Commercial

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), bevacizumab-nwgd (Jobevne) in the following cancers: 

​

​​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) (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 the 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 and 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 disease ​ in 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 ultrahypermutated 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 ultrahypermutated 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 ultrahypermutated 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 nonintensive 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 ultrahypermutated 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 ultrahypermutated 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 antiangiogenic 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 ultrahypermutated 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 ultrahypermutated phenotype [e.g., TMB >50 mut/Mb]) for any of the following:
  
• as the NCCN-preferred antiangiogenic 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 ultrahypermutated 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​
  

• ​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 ultrahypermutated 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 nonintensive 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 ultrahypermutated 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 ultrahypermutated 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 ultrahypermutated 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 ultrahypermutated 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 ultrahypermutated 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 regimens:
• 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 preoperative 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 preoperative 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 note​s: *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 note​s: *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 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.

• 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 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.​

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 note​s: *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 4-6 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-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 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 response (CR) or partial response (PR) 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 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 PR 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 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 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 

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​​​

• 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: 
  
  
• for isolated metastases
• for 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. ​

EXPERIMENTAL/INVESTIGATIONAL

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

MANDATES  

PENNSYLVANIA MEMBERS

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

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.