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 #:

MA08.072p

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

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™), bevacizumab-maly (Alymsys), bevacizumab-adcd (Vegzelma), and bevacizumab-nwgd (Jobevne) in the following cancers:

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], bevacizumab-adcd [Vegzelma], bevacizumab-nwgd [Jobevne]), there is no reliable evidence of the superiority of any one product of bevacizumab compared to other products. The Company has designated the following bevacizumab biosimilar products as its preferred products: bevacizumab-awwb (Mvasi) and bevacizumab-bvzr (Zirabev).

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

According to the US 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 (PS) (Eastern Cooperative Oncology Group [ECOG] 0-1, with good biliary drainage and adequate nutritional intake) in combination with any of the following:

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 one of intestinal types:

unresectable localized disease
stage IV resected ampullary cancer
metastatic disease at initial presentation

First-line therapy for intestinal type in select individuals with poor PS and ECOG PS 2 for intestinal-type metastatic disease
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

Therapy for disease progression in individuals with good PS 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
Therapy for disease progression in select individuals with poor PS and ECOG PS 2 with intestinal type, depending on the regimen used in first line, in combination with any of the following:

Capecitabine
Fluorouracil and leucovorin
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)

Pediatric Medulloblastoma: Children and Adolescents

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 for any of the following:

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 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, 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

Meningiomas:

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

Primary Spinal Cord Tumors:

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

Treatment for recurrent or progressive diseasein individuals with 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, adult glioblastoma, high-grade glioma: Other, with any of the following regimens:

as a single agent (NCCN preferred)
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) for any of the following:

local/regional recurrence
stage IVB or distant metastases

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

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 (NCCN-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

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

Preferred first-line, second-line, or subsequent therapy as clinically appropriate (if not used previously as first-line) in combination with atezolizumab, paclitaxel, and cisplatin or carboplatin and continued for maintenance therapy^ for any of the following:

locoregional recurrence
stage IVB or recurrence with distant metastases

NCCN note: ^Atezolizumab and bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

Second-line or subsequent therapy as a single agent for any of the following:

local/regional recurrence
stage IVB 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^

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) or neoadjuvant/definitive immunotherapy (dMMR/MSI-H) if intensive therapy recommended with any of the following:

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

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) or neoadjuvant/definitive immunotherapy (dMMR/MSI-H) if intensive therapy not recommended with any of the following:

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 PS) 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) for any of the following:

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) for any of the following:

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

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb] and not a candidate for immunotherapy) that are unresectable or medically inoperable in combination with any of the following:

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

NCCN preferred anti-angiogenic therapy as initial treatment for individuals with unresectable metachronous metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb] and are not candidates for immunotherapy) and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months for any of the following:

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

Second-line and subsequent therapy for progression of advanced or metastatic disease (proficient mismatch repair/microsatellite-stable [pMMR/MSS] and are not 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) for any of the following:

as the NCCN 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 (NCCN preferred), irinotecan and oxaliplatin, irinotecan (NCCN preferred), or FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin), if not previously given and if previously treated without irinotecan or oxaliplatin

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) in combination with trifluridine and tipiracil (NCCN preferred), if not previously given and in individuals who have progressed through all available regimens

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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]), 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 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb] 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) in combination with trifluridine and tipiracil (NCCN 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]), 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]: deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) and individual is not a candidate for immunotherapy) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months for any of the following 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 PS) 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 with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) 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 not previously given and if previously treated with irinotecan-based therapy without oxaliplatin
NCCN preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI, if not previously given and 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 not previously given and if previously treated without irinotecan or oxaliplatin

Appendiceal Neoplasms and Cancers

As neoadjuvant systemic therapy in combination with capecitabine or fluorouracil/leucovorin if intensive therapy is not recommended for any of the following:

biopsy-proven recurrence of high-risk disease and no previous cytoreductive surgery
metastatic disease in peritoneal-only

As neoadjuvant systemic therapy in combination with CAPEOX (capecitabine, oxaliplatin), FOLFIRI (fluorouracil, leucovorin, irinotecan) regimen, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) regimen, or FOLFOX (fluorouracil, leucovorin, oxaliplatin) regimen if intensive therapy is recommended for any of the following:

biopsy-proven recurrence of high-risk disease and no previous cytoreductive surgery
metastatic disease in peritoneal-only

As initial therapy* in combination with capecitabine, fluorouracil/leucovorin, FOLFIRI (fluorouracil, leucovorin, irinotecan) regimen, or FOLFOX (fluorouracil, leucovorin, oxaliplatin) regimen for any of the following:

metastatic disease in peritoneal-only with low-grade peritoneal deposits or pathology of peritoneal deposits unknown and diagnostic laparoscopy and/or CT scan suggests complete cytoreductive surgery is not possible
recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
extraperitoneal disease

NCCN note: *Prolonged chemotherapy exposure is not recommended for individuals who are not demonstrating a clinical response.

As initial therapy in combination with capecitabine or fluorouracil/leucovorin if intensive therapy is not recommended for any of the following:

recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
extraperitoneal disease

As initial therapy in combination with CAPEOX (capecitabine, oxaliplatin), FOLFIRI (fluorouracil, leucovorin, irinotecan) regimen, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) regimen, or FOLFOX (fluorouracil, leucovorin, oxaliplatin) regimen if intensive therapy is recommended for any of the following:

recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
extraperitoneal disease

Second-line and subsequent therapy (if not previously given) in combination with irinotecan, irinotecan and oxaliplatin regimen, CAPEOX (capecitabine, oxaliplatin) regimen, FOLFIRI (fluorouracil, leucovorin, irinotecan) regimen, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) regimen, or FOLFOX (fluorouracil, leucovorin, oxaliplatin) regimen for any of the following:

recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic peritoneal-only disease
extraperitoneal disease

Second-line and subsequent therapy (if not previously given) in combination with trifluridine and tipiracil (bevacizumab combination preferred) and individual has progressed through all available regimens besides fruquintinib, regorafenib or trifluridine/tipiracil with or without bevacizumab for any of the following:

recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic peritoneal-only disease
extraperitoneal disease

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 for any of the following:

as initial therapy if proficient mismatch repair/microsatellite-stable (pMMR/MSS)
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 and proficient mismatch repair/microsatellite-stable (pMMR/MSS)
Initial therapy in combination with capecitabine or 5-FU/leucovorin (fluorouracil and leucovorin) regimen for advanced or metastatic disease and proficient mismatch repair/microsatellite-stable (pMMR/MSS) in individuals not appropriate for intensive therapy
Initial therapy in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) for advanced or metastatic disease and proficient mismatch repair/microsatellite-stable (pMMR/MSS) 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) in combination with atezolizumab for the treatment of individuals who have not received prior systemic therapy
Subsequent-line systemic therapy* (if not previously used) in combination with atezolizumab if progression on or after systemic therapy
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

NCCN note: *For those who have not been previously treated with a checkpoint inhibitor.

KIDNEY CANCER

In individuals with metastatic renal cell carcinoma in combination with interferon alfa.
Treatment for relapse or stage IV disease 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 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 (NCCN 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 PS 0-2 and clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in individuals with 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

As first-line systemic therapy in combination with pemetrexed and (cisplatin or carboplatin) (NCCN preferred for epithelioid histology) for*^% for any of the following:

adjuvant treatment of medically operable disease and complete cytoreduction achievable; with pre-operative low-risk features^ following cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), if presence of any surgical/pathologic high-risk^‡ features
medically operable disease and complete cytoreduction achievable; with pre-operative low risk features^ if progression following CRS + HIPEC if no prior adjuvant systemic therapy given
medically inoperable disease; complete cytoreduction not achievable, or presence of any high-risk features^‡

NCCN notes: *May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma.
^% Best supportive care is recommended for individuals presenting with PS 3-4.
^Low-risk features: epithelioid histology; absence of any high-risk features.
^‡High-risk features: biphasic/sarcomatoid histology, nodal metastasis, Ki-67 >9%, thrombocytosis, PS=2, bicavitary disease, high disease burden/incomplete cytoreduction (Peritoneal Cancer Index [PCI] >17, completeness of cytoreduction [cc] score >1).

Used in combination with (cisplatin or carboplatin) and pemetrexed (NCCN preferred for epithelioid histology) as first-line systemic therapy*^ for any of the following:

clinical stage I disease and epithelioid histology as initial treatment
clinical stage II-IV disease and epithelioid histology, sarcomatoid or biphasic histology (any stage), or if medically inoperable as initial treatment
clinical stage I disease and epithelioid histology following surgical exploration (if induction systemic therapy not given)

NCCN notes: *May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma.
^Best supportive care is recommended for individuals presenting with PS 3-4.

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 in combination with pemetrexed and (cisplatin or carboplatin)

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

Subsequent systemic therapy*^% in combination with atezolizumab if not previously treated with immune checkpoint inhibitors

NCCN notes: *May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma.
^% Best supportive care is recommended for individuals presenting with PS 3-4.

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

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

^%Best supportive care is recommended for individuals presenting with PS 3-4.

Used in combination with (cisplatin or carboplatin) and pemetrexed (NCCN preferred) as induction systemic therapy*^ prior to surgical exploration for clinical stage I disease and epithelioid histology

NCCN notes: *May also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma.
^Best supportive care is recommended for individuals presenting with PS 3-4.

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 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 PS 0-2 in combination with atezolizumab, carboplatin, and paclitaxel for nonsquamous cell histology
Treatment for recurrent, advanced, or metastatic disease in individuals with PS 0-2, tumors of nonsquamous cell histology, if contraindications** to PD-1 or PD-L1 inhibitors or if EGFR exon 19 deletion or L858R mutation; ALK, RET, or ROS1 gene fusion and no history of recent hemoptysis in combination with any of the following:

carboplatin and either paclitaxel or pemetrexed
cisplatin and pemetrexed

The above regimens are used for any of the following:

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
subsequent therapy for RET gene fusion positive tumors and prior pralsetinib, selpercatinib, or cabozantinib
first-line therapy for ERBB2 (HER2) mutation–positive tumors
first-line therapy for NRG1 gene fusion 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 alectinib, brigatinib, ceritinib, crizotinib, ensartinib, or lorlatinib
subsequent therapy for ROS1 rearrangement positive tumors and prior crizotinib, entrectinib, repotrectinib, taletrectinib, or lorlatinib
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 PS 0-2, 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 and no EGFR exon 19 deletion or L858R mutation; ALK, RET, or ROS1 gene fusion) 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 therapy for ERBB2 (HER2) mutation–positive tumors
first-line therapy for NRG1 gene fusion–positive tumors
subsequent therapy for EGFR S768I, L861Q, and/or G719X mutation positive–tumors and prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib 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 PS 0-2 in combination with atezolizumab, carboplatin and paclitaxel for nonsquamous cell histology
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 PS 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology with no history of recent hemoptysis
Continuation maintenance therapy for recurrent, advanced, or metastatic disease with PD-L1 expression <1% that are negative for actionable molecular biomarkers* (may be KRAS G12C mutation positive) in individuals with PS 0-2, 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 biomarker testing including molecular assessment of EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, NRG1, and ERBB2 (HER2), via biopsy and/or plasma testing. Treatment is guided by available results and, if unknown, these individuals are treated as though they do not have driver oncogenes. For those who require an urgent start to therapy but biomarker testing is pending, consider holding immunotherapy for one cycle, unless confirmed that no driver mutations are present.
**Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents, and some oncogenic drivers (i.e., EGFR exon 19 deletion or L858R mutation; ALK, RET, or ROS1 gene fusion) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors

OVARIAN CANCER

Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

For the treatment of individuals who are poor surgical candidates or have low likelihood of optimal cytoreduction in combination with carboplatin and either paclitaxel or docetaxel (NCCN preferred with paclitaxel), or with oxaliplatin and docetaxel for any of the following:

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

NCCN note: *Bevacizumab-containing regimens should be used with caution and withheld for 4 to 6 weeks prior to IDS due to potential interference with postoperative healing.

As primary adjuvant therapy for pathologic stage II-IV disease in combination with paclitaxel or docetaxel and carboplatin (NCCN preferred with paclitaxel)
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
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-preferredtargeted therapy as a single agent for persistent disease or recurrence (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 (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 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 complete remission or partial remission to primary therapy including bevacizumab for any of the following regimens:

as a single agent in individuals BRCA1/2 wild-type or unknown and HR proficient or status unknown
in combination with olaparib (or niraparib if unable to tolerate 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 for any of the following:

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 (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)

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting.

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 [≥25% positive tumor cells]), or gemcitabine (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

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 any of the following:

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 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)

Neoadjuvant systemic therapy for those who are poor surgical candidates or have low likelihood of optimal cytoreduction for any of the following:

in combination with oxaliplatin and docetaxel
in combination with carboplatin and paclitaxel or docetaxel (NCCN preferred with paclitaxel)

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 (NCCN 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) 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 (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) for any of the following:

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 (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)

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting.

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) (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
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

Neoadjuvant systemic therapy for those who are poor surgical candidates or have low likelihood of optimal cytoreduction in combination with any of the following:

oxaliplatin and docetaxel
carboplatin and paclitaxel or docetaxel (NCCN preferred with paclitaxel)

Adjuvant treatment in combination with any of the following:

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

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

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting

As NCCN-preferred targeted therapy as a single agent for persistent disease or recurrence (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 (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 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; [≥25% positive tumor cells]) 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

As an NCCN-preferred targeted therapy as a single agent for persistent disease or recurrence 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 (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) or docetaxel for pathologic stage II-IV, grade 1 endometrioid carcinoma
For persistent disease or recurrence for any of the following:

as immediate treatment for serially rising CA-125 in individuals that previously received chemotherapy (platinum-sensitive or platinum-resistant)*
for progression on primary, maintenance, or recurrence therapy (platinum-resistant)*
for stable or persistent disease (if not on maintenance therapy) (platinum-resistant)*
for complete remission and relapse <6 months after completing chemotherapy (platinum-resistant)*
in individuals with complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive)

in combination with any of the following:

carboplatin and gemcitabine (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)

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

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting.

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), topotecan (NCCN preferred), mirvetuximab soravtansine-gynx (in folate receptor-alpha expressing tumors [≥25% positive tumor cells]
Used for platinum-sensitive or platinum-resistant* recurrence in combination with any of the following:

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)

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting.

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

Mucinous Neoplasms of the Ovary

Neoadjuvant systemic therapy for individuals who are poor surgical candidates or have low likelihood of optimal cytoreduction carboplatin and paclitaxel or docetaxel (NCCN preferred with paclitaxel)

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 any of the following:

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) 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
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:

carboplatin* and gemcitabine
carboplatin* and paclitaxel
carboplatin* and liposomal doxorubicin

NCCN note: *Platinum agents have limited activity when the disease has demonstrated growth through a platinum-based regimen, and platinum rechallenge is generally not recommended in this setting.

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

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 in combination with temozolomide, as NCCN-preferred therapy.

UTERINE CANCER/ ENDOMETRIAL CARCINOMA

Primary treatment in combination with carboplatin and paclitaxel (NCCN preferred) and continued as a single agent for maintenance therapy^ for individuals with stage III-IV endometrioid adenocarcinoma for any of the following:

preoperatively for individuals presenting with abdominal/pelvic-confined disease that is suitable for primary surgery
with or without external beam radiation therapy (EBRT), stereotactic body radiation therapy, and/or total hysterectomy/bilateral salpingo-oophorectomy (TH/BSO) for distant metastases that are suitable for primary surgery
with sequential EBRT and with or without brachytherapy for locoregional extrauterine disease that is not suitable for primary surgery
for locoregional extrauterine disease or distant metastases that are not suitable for primary surgery

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

Adjuvant treatment for surgically staged individuals in combination with carboplatin and paclitaxel (NCCN preferred) and continued as a single agent for maintenance therapy^ with or without EBRT and with or without vaginal brachytherapy for stage III-IV endometrioid adenocarcinoma

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

In combination with carboplatin and paclitaxel (NCCN preferred) and continued as a single agent for maintenance therapy^ for stage III-IV tumors including serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, or carcinosarcoma for any of the following:

that is suitable for primary surgery as additional treatment with or without sequential EBRT and with or without vaginal brachytherapy after total hysterectomy/bilateral salpingo-oophorectomy (TH/BSO)
that is not suitable for primary surgery as primary treatment with or without sequential EBRT and with or without brachytherapy

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

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 recurrent disease for any of the following:

therapy for isolated metastases
for disseminated metastases with or without sequential palliative EBRT
after surgical exploration, with sequential EBRT for locoregional recurrence (not confined to vagina or paravaginal soft tissue) in individuals with pelvic or para-aortic lymph node disease
after surgical exploration, with or without sequential EBRT for locoregional recurrence (not confined to vagina or paravaginal soft tissue) in individuals with microscopic residual upper abdominal/ peritoneal disease
with or without sequential palliative EBRT or brachytherapy for locoregional recurrence in individuals who have received prior EBRT to site of recurrence

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

Second-line or subsequent therapy as a single agent for recurrent disease that has progressed on prior cytotoxic chemotherapy for (except for therapy with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with no prior radiation therapy to site of recurrence, or previous vaginal brachytherapy only; therapy after surgical exploration, with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with disease confined to the vagina or paravaginal soft tissue) for any of the following indications:

isolated metastases
disseminated metastases with or without sequential palliative EBRT
with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with no prior RT to site of recurrence, or previous brachytherapy only
after surgical exploration, with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with disease confined to the vagina or paravaginal soft tissue
after surgical exploration, with sequential EBRT for locoregional recurrence (not confined to vagina or paravaginal soft tissue) in individuals with pelvic or para-aortic lymph node disease
after surgical exploration, with or without sequential EBRT for locoregional recurrence (not confined to vagina or paravaginal soft tissue) in individuals with microscopic residual upper abdominal/ 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

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 tumors (combined positive score [CPS] ≥1) for one of the following:

local/regional recurrence if prior intracavitary brachytherapy only, or prior EBRT with or without brachytherapy and noncentral disease
stage IVB or recurrent 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 (NCCN-preferred regimens), or in combination with paclitaxel and topotecan for one of the following:

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 one of the following:

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 paclitaxel and carboplatin or cisplatin (both preferred) and continued for maintenance therapy^ for any of the following:

as additional treatment following primary therapy with concurrent chemoradiation for locally advanced unresectable disease or initially unresectable nodes regardless of stage that is clinically suspicious for residual tumor at the primary site and/or nodes at least 3 months after completion of treatment and remains unresectable
as additional treatment following primary therapy with concurrent chemoradiation for locally advanced disease or initially unresectable nodes regardless of stage that is clinically suspicious for residual tumor at primary site and/or nodes at least 3 months after completion of treatment with positive margins for invasive disease following resection that was deemed operable
as primary treatment for metastatic disease beyond the pelvis (stage IVB)
for vulva-confined recurrence (nodes clinically and radiographically negative) previously irradiated and unresectable
for confirmed isolated inguinofemoral/pelvic lymph node recurrence if prior EBRT
for confirmed recurrence with distant metastasis or prior pelvic EBRT

NCCN note: ^Bevacizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

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 pembrolizumab, paclitaxel and cisplatin or carboplatin (both preferred) and continued for maintenance therapy^ for any of the following:

as additional treatment following primary therapy with concurrent chemoradiation for locally advanced unresectable disease or initially unresectable nodes regardless of stage that is clinically suspicious for residual tumor at the primary site and/or nodes at least 3 months after completion of treatment and remains unresectable
as additional treatment following primary therapy with concurrent chemoradiation for locally advanced disease or initially unresectable nodes regardless of stage that is clinically suspicious for residual tumor at primary site and/or nodes at least 3 months after completion of treatment and with positive margins for invasive disease following resection that was deemed operable
as primary treatment for metastatic disease beyond the pelvis (stage IVB)
for vulva-confined recurrence (nodes clinically and radiographically negative) previously irradiated and unresectable
for confirmed isolated inguinofemoral/pelvic lymph node recurrence if prior EBRT
for confirmed recurrence with distant metastasis or prior pelvic EBRT

NCCN note: ^Bevacizumab and pembrolizumab may be continued as a maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules.

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.

ADDITIONAL INDICATIONS

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

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

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.

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.

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

The PD-L1 IHC 22C3

pharmDx test 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.

Peritoneal Cancer Index (PCI)

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 use of bevacizumab 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]. 11/13/25. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 21, 2025.

Bevacizumab (Avastin®) labeling. Genentech, Inc., South San Francisco, CA. 09/2022. Available at: https://www.avastin-hcp.com/. Accessed December 21, 2025.

Eastern Cooperative Oncology Group (ECOG). ECOG performance status. Available at: http://ecog-acrin.org/resources/ecog-performance-status. Accessed December 21, 2025.

Elsevier’s Clinical Pharmacology Compendium. Bevacizumab (Avastin®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™). 12/11/2025. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/monograph/2709?n=Avastin [via subscription only]. Accessed December 21, 2025.

Lexi-Drugs Compendium. bevacizumab (Avastin). 12/20/2025. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 21, 2025.

Mvasi (bevacizumab-awwb) labeling. Amgen Inc., Thousand Oaks, CA. 02/2023. Available at: https://www.mvasi.com/hcp. Accessed December 21, 2025.

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 December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Appendiceal Neoplasms and Cancers. v.1.2026. [NCCN Web site]. 10/30/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Pediatric Central Nervous System Cancers. v.1.2026. [NCCN Web site]. 11/25/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Ampullary Adenocarcinoma. v.2.2025. [NCCN Web site]. 01/10/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ampullary.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Central nervous system cancers. v.3.2025. [NCCN Web site]. 12/05/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Cervical cancer. v.2.2026. [NCCN Web site]. 11/10/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Colon cancer. v.5.2025. [NCCN Web site]. 10/30/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Hepatocellular carcinoma. v.2.2025. [NCCN Web site]. 10/22/2025. 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.1.2026. [NCCN Web site]. 07/24/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Malignant Pleural Mesothelioma. v.2.2026. [NCCN Web site]. 10/03/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer. v.2.2026. [NCCN Web site]. 12/02/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. v.3.2025. [NCCN Web site]. 07/16/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Rectal cancer. v.4.2025. [NCCN Web site]. 10/31/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Small bowel adenocarcinoma. v.4.2025. [NCCN Web site]. 10/31/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Soft Tissue Sarcoma. v.1.2025. [NCCN Web site]. 05/02/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms. v.2.2026. [NCCN Web site]. 11/14/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Vaginal cancer (Squamous cell carcinoma). v.2.2026. [NCCN Web site]. 12/04/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf. Accessed December 21, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Vulvar cancer (Squamous cell carcinoma). v.1.2026. [NCCN Web site]. 11/07/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf. Accessed December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Bevacizumab (Avastin®), bevacizumab-awwb (Mvasi™), bevacizumab-bvzr (Zirabev™). 08/20/2025. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ [via subscription only]. Accessed December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

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 December 21, 2025.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment A.

HCPCS Level II Code Number(s)

C9257 Injection, bevacizumab, 0.25 mg

J9035 Injection, bevacizumab, 10 mg

Q5107 Injection, bevacizumab, 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

Q5160 Injection, bevacizumab-nwgd (Jobevne), biosimilar, 10 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.072p:

03/23/2026

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
Hepatobiliary 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 ICD-10 codes have been removed from this policy:

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 added to this policy:

C50.A1 Malignant inflammatory neoplasm of right breast

C50.A2 Malignant inflammatory neoplasm of left breast

Z17.32 Human epidermal growth factor receptor 2 negative status

The following HCPCS code has been added to this policy:
Q5160 – Injection, bevacizumab-nwgd (Jobevne), biosimilar, 10 mg will be added.

Revisions From MA08.072o:

01/01/2025

The following indications were revised, per FDA or NCCN:

CNS tumors
Cervical carcinoma
Colon or rectal carcinoma
Hepatobiliary 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

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 lymphoma, 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
Cervical 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:

3/23/2026

Version Issued Date:

4/6/2026

Version Reissued Date: