therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide (NCCN-preferred), oral cyclophosphamide and pembrolizumab, liposomal doxorubicin (NCCN-preferred), weekly paclitaxel (NCCN-preferred), or topotecan (NCCN-preferred), gemcitabine, mirvetuximab soravtansine-gynx (in folate receptor-alpha–expressing tumors; useful in certain circumstances) except for immediate treatment of biochemical relapse for any of the following:

as immediate treatment for serially rising CA-125 in individuals who 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 who 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 in platinum-sensitive disease)

carboplatin and paclitaxel (NCCN preferred in platinum-sensitive disease)

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

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 who 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

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

Grade 1 Endometrioid Carcinoma

Therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide (NCCN-preferred), oral cyclophosphamide and pembrolizumab, liposomal doxorubicin (NCCN preferred), weekly paclitaxel (NCCN preferred), or topotecan (NCCN preferred), gemcitabine, mirvetuximab, soravtansine-gynx (in folate receptor-alpha–expressing tumors; useful in certain circumstances) except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals who 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 who 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

For 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 who 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 therapy in combination with gemcitabine for platinum-resistant recurrence

As therapy for platinum-resistant recurrence in combination with oral cyclophosphamide (NCCN preferred), oral cyclophosphamide and pembrolizumab, liposomal doxorubicin (NCCN preferred), weekly paclitaxel (NCCN preferred), or topotecan (NCCN preferred), mirvetuximab soravtansine-gynx (in folate receptor-alpha–expressing tumors)

As treatment 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 who previously received chemotherapy in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy in combination with:

carboplatin and gemcitabine (NCCN preferred in platinum-sensitive disease)

carboplatin and paclitaxel (NCCN preferred in platinum-sensitive disease)

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

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 who 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 who 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 adjuvant treatment for pathologic stage II-IV disease in combination with carboplatin and paclitaxel

As adjuvant treatment in combination with oxaliplatin and docetaxel for pathologic stage II-IV disease

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 who 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 therapy for platinum-resistant persistent disease or recurrence in combination with oral cyclophosphamide (NCCN preferred), oral cyclophosphamide and pembrolizumab
liposomal doxorubicin (NCCN preferred), weekly paclitaxel (NCCN preferred), or topotecan (NCCN preferred) gemcitabine, mirvetuximab soravtansine-gynx (in folate receptor-alpha–expressing tumors),
except for immediate treatment of biochemical relapse

as immediate treatment for serially rising CA-125 in individuals who 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

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

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 and continued as a single agent for maintenance therapy for advanced and recurrent disease only for any of the following:

second-line or subsequent therapy for isolated metastases

for disseminated metastases with or without sequential palliative external beam radiation therapy (EBRT)

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 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

VAGINAL CANCER

or:

local/regional recurrence if prior intracavitary brachytherapy only, or prior EBRT with or without brachytherapy and noncentral disease

stage IVB or recurrent distant metastases

local/regional recurrence if prior intracavitary brachytherapy only, or prior EBRT with or without brachytherapy and noncentral disease

stage IVB or recurrent distant metastases

Second-line or subsequent therapy as a single agent for

local/regional recurrence

stage IVB or recurrent distant metastases

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 (NCCN-preferred regimen) for any of the following:

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

as additional treatment following primary therapy with concurrent chemoradiation for locally advanced disease or initially unresectable nodes regardless of T stage with positive margins for invasive disease following resection

as primary treatment for metastatic disease beyond the pelvis (Stage IVB)

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

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

In accordance with the Centers for Medicare & Medicaid Services (CMS) and in addition to the indications above, bevacizumab (Avastin®), as a part of anti-cancer chemotherapy regimen, are covered for the following Micromedex Category IIb indications:

Malignant mesothelioma of pleura, Unresectable disease, first-line therapy, in combination with pemetrexed and cisplatin

Metastatic breast cancer, HER2-negative, as first-line therapy, in combination with paclitaxel

Metastatic breast cancer, HER2-negative, as second-line therapy in combination with other chemotherapy

Metastatic breast cancer, In combination with capecitabine in patients previously treated with an anthracycline and a taxane

Metastatic colorectal cancer, First-line therapy, in combination with oxaliplatin and capecitabine

Metastatic colorectal cancer, In previously untreated elderly patients, ineligible for oxaliplatin- or irinotecan-based chemotherapy

Nonsquamous non-small cell lung cancer, Stage IIIB/IV, continuation maintenance therapy as a single-agent following platinum-based, first-line therapy

Nonsquamous non-small cell lung cancer, Stage IIIB/IV, first-line therapy in combination with pemetrexed and carboplatin

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.

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

There is no Medicare coverage criteria addressing the use of bevacizumab and related biosimilars for other indications; therefore, the Company policy is applicable.

BLACK BOX WARNINGS

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

BENEFIT APPLICATION

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

For Medicare Advantage members, certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy ben

efit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when bevacizumab and related biosimilars are covered under a member's medical benefit (Part B benefit). It does not address instances when bevacizumab and related biosimilars are covered under a member’s pharmacy benefit (Part D benefit).

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.

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.

The Peritoneal Cancer Index (PCI) is calculated by dividing the abdomen and pelvis into 13 regions and assigning a score to each region based on the size of the largest tumor:
Regions
The abdomen and pelvis are divided into nine regions (0–8), and the small bowel is divided into four regions.
Lesion size scores
Each region is assigned a score of 0–3 based on the size of the largest tumor:
0: No tumors
1: Tumors up to 5 mm
2: Tumors 5–25 mm
3: Tumors greater than 25 mm
Total PCI
The sum of all 13 lesion size scores is the total PCI, which ranges from 0–39.
A lower PCI, around 10–20, indicates a better prognosis and limited disease spread. Higher scores indicate more widespread and/or larger tumors in the peritoneal cavity. The PCI is a diagnostic and prognostic tool that combines cancer implant size with cancer distribution

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 two 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, because 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 2024. [

Lexicomp Online Web site]. 10/30/24. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 2, 2024.

Bevacizumab (Avastin®) labeling. Genentech, Inc., South San Francisco, CA. 09/2022. Available at: https://www.avastin-hcp.com/. Accessed November 2, 2024.

Eastern Cooperative Oncology Group (ECOG). ECOG performance status. Available at: http://ecog-acrin.org/resources/ecog-performance-status. Accessed November 2, 2024.

Elsevier’s Clinical Pharmacology Compendium. Bevacizumab (Avastin®), bevacizumab-

awwb (

Mvasi™), bevacizumab-

bvzr (

Zirabev™). 11/14/2024. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/monograph/2709?n=Avastin [via subscription only]. Accessed November 18, 2024.

Lexi-Drugs Compendium. bevacizumab (Avastin). 10/22/2024. [

Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 2, 2024.

Mvasi (bevacizumab-

awwb) labeling. Amgen Inc., Thousand Oaks, CA. 02/2023. Available at: https://www.mvasi.com/hcp. Accessed November 2, 2024.

National Cancer Institute (NCI). Ovarian epithelial, fallopian tube, and primary peritoneal cancer treatment (PDQ®). Health professional version. 07/25/2024. [NCI Web site]. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional/page1. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Pediatric Central Nervous System Cancers. v.1.2025. [NCCN Web site]. 11/08/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™.

Ampullary Adenocarcinoma. v.2.2024. [NCCN Web site]. 08/02/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ampullary.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Central nervous system cancers. v.3.2024. [NCCN Web site]. 09/30/2024. 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.4.2024. [NCCN Web site]. 09/24/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Colon cancer. v.5.2024. [NCCN Web site]. 08/22/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Hepatocellular carcinoma. v.3.2024. [NCCN Web site]. 09/24/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Kidney cancer. v.2.2025. [NCCN Web site]. 09/06/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Malignant Pleural Mesothelioma. v.3.2024. [NCCN Web site]. 10/04/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer. v.11.2024. [NCCN Web site]. 10/15/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. v.3.2024. [NCCN Web site]. 07/15/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Rectal cancer. v.3.2024. [NCCN Web site]. 09/27/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Small bowel adenocarcinoma. v.5.2024. [NCCN Web site]. 09/13/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf. Accessed November 2, 2024.

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 November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms. v.3.2024. [NCCN Web site]. 09/20/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Vaginal cancer (Squamous cell carcinoma). v.2.2025. [NCCN Web site]. 08/08/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf. Accessed November 2, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Vulvar cancer (Squamous cell carcinoma). v.4.2024. [NCCN Web site]. 05/01/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf. Accessed November 2, 2024.

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 November 2, 2024.

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 November 2, 2024.

Truven Health Analytics. Micromedex®

DrugDex® Compendium. Bevacizumab (Avastin®), bevacizumab-

awwb (

Mvasi™), bevacizumab-

bvzr (

Zirabev™). 10/15/2024. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ [via subscription only]. Accessed November 2, 2024.

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 November 2, 2024.

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 November 2, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. bevacizumab-

bvzr (

Zirabev™). Package insert. [FDA Web site]. 08/28/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed November 2, 2024.

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. 10/29/2015. Available at: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm237095.htm. Accessed November 2, 2024.

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. 08/2024. Available at: https://www.zirabev.com/. Accessed November 2, 2024.

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

Revisions From MA08.072o:

01/01/2025

This policy has been updated to communicate the revised medical necessity criteria, which reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

The following indications were revised, per FDA or NCCN:

CNS tumors
Cervical carcinoma
Colon or rectal carcinoma
Hepatobilliary carcinoma
Kidney
Mesothelioma
Non-squamous non-small lung cancer (NSCLC)
Ovarian, fallopian tube, or primary peritoneal cancer
Small bowel adenocarcinoma
Uterine cancer
Vulvar cancer

The following indications were added to this policy, in alignment with NCCN compendia:

Vaginal cancer
Pediatric central nervous system cancers

Dosing and frequency requirements were removed.

The following ICD-10 codes have been added to this policy:

C45.2 Mesothelioma of pericardium

C45.7 Mesothelioma of other sites

C45.9 Mesothelioma, unspecified

C52 Malignant neoplasm of vagina

C57.9 Malignant neoplasm of female genital organ, unspecified

C72.1 Malignant neoplasm of cauda equina

C83.59 Lymphoblastic (diffuse) lymphoma, extranodal and solid organ sites

C83.79 Burkitt lymphoma, extranodal and solid organ sites

C84.49 Peripheral T-cell lymphoma, not elsewhere classified, extranodal and solid organ sites

D42.0 Neoplasm of uncertain behavior of cerebral meninges

D42.1 Neoplasm of uncertain behavior of spinal meninges

D42.9 Neoplasm of uncertain behavior of meninges, unspecified

D43.0 Neoplasm of uncertain behavior of brain, supratentorial

D43.1 Neoplasm of uncertain behavior of brain, infratentorial

D43.4 Neoplasm of uncertain behavior of spinal cord

D43.9 Neoplasm of uncertain behavior of central nervous system, unspecified

G93.6 Cerebral edema

I67.89 Other cerebrovascular disease

I67.9 Cerebrovascular disease, unspecified

Q85.02 Neurofibromatosis, type 2

Q85.03 Schwannomatosis

Q85.83 Von Hippel-Lindau syndrome

The following ICD-10 codes with uncpecified laterality have been removed from this policy.

Revisions From MA08.072n:

10/01/2024

This policy has been identified for the ICD-10 code update, effective 10/01/2024.
Inclusion of a policy in a Code Update memo does not imply that a full review of
the policy was completed at this time.

The following ICD-10 codes have been added to this policy:
C83.390 Primary central nervous system lymphoma
C83.398 Diffuse large B-cell lymphoma of other extranodal and solid organ sites

The following ICD-10 code has been removed from this policy:
C83.39 Diffuse large B-cell llymphoma, extranodal and solid organ sites

Revisions From MA08.072m:

01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
05/22/2023	This policy has been updated to communicate the revised medical necessity criteria, including dosing and frequency requirements, which reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia. The following indications were revised, per FDA or NCCN: CNS tumors Cervical carcinoma Colon or Rectal carcinoma Hepatocellular carcinoma (HCC) Kidney Mesothelioma Non-squamous non-small lung cancer (NSCLC) Ovarian, Fallopian tube, or primary peritoneal cancer Small Bowel Adenocarcinoma Uterine cancer Vulvar cancer The following ICD-10 codes have been added to this policy: C45.1 Mesothelioma of peritoneum

01/01/2024

Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.

05/22/2023

This policy has been updated to communicate the revised medical necessity criteria, including dosing and frequency requirements, which reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

The following indications were revised, per FDA or NCCN:

CNS tumors
Cervical carcinoma
Colon or Rectal carcinoma
Hepatocellular carcinoma (HCC)
Kidney
Mesothelioma
Non-squamous non-small lung cancer (NSCLC)
Ovarian, Fallopian tube, or primary peritoneal cancer
Small Bowel Adenocarcinoma
Uterine cancer
Vulvar cancer

The following ICD-10 codes have been added to this policy:

C45.1 Mesothelioma of peritoneum

Revisions From MA08.072l:

01/04/2023

This policy has been identified for the HCPCS code update, effective 04/01/2023.

The following HCPCS code has been added to this policy:
Q5129 Injection, bevacizumab-adcd (vegzelma), biosimilar, 10 mg

Revisions From MA08.072k:

01/01/2023

This policy has been identified for the HCPCS code update, effective 01/01/2023.

The following HCPCS code has been added to this policy:
Q5126 Injection, bevacizumab-maly, biosimilar, (alymsys), 10 mg

The following HCPCS code has been removed from this policy:
C9142 Injection, bevacizumab-maly, biosimilar, (alymsys), 10 mg
J3590 Unclassified biologics

Revisions From MA08.072j:

10/01/2022

This policy has been identified for the HCPCS code update, effective 10/01/2022.

The following HCPCS code has been added to this policy:
C9142 Injection, bevacizumab-maly, biosimilar, (alymsys), 10 mg
J3590 Unclassified biologics

Revisions From MA08.072i:

02/28/2022

The following indication was removed from this policy, in alignment with NCCN compendia:

Breast cancer

The following indications were revised, per FDA or NCCN:

CNS tumors
Cervical carcinoma
Colon or Rectal carcinoma
Hepatocellular carcinoma (HCC)
NSCLC
Ovarian, Fallopian tube, or primary peritoneal cancer
Vulvar cancer

The following ICD-10 codes have been added to this policy:

C17.0 Malignant neoplasm of duodenum
C17.1 Malignant neoplasm of jejunum
C17.2 Malignant neoplasm of ileum
C17.3 Meckel's diverticulum, malignant
C17.8 Malignant neoplasm of overlapping sites of small intestine
C17.9 Malignant neoplasm of small intestine, unspecified
C24.1 Malignant neoplasm of ampulla of Vater
C49.3   Malignant neoplasm of connective and soft tissue of thorax
C49.4   Malignant neoplasm of connective and soft tissue of abdomen
C49.5   Malignant neoplasm of connective and soft tissue of pelvis
C49.8   Malignant neoplasm of overlapping sites of connective and soft tissue
C49.9   Malignant neoplasm of connective and soft tissue, unspecified
C57.7 Malignant neoplasm of other specified female genital organs
C72.9   Malignant neoplasm of central nervous system, unspecified
C79.31 Secondary malignant neoplasm of brain
C83.30 Diffuse large B-cell lymphoma, unspecified site
C83.39 Diffuse large B-cell lymphoma, extranodal and solid organ sites
C83.80 Other non-follicular lymphoma, unspecified site
C83.89 Other non-follicular lymphoma, extranodal and solid organ sites
C85.89 Other specified types of non-Hodgkin lymphoma, extranodal and solid organ sites
C85.99 Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites
D39.10 Neoplasm of uncertain behavior of unspecified ovary
D39.11 Neoplasm of uncertain behavior of right ovary
D39.12 Neoplasm of uncertain behavior of left ovary
D39.8   Neoplasm of uncertain behavior of other specified female genital organs
D39.9   Neoplasm of uncertain behavior of female genital organ, unspecified

The following ICD-10 codes have been deleted from this policy:

C50.011 Malignant neoplasm of nipple and areola, right female breast
C50.012 Malignant neoplasm of nipple and areola, left female breast
C50.019 Malignant neoplasm of nipple and areola, unspecified female breast
C50.021 Malignant neoplasm of nipple and areola, right male breast
C50.022 Malignant neoplasm of nipple and areola, left male breast
C50.029 Malignant neoplasm of nipple and areola, unspecified male breast
C50.111 Malignant neoplasm of central portion of right female breast
C50.112 Malignant neoplasm of central portion of left female breast
C50.119 Malignant neoplasm of central portion of unspecified female breast
C50.121 Malignant neoplasm of central portion of right male breast
C50.122 Malignant neoplasm of central portion of left male breast
C50.129 Malignant neoplasm of central portion of unspecified male breast
C50.211 Malignant neoplasm of upper-inner quadrant of right female breast
C50.212 Malignant neoplasm of upper-inner quadrant of left female breast
C50.219 Malignant neoplasm of upper-inner quadrant of unspecified female breast
C50.221 Malignant neoplasm of upper-inner quadrant of right male breast
C50.222 Malignant neoplasm of upper-inner quadrant of left male breast
C50.229 Malignant neoplasm of upper-inner quadrant of unspecified male breast
C50.311 Malignant neoplasm of lower-inner quadrant of right female breast
C50.312 Malignant neoplasm of lower-inner quadrant of left female breast
C50.319 Malignant neoplasm of lower-inner quadrant of unspecified female breast
C50.321 Malignant neoplasm of lower-inner quadrant of right male breast
C50.322 Malignant neoplasm of lower-inner quadrant of left male breast
C50.329 Malignant neoplasm of lower-inner quadrant of unspecified male breast
C50.411 Malignant neoplasm of upper-outer quadrant of right female breast
C50.412 Malignant neoplasm of upper-outer quadrant of left female breast
C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast
C50.421 Malignant neoplasm of upper-outer quadrant of right male breast
C50.422 Malignant neoplasm of upper-outer quadrant of left male breast
C50.429 Malignant neoplasm of upper-outer quadrant of unspecified male breast
C50.511 Malignant neoplasm of lower-outer quadrant of right female breast
C50.512 Malignant neoplasm of lower-outer quadrant of left female breast
C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast
C50.521 Malignant neoplasm of lower-outer quadrant of right male breast
C50.522 Malignant neoplasm of lower-outer quadrant of left male breast
C50.529 Malignant neoplasm of lower-outer quadrant of unspecified male breast
C50.611 Malignant neoplasm of axillary tail of right female breast
C50.612 Malignant neoplasm of axillary tail of left female breast
C50.619 Malignant neoplasm of axillary tail of unspecified female breast
C50.621 Malignant neoplasm of axillary tail of right male breast
C50.622 Malignant neoplasm of axillary tail of left male breast
C50.629 Malignant neoplasm of axillary tail of unspecified male breast
C50.811 Malignant neoplasm of overlapping sites of right female breast
C50.812 Malignant neoplasm of overlapping sites of left female breast
C50.819 Malignant neoplasm of overlapping sites of unspecified female breast
C50.821 Malignant neoplasm of overlapping sites of right male breast
C50.822 Malignant neoplasm of overlapping sites of left male breast
C50.829 Malignant neoplasm of overlapping sites of unspecified male breast
C50.911 Malignant neoplasm of unspecified site of right female breast
C50.912 Malignant neoplasm of unspecified site of left female breast
C50.919 Malignant neoplasm of unspecified site of unspecified female breast
C50.921 Malignant neoplasm of unspecified site of right male breast
C50.922 Malignant neoplasm of unspecified site of left male breast
C50.929 Malignant neoplasm of unspecified site of unspecified male breast

Revisions From MA08.072h:

10/01/2021

This policy has been identified for the ICD-10 CM code update, effective 10/01/2021.

The following ICD-10 CM code has been added to this policy:

C56.3 Malignant neoplasm of bilateral ovaries

Revisions From MA08.072g:

01/18/2021

This policy has been updated to communicate the revised medical necessity criteria, including dosing and frequency requirements, which reflects the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia. Additionally, the coverage of non-preferred products has been further clarified.

The following indication was added to the policy: hepatocellular carcinoma (HCC)

The following indication was removed from this policy, in alignment with NCCN compendia: AIDS-related Kaposi's sarcoma.

The following indications were revised, per FDA or NCCN:

CNS Tumors
Cerival Carcinoma
Colon or Rectal Carcinoma
Malignant Pleural Mesothelioma
NSCLC
Ovarian, Fallopian tube, or primary peritoneal cancer
Vulvar Cancer

The following ICD-CM codes have been added to this policy:

C22.0 Liver cell carcinoma

C22.1 Intrahepatic bile duct carcinoma

C22.2 Hepatoblastoma

C22.3 Angiosarcoma of liver

C22.4 Other sarcomas of liver

C22.7 Other specified carcinomas of liver

C22.8 Malignant neoplasm of liver, primary, unspecified as to type

C22.9 Malignant neoplasm of liver, not specified as primary or secondary

The following ICD-CM codes have been deleted from this policy:

C46.0 Kaposi's sarcoma of skin

C46.1 Kaposi's sarcoma of soft tissue

C46.2 Kaposi's sarcoma of palate

C46.3 Kaposi's sarcoma of lymph nodes

C46.4 Kaposi's sarcoma of gastrointestinal sites

C46.50 Kaposi's sarcoma of unspecified lung

C46.51 Kaposi's sarcoma of right lung

C46.52 Kaposi's sarcoma of left lung

C46.7 Kaposi's sarcoma of other sites

C46.9 Kaposi's sarcoma, unspecified

Revisions From MA08.072f:

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 MA08.073f.

Revisions From MA08.072e:

10/01/2019

This policy has been identified for the HCPCS code update, effective 10/01/2019.

The following HCPCS code has been added to this policy:
Q5118 Injection, bevacizumab-bvzr, biosimilar, (Zirabev), 10 mg

Revisions From MA08.072d:

06/17/2019

This policy has undergone a routine review and the medical necessity criteria, including dosing and frequency requirements, have been revised to reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

Revisions From MA08.072c:

01/01/2019

This policy has been identified for the HCPCS code update, effective 01/01/2019.

The following HCPCS code has been added to this policy:
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

The following HCPCS code has been removed from this policy:
J3590 Unclassified biologics

Revisions From MA08.072b:

09/20/2017

This Policy was updated to include the new biosimilar, bevacizumab-awwb (Mvasi™). This Policy was also updated in consideration of FDA labeling, National Comprehensive Cancer Network (NCCN), and Ophthalmology review.

Revisions From MA08.072a:

11/10/2016

This policy has been reissued in accordance with the company's annual review process.

05/20/2015

This policy and the corresponding dosing and frequency attachment has been modified to reflect changes in coverage, per updates from the US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN), including the addition of Medical Necessity criteria for cervical, uterine, and endometrial cancers.

Medical Necessity was expanded to include any vascular diseases of the eye when performed by an ophthalmologist that are FDA-approved or that meet the requirements as an accepted-off-label use, as defined in the Company’s medical policy for off-label coverage for prescription drugs and biologics.

Revisions From MA08.072:

01/01/2015

This is a new policy.

Version Effective Date:

1/1/2025

Version Issued Date:

12/30/2024

Version Reissued Date: