Pending Policies - Prescription Drugs


Bevacizumab (Avastin) For Oncology Indications

Number:RX501.070

Effective Date:11-01-2018

Coverage:

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Bevacizumab may be considered medically necessary for the following U.S. Food and Drug Administration (FDA) labeled indications when the listed criteria are met.

DISEASE

CRITERIA

Cervical Cancer

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

Colon and Rectal Cancer-metastatic (mCRC)

Metastatic colorectal cancer, in combination with intravenous 5-FU based chemotherapy for first- or second-line treatment.

Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen.

Glioblastoma- recurrent

Recurrent glioblastoma in adults.

Non-Small Cell Lung Cancer (NSCLC) Non-Squamous

Unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC, in combination with carboplatin and paclitaxel for first-line treatment.

 

Ovarian, Fallopian Tube, or Primary Peritoneal Cancer- Epithelial

Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

Platinum-sensitive in combination with carboplatin and paclitaxel or carboplatin and gemcitabine followed by Avastin as a single agent.

Renal Cell Carcinoma- metastatic (mRCC)

Metastatic renal cell carcinoma in combination with interferon alfa.

Table key: 5-FU: 5-fluorouracil; FDA: Food and Drug Administration; mRCC: Metastatic Renal Cell Carcinoma; NSCLC: Non-small Cell Lung Cancer.

 

Bevacizumab may be considered medically necessary for the following off-label indications when the listed criteria are met.

Disease

Histology

Off-Label Indication/Criteria

AIDS-Related Kaposi Sarcoma

N/A

Subsequent systemic therapy given with antiretroviral therapy for relapsed/refractory advanced, cutaneous, oral, visceral, or nodal disease that:

  • Has progressed on or not responded to first-line systemic therapy; and
  • Progressed on alternate first-line systemic therapy.

Breast Cancer-Invasive

 

Ductal; Lobular; Mixed; Metaplastic; Tubular; Mucinous; Inflammatory; Papillary; Unknown.

 

In combination with paclitaxel (useful in certain circumstances, in select patients with high tumor burden, rapidly progressing disease, and visceral crisis) for recurrent or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-negative breast cancer:

  • With symptomatic visceral disease for visceral crisis.
  • That is hormone receptor-negative or hormone. receptor-positive and endocrine therapy refractory.

Central Nervous System Cancers

Anaplastic Gliomas and Glioblastomas

Treatment for recurrent anaplastic gliomas when used:

  • As a single agent; or
  • In combination with irinotecan, carmustine, lomustine, temozolomide, or carboplatin if monotherapy fails.

Adult intracranial and spinal ependymoma

(excluding Subependymoma)

As single-agent treatment for disease progression in adult patients with recurrent intracranial and spinal ependymoma cancer (excluding subependymoma).

Cervical Cancer

Squamous cell carcinoma; Adenocarcinoma

 

 

First-line or second-line therapy (if not previously used as first-line) in combination with paclitaxel and cisplatin, carboplatin, or topotecan, or second-line therapy as a single agent for:

  • Local/regional recurrence.
  • Stage IVB or distant metastases.

Colon Cancer

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Adenocarcinoma

 

 

 

 

Therapy used in combination with capecitabine or with FOLFOX, FOLFIRI, CapeOX, FOLFOXIRI, or 5-FU/LV regimen:

  • As primary treatment for locally unresectable or medically inoperable disease.
  • For unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy.
  • As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with imminent or existing obstruction.
    • For unresectable synchronous metastases of other sites.
    • As primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous 5-FU/LV or capecitabine therapy, or who have not received an previous chemotherapy.
    • For unresectable metachronous metastases that remain unresectable after primary treatment.

Initial treatment for unresectable synchronous liver and/or lung metastases in combination with:

  • FOLFOX regimen.
  • FOLFIRI regimen.
  • FOLFOXIRI regimen.
  • Cape OX regimen.

Therapy in combination with capecitabine or with FOLFOX, FOLFIRI, CapeOX, FOLFOXIRI or 5-FU/LV regimen:

  • As adjuvant treatment following synchronized or staged resection for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment.
  • As adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy.
  • As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment.

Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX, or CapeOX within the past 12 months when used:

  • In combination with irinotecan.
  • In combination with FOLFIRI regimen.

Subsequent therapy for progression of unresectable advanced or metastatic disease when used:

  • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI regimen for disease previously treated with oxaliplatin-based therapy without irinotecn.
  • In combination with FOLFOX or CapeOX regimen for disease previously treated with irinotecan-based therapy without oxaliplatin.
  • As the preferred anti-angiogenic agent in combination with irinotecn or FOLFIRI in patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.
  • In combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin in patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.

Malignant Pleural Mesothelioma

Epithelial, Sarcomatoid, Mixed

Used in combination with cisplatin and pemetrexed followed by single-agent maintenance bevacizumab as treatment of:

  • Unresectable clinical stage I-III disease and tumors of epithelial histology.
  • Clinical stage IV disease, tumors or sarcomatoid or mixed histology, or medically inoperable tumors in patients with performance status (OS) 0-2.

Non-Small Cell Lung Cancer (NSCLC)

Adenocarcinoma (with mixed subtypes); Large cell carcinoma

 

 

Treatment in combination with carboplatin and paclitaxel or pemetrexed or in combination with cisplatin and pemetrexed for recurrent or metastatic disease in patients with performance status 0-1, tumors of non-squamous cell histology, and no history of recent hemoptysis when used as:

  • Initial cytotoxic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PD-L1 <50% or unknown.
  • First-line or subsequent therapy for BRAF V600E-mutation positive tumors.
  • Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitnib, or osimertinib therapy.
  • Subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigantinib therapy.
  • Subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy.
  • Subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK, ROS1, and BRAF negative or unknown and prior pembrolizumab therapy.

Continuation maintenance therapy if given first line with chemotherapy for recurrent or metastatic disease in patients with performance status 0-2, tumors of nonsquamous cell histology, and no history of recent hemoptysis who achieve tumor response or stable disease following initial cytotoxic therapy when used:

  • As a single agent.
  • In combination with pemetrexed if previously used with a first-line pemetrexed/platinum chemotherapy regimen.

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer-Epithelial

 

 

Serous; Endometrioid

 

 

 

 

 

Consider as neoadjuvant chemotherapy in combination with paclitaxel and carboplatin for bulky stage III-IV disease or poor surgical candidates.

NOTE 1: Bevacizumab-containing regimens should be used with caution before interval debulking surgery due to potential interference with postoperative healing.

Used in combination with paclitaxel and carboplatin as

  • Primary treatment for patients with incomplete previous surgery and/or staging with suspected stage IA-IB, greade 2-3 or clear cell, or stage IC and no suspected residual disease.
  • Primary treatment for patients with incomplete previous surgery and/or staging with stage II-IV and suspected unresectable residual disease.
  • Primary adjuvant therapy for pathologic stage IA-IB (grade 2 serous/endometrioid or grade 3), stage IC (grades 1-3), or stage II-IV disease.

Serous; Endometrioid; Carcinosarcoma; Clear cell; Mucinous

 

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

Post-remission maintenance therapy as a single agent if used previously as part of a combination therapy, for patients with partial or complete remission following primary therapy for stage II-IV disease recurrence therapy for platinum-sensitive disease.

Therapy for persistent disease or recurrence when used as:

  • Preferred therapy if platinum-sensitive, in combination with carboplatin and gemcitabine;
  • If platinum-sensitive, in combination with carboplatin and paclitaxel;
  • As preferred therapy if platinum-resistant, in combination with liposomal doxorubicin, weekly paclitaxel, or topotecan;
  • As preferred therapy when used as a single agent.

Maintenance therapy for platinum-sensitive persistent disease or recurrence following response to combination therapy with:

  • Carboplatin, gemcitabine, and bevacizumab;
  • Carboplatin, paclitaxel, and bevacizumab.

Carcinosarcoma

(Malignant Mixed Müllerian Tumors)

Preferred adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage I-IV disease.

Clear cell

Adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV disease.

Mucinous

Adjuvant treatment for pathologic stage II-IV disease when used in combination with:

  • Carboplatin and paclitaxel;
  • Fluorouracil, leucovorin, and oxaliplatin;
  • Capecitabine and oxaliplatin.

Therapy for persistent disease or recurrence when used in combination with:

  • Fluorouracil, leucovorin, and oxaliplatin;
  • Capecitabine and oxaliplatin.

Grade 1 Serous/Endometrioid Epithelial Carcinoma

Adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV low-grade serous/grade 1 endometrioid epithelial carcinoma or borderline epithelial tumors with invasive implants.

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer-Malignant Sex Cord-Stromal Tumors

N/A

 

 

Single agent for clinical relapse in patients with stage II-IV disease.

Rectal Cancer

Adenocarcinoma

 

Therapy used in combination with capecitabine or with FOLFOX, FOLFIRI, FOLFOXIRI regimen, CapeOX, or 5-FU/leucovorin regimen when used:

  • As primary treatment for T3, any N; any T1-2, N1-2; T4, any N; and/or locally unresectable or medically inoperable disease with no metastases if resection is contraindicated following neoadjuvant therapy.
  • For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy.
  • Following short-course radiation therapy or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy.
  • As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction.
  • As primary treatment for synchronous unresectable metastases of other sites.
  • As primary treatment for  unresectable metachronous metastases in patients 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.
  • For unresectable metachronous metastases that remain unresectable after primary treatment.
  • Adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastses in patients who have received previous chemotherapy or had growth on neodjuvant chemotherapy.
  • Adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment.

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

  • FOLFIRI regimen;
  • FOLFOX regimen;
  • CapeOx regimen;
  • FOLFOXIRI regimen.

Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX or CapeOX regimen within the past 12 months:

  • In combination with irinotecan.
  • In combination with FOLFIRI regimen

Subsequent therapy after progression for unresectable advanced or metastatic disease:

  • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI regimen for disease previously treated with oxaliplatin-based therapy without irinotecan.
  • In combination with FOLFOX or CapeOX regimen for disease previously treated with irinnotecan-based therapy without oxaliplatin.
  • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.
  • In combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.

Renal Cell Carcinoma (RCC) (Kidney Cancer)

Clear cell; Non-clear cell

 

 

Therapy for relapse or surgically unresectable stage IV kidney cancer when used:

  • In combination with interferon alfa-2b as first-line therapy for predominant clear cell histology.
  • As preferred single-agent subsequent therapy for predominant clear cell histology.
  • As single-agent systemc therapy for non-clear cell histology.
  • In combination with erlotinib or everolimus for select patients with advanced papillary renal cell carcinoma including hereditary leimyomatosis and renal cell cancer.

Soft Tissue Sarcoma-Angiosarcoma

None

Single agent therapy for angiosarcoma.

Soft Tissue Sarcoma-Solitary Fibrous Tumor/Hemangiopericytoma

None

 

In combination with temozolomide for the treatment of solitary fibrous tumor and hemangiopericytoma.

Uterine Neoplasms-Endometrial Carcinoma

Endometrioid adenocarcinoma; Serous or clear cell carcinoma; Undifferentiated/dedifferentiated carcinoma; Carcinosarcoma

Single-agent therapy for disease that has progressed on prior cytotoxic chemotherapy.

Table key: AIDS: Acquired Immunodeficiency Syndrome; N/A: Non-applicable; 5-FU/LV: Fluorouracil and leucovorin; ALK: Anaplastic lymphoma kinase; BRAF: Human gene type; CapeOX: Capecitabine and oxaliplatin; EGFR: Estimated glomerular filtration rate; FOLFIRI: Fluorouracil, leucovorin, and irinotecan; FOLFOX: Fluorouracil, leucovorin, and oxaliplatin; FOLFOXIRI: Fluorouracil, leucovorin, oxaliplatin, and irinotecan; N: node; PD-L1: Programmed Death-Ligand-1; ROS1: A gene that makes protein; T: tumor.

Bevacizumab is considered experimental, investigational and/or unproven for any other cancer indication not listed above, including but not limited to, the following indications:

  • Adjuvant therapy, following surgery for stage II or III adenocarcinoma of the colon; or
  • Metastatic adenocarcinoma of the pancreas; or
  • Monotherapy for metastatic colorectal cancer; or

NOTE 2: Please refer to additional Medical Policies if indicated:

Description:

Bevacizumab (Avastin) is a humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF) A. VEGF, and the receptors contribute to tumor growth and metastases by promoting angiogenesis. This medical policy examines the label and off-label use of bevacizumab in patients with select tumor types. Bevacizumab is produced in a Chinese Hamster Ovary in a nutrient medium containing the antibiotic gentamicin. The Gentamicin is not detectable in the final product. (1)

Tumor Staging

Tumor staging is the process of determining the extent to which a cancer has developed by spreading. Contemporary practice is to assign a number from I to IV to a cancer, with stage I being an isolated cancer, and stage IV being a cancer which has metastases to other regions of the body as shown in Table 2. The tumor stage generally considers the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes are involved, and whether it has appeared in more distant locations (metastasized). Staging is useful for the determination of which treatment regimen would be used for a select tumor indication. (2)

Table 2. Overall Staging Definitions (2)

Stage

Characteristics

I

Tumor has not spread and can be surgically excised.

II

Tumor has not spread, but is larger and possibly with greater penetration or depth to the surrounding area(s).

III

Tumor has spread to the lymph nodes of any thickness and unresectable.

IV

There are metastases to other regions of the body, irrespective of the tumor size or depth.

Clinical staging may also be accessed by the tumor, node, and metastasis (TNM) classification staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. The AJCC TNM system classifies cancers by:

• T – The size and extent of primary tumor; and

• N – The involvement of regional lymph nodes; and

• M – The presence or absence of distant metastases.

Additional numbering and lettering may be assigned to any of the TNM categories to more accurately describe the pathological stage (e.g., cT3N1M0 or pT2N0). There is a TNM staging algorithm for cancers of virtually every anatomic site and histology, with the primary exception of pediatric cancers, brain tumors, and hematological malignancies. TNM is useful for treatment options in the management of cancer. (2)

Typically, oncologists utilize the Eastern Cooperative Oncology Group (ECOG) Performance Status (3) to assess disease progression, evaluate the physical status of an individual, and to determine a general prognosis and individual treatment plan (see table 1).

Table 1: 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 selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.

3

Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours.

4

Completely disabled; cannot carry on any selfcare; totally confined to bed or chair.

5

Dead.

Regulatory Status

In 2004, bevacizumab was approved by the U.S. Food and Drug Administration (FDA). Subsequently, the FDA expanded the labeled indications for bevacizumab to include the use in metastatic colorectal cancer, cervical cancer, recurrent glioblastoma (in adults), metastatic renal cell carcinoma (mRCC), nonsquamous non-small cell lung cancer (NSCLC), and recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer. Refer to <https://www.fda.gov> for the current FDA labelled indications. (1)

Bevacizumab is also given off-label for specific indications, including but not limited to the use in metastatic breast cancer, metastatic colorectal cancer (mCRC), nonsquamous NSCLC, glioblastoma, and ovarian cancer. (4, 5)

Black Box Warning

The U.S. FDA label (February 2017) provides the following black box warnings (1):

  • Gastrointestinal Perforations: Discontinue for gastrointestinal perforation.
  • Surgery and Wound Healing Complications: Discontinue in patients who develop wound healing complications that require medical intervention. Withhold for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed.
  • Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage

Terms and Definitions (6)

  • 5-FU: 5-fluorouracil.
  • 5-FU/LV: Fluorouracil and leucovorin.
  • Adjunctive treatment: Medicine that is given with cancer treatment but is for symptoms caused by the cancer.
  • Adjuvant chemotherapy: A type of cancer drug that is given after the main treatment used to cure the cancer.
  • Adjuvant treatment: Treatment that is given after the main treatment used to cure the cancer.
  • AIDS: Acquired Immunodeficiency Syndrome.
  • ALK: Anaplastic lymphoma kinase.
  • BRAF: Human gene type.
  • CA-125 (cancer antigen 125): A protein with sugar molecules made by ovarian cancer cells as well as normal cells.
  • CapeOX: Capecitabine and oxaliplatin.
  • Cervical cancer: Cancer that started in cells within the neck of the womb, which is called the cervix.
  • Colorectal cancer: Cancer that starts in the colon, rectum, or both.
  • Combination chemotherapy: The use of two or more chemotherapy drugs for treatment.
  • Complete remission: No cancer cells are found in the blood, bone marrow, or other parts of the body and all signs and symptoms of the cancer are gone.
  • Epithelial ovarian cancer: Cancer that starts in cells that form the outer layer of tissue that lines the ovaries.
  • Fallopian tube: The female organ through which an egg travels from an ovary to the womb.
  • FOLFIRI: Fluorouracil, leucovorin, and irinotecan.
  • FOLFOX: Fluorouracil, leucovorin, and oxaliplatin.
  • FOLFOXIRI: Fluorouracil, leucovorin, oxaliplatin, and irinotecan.
  • First-line treatment: The first set of treatments given to treat a disease.
  • Hormone receptor–negative: Cancer cells that do not use hormones to grow.
  • Hormone receptor–positive: Cancer cells that use hormones to grow.
  • Human epidermal growth factor receptor 2 (HER2): A protein on the edge of a cell that send signals for the cell to grow.
  • Interferon alfa (IFN): A drug used to activate the body's disease-fighting ability (immune system) to fight cancer cells.
  • Locally advanced cancer: Growth of cancer outside of the first (primary) tumor into nearby tissues.
  • Maintenance treatment /therapy: Treatment given to continue good treatment results.
  • Treatment given in a lower dose or less frequently to “maintain” good treatment results.
  • Metachronous metastases: The spread of cancer after treatment to sites far from the first tumor.
  • Metastasis: The spread of cancer cells from the first (primary) tumor to a distant site.
  • Metastatic: Containing cancer cells that have spread from the first tumor.
  • Metastatic recurrence: Cancer that has come back after treatment in tissues nearby or far from where the cancer started.
  • Monotherapy: The use of one type of therapy to treat a disease.
  • Neoadjuvant chemotherapy: Chemotherapy given to reduce the size of a tumor before surgery to remove it.
  • Neoadjuvant treatment: Treatment that is given before the main treatment used to cure a disease.
  • Nodule: A small mass of tissue.
  • Pathologic stage: A rating of the extent of cancer based on tests given after treatment.
  • Platinum-resistant: A lack of treatment response to a chemotherapy drug made with platinum.
  • Platinum-sensitive: A treatment response to a chemotherapy drug made with platinum.
  • Peritoneal cavity: The area inside the abdomen that contains the abdominal organs such as the intestines, stomach, and liver.
  • Persistent cancer: Cancer that is not completely removed or destroyed by treatment.
  • Primary treatment: The main treatment used to rid the body of cancer.
  • Primary tumor: The first mass of cancer cells in the body.
  • Progression or progressed: The growth or spread of cancer after being tested or treated.
  • Radiation therapy: The use of radiation to treat cancer.
  • Recurrent cancer: Cancer that has returned after a disease-free period.
  • Refractory: Disease that does not improve or go away in response to treatment.
  • Regional treatment: Treatment with cancer-killing drugs directed to a specific area of the body.
  • Relapsed: The worsening or return of cancer after a period of improvement.
  • Resectable: Cancer that can be removed by surgery.
  • Residual tumor: Cancer that was not removed during surgery.
  • ROS1: A gene that makes protein.
  • Second-line treatment: The next treatment used against a disease when the first treatment fails.
  • Single agent: One drug that is used for treatment.
  • Systemic therapy: Drugs that are used to treat cancer cells throughout the body.
  • Subsequent therapy: therapy that is administered after the first course of therapy is completed, stopped, or changed.
  • Symptom: A physical sign or patient report of a health condition.
  • Systemic therapy: Drugs that are used to treat cancer cells throughout the body.
  • Tumor burden: The extent of cancer in the body.
  • Unresectable: Cancer that can't be removed by surgery.
  • Visceral: Reference to the intestines that digest food; the gut.

Rationale:

This medical policy was created in 2009 and has been updated regularly with the MedLine database. Following is the key literature to date through April 24, 2018.

Acquired Immunodeficiency Syndrome (AIDS)-Related Kaposi Sarcoma

National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium

The 2018 National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (5) recommends the use of bevacizumab for subsequent systemic therapy when given with antiretroviral therapy (ART) for relapsed/refractory advanced, cutaneous, oral, visceral, or nodal disease that has progressed on or not responded to first-line systemic therapy and has progressed on alternate first-line systemic therapy. (category 2A).

The NCCN 2A recommendation is based on a phase II study performed in 2012 by Uldrick et al. (7, 8) Bevacizumab was accessed in 17 patients living with human immunodeficiency virus (HIV) and Kaposi sarcoma (HIV-KS) who had progressive or stable disease on antiretroviral therapy (ART). Thirteen patients had received prior chemotherapy for Kaposi sarcoma. The complete response rate was 19% and their partial response rate was 12% for an overall response rate of 31% (95%CI, 11% to 59%). Adverse events included hypertension (n=7), neutropenia (n=5), cellulitis (n=3) and headache (n=2). Bevacizumab was tolerated in patients with HIV-KS and has activity in a subset of patients.

Breast Cancer - Invasive (Ductal; Lobular; Mixed; Metaplastic; Tubular; Mucinous; Inflammatory; Papillary; Unknown)

In 2007, Miller et al. (9) completed an open-label, randomized, phase III study, women with metastatic breast cancer (n=722) treated with bevacizumab plus paclitaxel had significantly improved progression-free survival (PFS) compared to patients who received paclitaxel alone. Patients with metastatic breast cancer, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero or one, no prior therapy for metastatic disease (hormonal therapy or cytotoxic adjuvant therapy was allowed and previous adjuvant taxane therapy was permitted if patients had a disease-free interval of at least 12 months after treatment), and any human epidermal growth factor receptor type-2 (HER2) status (HER2-positive breast cancer permitted only if patients had previously received trastuzumab) were randomized to receive either intravenously paclitaxel 90 mg/m2 on days 1, 8, and 15 plus bevacizumab 10-mg/kilogram (kg) intravenously on days one and 15 of a 28-day cycle (n=368; median duration of paclitaxel therapy, 7.1 months) or paclitaxel alone (n=354; median duration of paclitaxel therapy, 5.1 months) until disease progression or unacceptable toxicity. Disease response was evaluated at baseline and every 12 weeks until progression using the Response Evaluation Criteria in Solid Tumors (RECIST). Twenty-one and 28 patients in the paclitaxel + bevacizumab and paclitaxel alone treatment groups, respectively, were considered ineligible by the investigators; therefore, 347 patients in the paclitaxel + bevacizumab arm (median age, 56 years [year]; range, 29-84 year; median duration of follow-up, 41.6 months) and 326 patients in the paclitaxel alone arm (median age, 55 years; range, 27-85 year; median duration of follow-up, 43.5 months) were included in the efficacy analysis. PFS was significantly improved in patients who received paclitaxel + bevacizumab compared to patients who received paclitaxel alone (11.8 months vs. 5.9 months; Hazard ratio [HR]=0.6; 95% CI, 0.51-0.7; p less than 0.001). Objective response rates (ORR) were also significantly improved in the paclitaxel + bevacizumab arm (36.9%) compared to the paclitaxel alone arm (21.2%; p less than 0.001). There was no significant difference in the secondary endpoint of overall median survival between the two treatment arms (26.7 months vs. 25.2 months; HR=0.88; p=0.16); however, the one-year survival rate was higher in the paclitaxel + bevacizumab arm (81.2% vs. 73.4%; p=0.01). Additionally, most patients’ deaths (88.8%) were attributed to progressive disease. No significant quality of life (QOL) differences was observed between the two treatment arms (evaluating the mean change in scores from baseline) using the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale, FACT-B subscale, or the Trial Outcome Index. Adverse effects reported more frequently in patients treated with paclitaxel + bevacizumab (n=365) compared to patients treated with paclitaxel alone (n=346) included grade III or IV sensory neuropathy (23.5% vs. 17.7%; p=0.05), hypertension (14.8% vs. 0%; p less than 0.001), infection (9.3% vs. 2.9%; p less than 0.001), fatigue (9.1% vs. 4.9%; p=0.04), proteinuria (3.5% vs. 0%; p less than 0.001), headache (grade III only, 2.2% vs. 0%; p=0.008), and cerebrovascular ischemia (1.9% vs. 0%; p=0.02).

On November 18, 2011 the U.S. Food and Drug Administration (FDA) stated that follow-up studies of bevacizumab failed to extend patient lives, therefore bevacizumab was at risk for potential FDA withdrawal for the use in the treatment for breast cancer. The FDA approval in 2008 was based on a trial showing it slowed growth of tumors caused by breast cancer. The "accelerated approval" was based on the condition that later studies would show a survival benefit. But in briefing documents, the FDA reviewers determined that the two follow-up studies recently submitted by Roche failed to show that the drug significantly extended lives compared to chemotherapy alone. Additionally, the FDA said that in follow-up studies, the drug did not slow tumor growth to the same degree as in earlier studies. Furthermore, patients taking bevacizumab showed significantly more side effects, including high blood pressure, fatigue and abnormal white blood cell levels. (10)

In 2011, Robert et al. (11) evaluated the regimens in bevacizumab for breast oncology (RIBBON-1), phase III, double-blind, placebo-controlled trial that compared first-line chemotherapy with or without bevacizumab as a treatment for HER2 negative locally recurrent or metastatic breast cancer. The primary endpoint was PFS. A total of 1237 enrolled participants were randomized to a chemotherapy regimen consisting of capecitabine, taxane based or anthracycline based regimen with or without bevacizumab. There were 615 participants in the capecitabine group with a median follow-up of 15.6 months, and 622 participants in the taxane/anthracycline group with a median follow-up of 19.2 months. The median PFS in the capecitabine cohort increased from 5.7 months in the placebo arm to 8.6 months in the bevacizumab arm (HR, 0.69; 95% CI, 0.56 to 0.84; p<0.001). The median PFS for the taxane/anthracycline cohort in the placebo arm was 9.0 months and 9.2 months in the bevacizumab arm (HR, 0.64; 95% CI, 0.52 to 0.80; p<0.001). The 1-year survival rate did not have any statistically significant difference in overall survival (OS) for either cohort. The incidence of grade 3 to 5 adverse events was higher in all the bevacizumab containing arms vs.the placebo containing arms. Regardless of the type of chemotherapy, hypertension and proteinuria were consistently increased in the bevacizumab containing arms of the treatment cohorts. There were higher rates of discontinuation related to the incidence of adverse events in the bevacizumab containing arm compared to the placebo arm (taxane: 24.1% with bevacizumab vs.7.8% placebo; anthracycline: 14.3% with bevacizumab vs. 4.0% placebo). However, in the capecitabine cohort, there was no difference in rates of discontinuation (11.9% for both arms). The authors concluded first-line bevacizumab combined with chemotherapy increased PFS in individuals with HER2-negative metastatic breast cancer.

In 2012, Bear et al. (12) evaluated the use of bevacizumab as neoadjuvant therapy to assess the complete tumor response in the breast, and the secondary endpoint of combined complete tumor response in both the breast and lymph nodes. This phase III trial had a total of 1206 participants with operable HER2-negative breast cancer and were randomized to one of three chemotherapy regimens: docetaxel, doxorubicin, cyclophosphamide; capecitabine, docetaxel, doxorubicin, cyclophosphamide; or gemcitabine, docetaxel/doxorubicin/cyclophosphamide. Subsequently, half of the participants in each chemotherapy group were randomly assigned to receive bevacizumab with each of the first 6 chemotherapy cycles and postoperatively for 10 additional doses. There were no significant differences in pathological complete response (pCR) between the chemotherapy groups (36.6% with docetaxel, 32.3% with docetaxel–capecitabine, and 40.2% with docetaxel–gemcitabine; p=0.09). Similarly, rates of breast-conserving surgery for these groups were not significant (46%, 43%, and 50%, respectively). There was a significant increase in the pCR in the breast with the addition of bevacizumab to chemotherapy from 28.2% to 34.5% (p=0.02). In a subset analysis, hormone-receptor-positive individuals had an increased response with bevacizumab compared to chemotherapy regimens alone (15.1% with bevacizumab vs. 23.2% without bevacizumab; p=0.007). There was a less-pronounced response observed in the hormone-receptor-negative individuals treated with bevacizumab compared to chemotherapy alone (51.5% vs. 47.1%; p=0.34). Among the 3 chemotherapy regimens, the docetaxel, capecitabine regimen had a significant difference in pCR in the breast with the addition of bevacizumab (36.1% vs. 23.5%; p=0.09). A larger proportion of individuals treated with chemotherapy (83%) completed the treatment protocol compared to 78% of the individuals treated with chemotherapy plus bevacizumab. Adverse events from bevacizumab accounted for 5% of the discontinuation rate. The addition of bevacizumab resulted in increased adverse events, particularly hypertension, left ventricular systolic dysfunction, mucositis and hand-foot syndrome. Bear and colleagues concluded bevacizumab had “modest but significant increase in the rate of pathological complete response in the breast, but the rate of pathological complete response in the breast and nodes was not significantly increased.”

In 2017 Miles et al. (13) performed a double-blind placebo-controlled randomized phase III trial. Eligible patients had previously untreated HER2-negative metastatic breast cancer. Plasma vascular endothelial growth factor-A (pVEGF-A) was measured before randomization to either paclitaxel 90 mg/m2 with either placebo or bevacizumab 10 mg/kg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were PFS in the intent-to-treat and pVEGF-A high populations. Of 481 patients randomized (242 placebo-paclitaxel; 239 bevacizumab-paclitaxel), 471 received study treatment. The stratified PFS HR was 0.68 (99% confidence interval, 0.51-0.91; log-rank p=0.0007) in the intent-to-treat population (median 8.8 months with placebo-paclitaxel vs.11.0 months with bevacizumab-paclitaxel) and 0.64 (96% confidence interval, 0.47-0.88; log-rank p=0.0038) in the pVEGF-A high subgroup. The PFS treatment by VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (45% vs. 27% with placebo), neutropenia (39% vs. 29%; grade ≥3: 25% vs. 13%) and hypertension (31% vs. 13%; grade ≥3: 11% vs. 4%). The study displayed a significant improvement in PFS with bevacizumab which is consistent with previous placebo-controlled first-line trials in metastatic breast cancer. Although the results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium and the NCCN clinical practice guideline for Breast Cancer (5, 7) recommend the off-label use of bevacizumab in combination with paclitaxel for recurrent or metastatic human epidermal growth factor receptor 2 (HER2) negative disease with symptomatic visceral disease or visceral crisis that is hormone receptor- negative or hormone receptor-positive, and endocrine therapy refractory (category 2A). This was based on modest improvement in response rate and time to progression, but bevacizumab did not improve OS.

Central Nervous System

Glioblastoma- Newly Diagnosed

In 2014, Gilbert et al. (14) stated that concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab is currently FDA approved for use in recurrent glioblastoma. The authors sought to determine if the addition of bevacizumab would improve OS in patients with newly diagnosed glioblastoma. In this randomized, double-blind, placebo-controlled trial, they treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy which was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab.

A total of 978 patients were enrolled, and 637 underwent randomization. There was no significant difference in the duration of OS between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; HR for death in the bevacizumab group, 1.13). PFS was longer in the bevacizumab group (10.7 months vs. 7.3 months; HR for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse QOL, and a decline in neurocognitive function were more frequent in the bevacizumab group. The authors concluded that the first-line use of bevacizumab did not improve OS in patients with newly diagnosed glioblastoma. PFS was prolonged but did not reach the prespecified improvement target. (NCT00884741).

In 2014, Chinot et al. (15) evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. In this phase 3 study, patients with supratentorial glioblastoma were randomly assigned to receive intravenous bevacizumab (10 mg per kg of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kg intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kg intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed PFS and OS. A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median PFS was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified HR for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to PFS was observed across subgroups. OS did not differ significantly between groups (stratified HR for death, 0.88; 95% CI, 0.76 to 1.02; p=0.10). The respective OS rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (p=0.049) and 33.9% and 30.1% at 2 years (p=0.24). Baseline health-related QOL and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved PFS and maintenance of baseline QOL and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.

Glioblastoma (Recurrent), Anaplastic Gliomas, and Glioblastomas

In 2013, the U.S. FDA granted approval to bevacizumab (Genentech, Inc.) as a single agent for adult patients with progressive glioblastoma following prior therapy. The FDA labeled indication was revised February 5, 2017 and base their approval on the following studies (1):

  • A multicenter, randomized (2:1), open-label study in patients with recurrent glioblastoma (NCT01290939) evaluated the safety and efficacy of Avastin. Patients with first progression following radiotherapy and temozolomide were randomized (2:1) to receive Avastin (10 mg/kg every 2 weeks) with lomustine (90 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6 weeks) alone until disease progression or unacceptable toxicity. Randomization was stratified by World Health Organization (WHO) performance status (0 vs. >0), steroid use (yes vs. no), largest tumor diameter (≤ 40 vs. >40 mm), and institution. The main outcome measure was OS. Secondary outcome measures were investigator-assessed PFS and ORR per the modified Response Assessment in Neuro-oncology (RANO) criteria, health related QOL, cognitive function, and corticosteroid use.
  • A total of 432 patients were randomized to receive lomustine alone (n=149) or Avastin with lomustine (n=283). The median age was 57 years; 24.8% of patients were ≥ 65 years. The majority of patients with were male (61%); 66% had a WHO performance status score >0; and in 56% the largest tumor diameter was ≤ 40 mm. Approximately 33% of patients randomized to receive lomustine received Avastin following documented progression.

No difference in OS (HR 0.91, p-value of 0.4578) was observed between arms; therefore, all secondary outcome measures are descriptive only. PFS was longer in the Avastin with lomustine arm [HR 0.52 (95% CI: 0.41, 0.64)] with a median PFS of 4.2 months in the Avastin with lomustine arm and 1.5 months in the lomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the Avastin with lomustine arm discontinued corticosteroids (23% vs. 12%).

  • One single arm single center study and a randomized noncomparative multicenter study (NCT00345163) evaluated the efficacy and safety of Avastin 10 mg/kg every 2 weeks in patients with previously treated GBM. Response rates in both studies were evaluated based on modified WHO criteria that considered corticosteroid use. In AVF3708g, the response rate was 25.9% (95% CI: 17%, 36.1%) with a median duration of response of 4.2 months (95% CI: 3, 5.7). In Study NCI 06-C-0064E, the response rate was 19.6% (95% CI: 10.9%, 31.3%) with a median duration of response of 3.9 months (95% CI: 2.4, 17.4).

Kreisl (16) completed a phase II trial (2009) evaluating the single-agent activity of bevacizumab in patients with recurrent glioblastoma. Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m² or 125 mg/ m² very 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. Pretreated patients (n+48) were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (5 thromboembolic events, 1 bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median PFS was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month OS was 57% (95% CI, 44% to 75%). Median OS was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging (MRI) response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. This phase II trial determined that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.

Effective 2nd-line therapies are absent in glioblastoma of the brain leading to poor survival rates. In 2008, Cloughesy et al. (17) completed a randomized, non-comparative, phase II trial (n=167), evaluating bevacizumab alone or in combination with irinotecan which demonstrated a favorable six-month PFS, and OS in patients with relapsed, refractory GBM. Patients with recurrent GBM who had previously received temozolomide were eligible for study enrollment. In a single-arm Phase II trial of bevacizumab + irinotecan (CPT) in recurrent GBM, activity was demonstrated, warranting further investigation of clinical benefit of bevacizumab alone, and in combination with CPT. One hundred sixty-seven patients (pts) with recurrent GBM were randomized 1:1 to bevacizumab (10 mg/kg q 2 wks) (Arm 1, n=85) or bevacizumab + CPT (340 mg/m2 if enzyme-inducing anti- epileptic drugs and 125 mg/m2 for non- anti-epileptic drugs (Arm 2, n=82), The co- primary endpoints were PFS-6 (defined at 24-weeks) and ORR determined by an independent radiology facility (IRF), with secondary endpoints of safety, PFS, and duration of response determined by IRF, and OS. The trial provided approximately 80% power to detect 13% improvement in PFS-6 from an assumed rate of 15%, and 90% power to detect 13% improvement in ORR from assumed rates of 5% (Arm 1) and 10% (Arm 2) (2-sided significance level of 0.025). The median OS was based on 61.2% of deaths for bevacizumab alone and 67.1% of deaths for bevacizumab + CPT. One intracranial hemorrhage occurred in Arm 1 and one in Arm 2 during planned treatment period. The dose of corticosteroid required diminished from baseline to cycle 4. The study concluded, both the PFS6 and OS of >9 months with bevacizumab alone or with CPT provides encouraging evidence of significant activity in this poor prognosis population. In addition, the reduction in corticosteroid use has the potential to provide benefit to patients.

Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma)

In 2016, Morris and colleagues (18) retrospectively reviewed neurofibromatosis Type 2 (NF2) patients treated with bevacizumab for rapidly growing schwannoma. The records of 95 NF2 patients receiving bevacizumab were reviewed regarding spinal ependymoma prevalence, behavior, and response to treatment. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. The researchers noted that bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium and the NCCN clinical practice guidelines for Central Nervous System (CNS) Cancer (5, 7) recommend the off-label use of bevacizumab for the following indications.

Recurrent Anaplastic Glioma and Gioblastomas

  • Bevacizumab when used a single agent (2A recommendation) The NCCN indicated that patients who have good performance status but evidence of radiologic progression may benefit from continuation of bevacizumab to prevent rapid neurologic deterioration.
  • Bevacizumab in combination with chemotherapy (irinotecan, carmustine, lomustine, temozolomide, or carboplatin; 2A recommendation; 2B with carboplatin). Bevacizumab plus chemotherapy can be considered if bevacizumab monotherapy fails.

Recurrent Intracranial and Spinal Ependymoma Cancer (Excluding Subependymoma)

  • As single-agent treatment for disease progression in adult patients; 2A recommendation. Patients who have good performance status but evidence of radiologic progression may benefit from continuation of bevacizumab to prevent rapid neurologic deterioration.

Cervical Cancer

On August 14, 2014, the FDA (1, 19) approved bevacizumab in combination with paclitaxel and either cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer. The FDA approval is based on the results of an international randomized trial (four-arm 2x2 factorial design) with 2 primary comparisons of OS. The first compared bevacizumab and chemotherapy vs. chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) alone. The second compared the platinum doublet (paclitaxel and cisplatin) vs. non-platinum doublet chemotherapy (i.e., paclitaxel and topotecan), irrespective of the addition of bevacizumab. The study enrolled 452 patients: 227 patients were assigned to receive chemotherapy and bevacizumab, and 225 patients were assigned to receive chemotherapy alone. The chemotherapy could be either paclitaxel in combination with cisplatin or paclitaxel in combination with topotecan. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All enrolled patients had high performance status (GOG status of 0 or 1); 80 percent had received prior radiation, and 74 percent had received prior chemotherapy concurrent with radiation. Efficacy in the first primary comparison demonstrated a statistically significant improvement in OS in patients who received bevacizumab and chemotherapy compared to chemotherapy alone (HR=0.74; 95 percent CI: 0.58, 0.94; p= 0.013, log-rank test). Results showed an increase in OS to 16.8 months in participants who received chemotherapy in combination with bevacizumab as compared to 12.9 months for those receiving chemotherapy alone.

In the second primary comparison, patients who received paclitaxel plus topotecan (with or without bevacizumab) arms did not demonstrate an improvement in OS compared with patients who received paclitaxel plus cisplatin (with or without bevacizumab) [HR 1.15 (95 percent CI: 0.91, 1.46)]. However, the HR for addition of bevacizumab to either chemotherapy regimen was similar (HR 0.72 for paclitaxel/cisplatin and HR 0.76 for paclitaxel/topotecan). The results suggest that the regimen of paclitaxel with topotecan plus bevacizumab is an acceptable alternative for women with advanced cervical cancer who are not candidates for platinum treatment. The most common adverse reactions (20%) in patients treated with bevacizumab and chemotherapy were fatigue, decreased appetite, high blood pressure, high blood sugar, hypomagnesemia, urinary tract infection, headache, and decreased weight. Gastrointestinal (GI) perforations were reported in 3.2 percent of bevacizumab-treated patients, all of whom had had prior pelvic radiation. GI-vaginal fistulae occurred in 8.2 percent of bevacizumab treated patients and 0.9 percent of patients who did not receive bevacizumab, all of whom also had had prior pelvic radiation. Several other grade 3 or greater adverse reactions were also more common in patients receiving chemotherapy plus bevacizumab than in patients who received chemotherapy, including venous thromboembolic events, hemorrhage, high blood pressure, proteinuria, and wound healing complications. (1, 19)

Vascular endothelial growth factor (VEGF) is a key promoter of tumor progression in cervical carcinoma. The gynecologic oncology group (GOG) conducted a phase II trial to assess the efficacy and tolerability of bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody. (20) Treatment consisted of bevacizumab 15 mg/kg IV every 21 days until disease progression or prohibitive toxicity. Primary end points were PFS at 6 months and toxicity. Forty-six patients were enrolled (median age, 46 years); 38 patients (82.6%) received prior radiation as well as either one (n = 34, 73.9%) or two (n = 12, 26.1%) prior cytotoxic regimens for recurrent disease. Grade 3 or 4 adverse events at least possibly related to bevacizumab included hypertension (n = 7), thrombo-embolism (n = 5), GI (n = 4), anemia (n = 2), other cardiovascular (n = 2), vaginal bleeding (n = 1), neutropenia (n = 1), and fistula (n = 1). One grade 5 infection was observed. Eleven patients (23.9%; two-sided 90% CI, 14% to 37%) survived progression free for at least 6 months, and five patients (10.9%; two-sided 90% CI, 4% to 22%) had partial responses. The median response duration was 6.21 months (range, 2.83 to 8.28 months). The median PFS and OS times were 3.40 months (95% CI, 2.53 to 4.53 months) and 7.29 months (95% CI, 6.11 to 10.41 months), respectively. The study determined that bevacizumab appears to be well tolerated and active in the second- and third-line treatment of patients with recurrent cervical cancer and merits phase III investigation.

In 2013, Tewari et al. (21) performed a randomized phase III trial investigating the addition of bevacizumab to chemotherapy regimens to treat recurrent, persistent, or metastatic cervical cancer that was not amenable to curative therapy with surgery and/or radiation therapy. OS was the primary endpoint of the study. Four hundred fifty-two (n=452) participants with squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix were randomized to one of four possible treatment arms. The study regimens were cisplatin/paclitaxel, topotecan/paclitaxel and bevacizumab (15mg/kg every three weeks) added to both regimens. The treatment cycles repeated every 21 days and continued until disease progression, unacceptable toxicity, or complete response. The addition of bevacizumab resulted in an improved response rate of 48% vs. 36% in the chemotherapy-only arm (p=0.0078). There was a significantly improved median OS of 17 months reported with the bevacizumab combination vs. 13.3 months (p=0.0035) for those treated with chemotherapy alone. The addition of bevacizumab had increased side effects compared to the chemotherapy alone, with grade 3-4 bleeding (5% vs. 1%), thrombosis/embolism (9% vs. 2%) and gastrointestinal fistula (3% vs. 0%).

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium and the NCCN clinical practice guideline for Cervical Cancer (5, 7) recommends the off-label use of bevacizumab for squamous cell carcinoma and adenocarcinoma of the cervix when used as first-line or second-line therapy (if not previously used as first-line) in combination with paclitaxel and cisplatin, carboplatin, or topotecan (category 2B), or as second-line therapy as a single agent (category 1).

Colon and Rectal Cancer, Metastatic (mCRC)

The FDA granted approval to bevacizumab for the following indications (1):

  • For mCRC, in combination with intravenous 5-fluorouracil (5-FU) based chemotherapy for first- or second-line treatment.
  • For mCRC, in combination with fluoropyrimidine­ irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for patients who have progressed on a first-line Avastin-containing regimen.

The FDA approval is based on a randomized, open-label, multinational clinical trial conducted in patients with mCRC that had progressed during, or within 3 months of, discontinuation of first-line bevacizumab-based combination chemotherapy with fluoropyrimidine–oxaliplatin or fluoropyrimidine–irinotecan. In the trial, 820 patients were randomly assigned to receive chemotherapy alone (n=411) or chemotherapy in combination with bevacizumab (n=409). Patients received chemotherapy with either fluoropyrimidine–irinotecan-based therapy or fluoropyrimidine–oxaliplatin-based therapy, depending on their prior treatment (i.e., patients who received prior treatment with oxaliplatin received irinotecan-based therapy and patients who received prior treatment with irinotecan received oxaliplatin-based therapy). The treatment cycles for both groups were repeated every 2 or 3 weeks, depending on the chemotherapy regimen used, and bevacizumab was administered at a dose of 5 mg/kg by intravenous infusion every 2 weeks or 7.5 mg/kg by intravenous infusion every 3 weeks. Bevacizumab was continued until disease progression or unacceptable toxicity. The primary efficacy endpoint was OS. Treatment was stratified by first-line treatment (irinotecan-based vs. oxaliplatin-based), time to progression on first-line treatment (more than 9 months vs. 9 months or less), time since last dose of bevacizumab (more than 42 days vs. 42 days or less), and ECOG performance status (0–1 vs. 2). The median age of the study population was 63 years, 64% were men, and 96% had an ECOG performance status of 0 or 1. Chemotherapy plus bevacizumab was associated with a statistically significant improvement in OS compared with chemotherapy alone (HR 0.81 [95% CI 0.69, 0.94], p=0.0062). Median OS was 11.2 months for patients receiving chemotherapy plus bevacizumab and 9.8 months for patients receiving chemotherapy alone. PFS was also statistically significantly improved in patients who received chemotherapy plus bevacizumab compared with those who received chemotherapy alone (HR 0.68 [95% CI 0.59, 0.78], p<0.0001). Median PFS was 5.7 months for patients receiving chemotherapy plus bevacizumab and 4.0 months for patients receiving chemotherapy alone. No new safety concerns were observed. The safety data were consistent with the known safety profile established in previously approved indications.

In 2003, Kabbinavar and colleges (22) completed a phase II study where they investigated the safety and efficacy of 2 doses of bevacizumab, a monoclonal antibody to VEGF, plus fluorouracil (FU)/leucovorin (LV) vs. FU/LV alone in patients with mCRC. One hundred four (n=104) previously untreated patients with measurable mCRC were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m2)/LV (500 mg/m2) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle. Compared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval [CI], 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, 2 of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in 1 patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns. The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for mCRC.

Saltz et al. (23) evaluated the safety and efficacy of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with mCRC. Patients were randomly assigned, in a 2 x 2 factorial design, to XELOX vs. FOLFOX-4, and then to bevacizumab vs. placebo. The primary end point was PFS. A total of 1,401 patients were randomly assigned. Median PFS was 9.4 months in the bevacizumab group and 8.0 months in the placebo group. Median OS was 21.3 months in the bevacizumab group and 19.9 months in the placebo group. Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The study concluded the addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with mCRC. OS differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

Giantonia and colleagues (24) conducted a study to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated mCRC. Eight hundred twenty-nine (n=829) mCRC patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to 1 of 3 treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was OS, with additional determinations of PFS, response, and toxicity. The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding HR for death = 0.75; p=0.0011), and 10.2 months for those treated with bevacizumab alone. The median PFS for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding HR for progression = 0.61; P<0.0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P<0.0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison); therefore, demonstrating the addition of bevacizumab to FOLFOX4 improves survival duration for patients with previously treated mCRC.

In 2009, Alberts et al. (25) researched the effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer. Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Researchers assessed the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a HR of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. The outcome measure included evaluation of disease-free survival in patients with wild-type KRAS mutations. Secondary end points included OS and toxicity. Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs. 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs. 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs. 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P<0 .001) and failure to complete 12 cycles (33% vs. 23%; OR, 1.6; 95% CI, 1.4-1.9; P<0.001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Among patients with stage III resected colon cancer; the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival.

Fluoropyrimidine-based chemotherapy plus the anti-VEGF antibody bevacizumab is standard first-line treatment for mCRC. In 2009, Tol and colleagues (26) studied the effect of adding the anti-epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for mCRC. Investigators randomly assigned 755 patients with previously untreated mCRC to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was PFS. The mutation status of the KRAS gene was evaluated as a predictor of outcome. The median PFS was 10.7 months in the CB group and 9.4 in the CBC group (p=0.01). Quality-of-life scores were lower in the CBC group. The OS and response rates did not differ significantly in the two groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased PFS as compared with cetuximab-treated patients with wild-type-KRAS tumors or patients with mutated-KRAS tumors in the CB group. The study determined that the addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter PFS and inferior QOL. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group.

In 2015, Martin et al. (27) aimed to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, FOLFOX and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis. Patients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and PFS. The intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs. 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs. 31%) and extrahepatic disease (56% vs. 32%, p=.02). The median numbers of chemotherapy cycles were similar (10 vs. 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs. 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm vs. the FOLFOX/bevacizumab arm at 2 (78% vs. 54%, P = .02), 4 (95% vs. 70%, P = .03), and 6 months (76% vs. 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm vs. the FOLFOX/bevacizumab arm (35% vs. 16%, P = .05), and there was improved median PFS (15.3 vs. 7.6 months). The study concluded that simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This approach leads to improved overall response rates, improved hepatic PFS, and more durable overall PFS in patients downsized to resection.

In 2015, Haller et al. (28) evaluated the impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer. Efficacy and safety of adjuvant XELOX/FOLFOX vs. LV/5-FU were compared with respect to age and medical comorbidity using pooled data from four randomized, controlled trials, selected for access to patient-level medical comorbidity data and including commonly endorsed and utilized regimens. Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, medical comorbidity (low vs. high), or age (<70 vs. ≥70), and compared for disease-free survival (DFS), OS, and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage. Disease-free survival benefits were shown for XELOX/FOLFOX vs. LV/5-FU regardless of age or medical comorbidity, although benefits were modestly attenuated for patients aged ≥70. HR(s) were 0.68 (P<0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P<0.0001) and 0.59 (P<0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P<0.0001) and 0.58 (P<0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and medical comorbidity scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and medical comorbidity scores. ONS: Results support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III colon cancer in all age groups and in patients with comorbidities, consistent with those who were eligible for the clinical trials.

In 2015, Simkens and colleagues (29) evaluated the duration of first-line treatment with chemotherapy in combination with bevacizumab in a phase III unblinded randomized controlled trial (CAIRO3) of individuals with metastatic colorectal cancer. This study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab vs. observation. A total of 64 hospitals evaluated individuals older than 18 years with previously untreated metastatic CRC, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Participants (n=558) were randomized to either maintenance treatment with capecitabine and bevacizumab (n=279; maintenance group) or observation (n=279; observation group). Disease status was assessed every 9 weeks. On first progression (defined as PFS1), participants in both groups received induction with CAPOX-B until second progression (PFS2). The final analysis was completed by intention to treat. Median follow-up was 48 months. The primary endpoint of median PFS2 was significantly improved in participants on maintenance treatment compared to observation, 11.7 months vs. 8.5 months (HR 0.67, 95% CI, 0.56-0.81; p<0.0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated; however, the incidence of hand-foot syndrome was increased (23%, n=64 participants). The study concluded that global QOL did not deteriorate during maintenance treatment with capecitabine plus bevacizumab after 6 cycles of CAPOX-B in individuals with metastatic CRC.

Adjuvant Treatment of Colon Cancer

The FDA label (1) does not recommend bevacizumab for the adjuvant treatment of colon cancer. The lack of efficacy of bevacizumab (Avastin) is based on 2 randomized, open-label, multicenter clinical studies. de Gramont et al. (30) evaluated 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive Avastin at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (n=1155), or on a 3-weekly schedule with XELOX (n=1145) or FOLFOX4 alone (n=1151). The main outcome measure was disease-free survival in patients with stage III colon cancer. The median age was 58 years; 54% were male, 84% were White and 29% were ≥ 65 years. Eighty-three percent had stage III disease. The addition of Avastin to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving Avastin with FOLFOX4 or with XELOX. The HR for DFS were 1.17 (95% CI: 0.98,1.39) for Avastin with FOLFOX4 vs. FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for Avastin with XELOX vs. FOLFOX4 alone. The HR for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of Avastin with FOLFOX4 vs. FOLFOX4 alone and Avastin with XELOX vs. FOLFOX4 alone, respectively. Similar lack of efficacy for DFS were observed in the Avastin-containing arms compared to FOLFOX4 alone in the high-risk stage II cohort.

In a second study (1) patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (n=1354) or mFOLFOX6 alone (n=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of Avastin to mFOLFOX6 [HR 0.96 (95% CI: 0.75,1.22)].

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the NCCN clinical practice guideline for Colon Cancer (4, 7) recommends the off-label use of bevacizumab to include:

  • Therapy used in combination with capecitabine or with FOLFOX, FOLFIRI, CapeOX, FOLFOXIRI, or 5-FU/LV regimen when used:
    • As primary treatment for locally unresectable or medically inoperable disease (category 2A);
    • For unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy (category 2A);
    • As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with imminent or existing obstruction. (category 2A);
    • For unresectable synchronous metastases of other sites. (category 2A);
    • As primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous 5-FU/LV or capecitabine therapy, or who have not received any previous chemotherapy. (category 2A):
    • For unresectable metachronous metastases that remain unresectable after primary treatment. (category 2A):
  • Initial treatment for unresectable synchronous liver and/or lung metastases in combination with:
    • FOLFOX regimen (category 2A).
    • FOLFIRI regimen (category 2A).
    • FOLFOXIRI regimen (category 2A).
    • CapeOX regimen (category 2A).
  • Therapy in combination with capecitabine or with FOLFOX, FOLFIRI, CapeOX, FOLFOXIRI or 5-FU/LV regimen:
    • As adjuvant treatment following synchronized or staged resection for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment (category 2B);
    • As adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy (category 2B);
    • As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment (category 2B);
  • Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX, or CapeOX within the past 12 months when used:
    • In combination with irinotecan (category 2A);
    • In combination with FOLFIRI regimen (category 2A).
  • Subsequent therapy for progression of unresectable advanced or metastatic colon cancer when used:

    • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI regimen for disease previously treated with oxaliplatin-based therapy without irinotecan (category 2A);
    • In combination with FOLFOX or CapeOX regimen for disease previously treated with irinotecan-based therapy without oxaliplatin (category 2A);
    • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI in patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin (category 2A);
    • In combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin in patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin (category 2A).

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for rectal carcinoma (4) recommends the off-label use of bevacizumab for rectal adenocarcinoma for the following indications:

  • Therapy used in combination with capecitabine or with FOLFOX, FOLFIRI, FOLFOXIRI regimen, CapeOX, or 5-FU/leucovorin regimen when used:
  • As primary treatment for T3, any N; any T1-2, N1-2; T4, any N; and/or locally unresectable or medically inoperable disease with no metastases if resection is contraindicated following neoadjuvant therapy. (2A recommendation).
  • For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy. (2A recommendation).
  • Following short-course radiation therapy or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy. (2A recommendation).
  • As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction. (2A recommendation).
  • As primary treatment for synchronous unresectable metastases of other sites. (2A recommendation).
  • As primary treatment for unresectable metachronous metastases in patients 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. (2A recommendation).
  • For unresectable metachronous metastases that remain unresectable after primary treatment. (2A recommendation).
  • Adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy. (2B recommendation).
  • Adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. (2B recommendation).

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

  • FOLFIRI regimen.
  • FOLFOX regimen.
  • CapeOx regimen.
  • FOLFOXIRI regimen.

Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX or CapeOX regimen within the past 12 months:

  • In combination with irinotecan.
  • In combination with FOLFIRI regimen.

Subsequent therapy after progression for unresectable advanced or metastatic rectal adenocarcinoma when used:

  • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI regimen for disease previously treated with oxaliplatin-based therapy without irinotecan.
  • In combination with FOLFOX or CapeOX regimen for disease previously treated with irinotecan-based therapy without oxaliplatin.
  • As the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.
  • In combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin.

Malignant Pleural Mesothelioma (Epithelial, Sarcomatoid, Mixed)

The 2018 NCCN Drugs and Biologics Compendium (7) and the NCCN clinical practice guideline for Malignant Pleural Mesothelioma (Epithelial, Sarcomatoid, Mixed) (4) recommends the off-label use of bevacizumab when used in combination with cisplatin and pemetrexed followed by single-agent maintenance bevacizumab as treatment of:

  • Unresectable clinical stage I-III disease and tumors of epithelial histology (category 1);
  • Clinical stage IV disease, tumors of sarcomatoid or mixed histology, or medically inoperable tumors in patients with performance status (PS) 0-2 (category 1).

The FDA approval was based on an improvement in survival time when bevacizumab was added to a standard chemotherapy regimen. Bevacizumab is associated with an increased risk of hemorrhage, and the FDA label notes that bevacizumab should not be given to those with a history of hemoptysis. The FDA labelled indication for bevacizumab I for the use in unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC, in combination with carboplatin and paclitaxel for first-line treatment. (1)

Currently the use of bevacizumab in advanced non-squamous NSCLC is controversial among elderly patients. In 2014, Langer et al. (32) study aimed to compare OS for Medicare patients diagnosed with NSCLC and treated with either first-line bevacizumab-carboplatin-paclitaxel (BCP) or carboplatin-paclitaxel (CP). Patients ≥ 65 years old, first diagnosed with non-squamous NSCLC stage IIIB/IV between 2006 and 2009, and treated with either first-line BCP or CP, were selected from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database that links cancer registry and U.S. Medicare claims data. Kaplan-Meier estimates were used to evaluate survival. Multivariable Cox proportional hazards models were used to compare the effect of BCP vs. CP on the hazard of death. Age-stratified analyses were conducted for patients aged 65-74 and ≥ 75 years. Of 1706 patients in the study, 592 (34.7%) received BCP and 1114 (65.3%) received CP; 692 (40.6%) were ≥ 75 years. Adjusted median survival time in the BCP vs. CP cohorts was 10.5 vs. 8.5 months (p=0.008). The difference in median survival favoring the BCP cohort was statistically significant for both patients aged ≥75 years (2.8 months, p = 0.019), and patients aged 65-74 years (1.5 months, p = 0.018). The adjusted hazard of death did not differ between the cohorts (HR: 0.96, 95% CI: 0.86-1.06); however, during the first year of follow-up, when most deaths (>60%) occurred, the hazard of death was 18% lower for the BCP cohort (HR: 0.82, 95% CI: 0.71-0.94). BCP patients also had 18% fewer hospital admissions than CP patients (adjusted incidence rate ratio (IRR): 0.82, 95% CI: 0.72-0.94) and 23% fewer inpatient days (IRR: 0.77, 95% CI: 0.65-0.91). This retrospective analysis determined that first-line therapy with BCP was associated with longer survival and fewer hospitalizations than CP.

In 2016, Langer et al. (33) accessed patient-level data from 2 phase III studies in patients with previously untreated, advanced-stage, nonsquamous NSCLC to examine outcomes with bevacizumab and chemotherapy based on age. Data from patients randomized to paclitaxel-carboplatin (PC)+bevacizumab in the ECOG and PointBreak studies were pooled and compared with patients randomized to PC alone. Patients were grouped by age and a multivariable model was used to calculate HRs and corresponding 95% CIs using time-to-event outcomes. Adverse events (AEs) were assessed by age group in each study. The PC+ bevacizumab and PC arms comprised 901 and 444 patients, respectively. PC + bevacizumab was associated with significant increases in OS relative to PC in patients below 65 years (HR 0.75; 95% CI, 0.62-0.89), 65 to 74 years (HR, 0.80; 95% CI, 0.64-1.00), 70 to 74 years (HR, 0.68; 95% CI, 0.48-0.96), and below 75 years (HR, 0.78; 95% CI, 0.68-0.89) but not in those aged 75 years or above (HR, 1.05; 95% CI, 0.70-1.57). Increased incidence of grade ≥3 AEs was reported with PC + bevacizumab vs. PC in patients below 75 years (63% vs. 48%; P<0.05) and 75 years or above (81% vs. 56%; P <0.05). This analysis concluded that the survival benefits associated with PC + bevacizumab extend to patient subgroups below 75 years with advanced-stage NSCLC; no benefit, however, was observed for bevacizumab-eligible patients who were 75 years or above.

In 2016, Karayama et al. (34) evaluated the clinical benefit of bevacizumab as maintenance therapy. One hundred ten chemotherapy-naïve patients with non-squamous NSCLC were randomly assigned maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after 4 cycles of induction therapy with carboplatin (area under the curve = 6), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). The primary end-point was 1-year PFS rate. Fifty-five patients were assigned to the 2 groups. The mean 1-year PFS rate was 43.9% (95% CI: 29.6-59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1-51.0%) in the pemetrexed maintenance group, and the difference was not significant (p = 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1-19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7-14.1, HR: 0.73, 95% CI: 0.44-1.19, log-rank p = 0.198) in the pemetrexed maintenance group. Nasal hemorrhage, hypertension, and proteinuria were more frequent in the combination maintenance group, but they were mild and tolerable. Both maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the NCCN clinical practice guideline for NSCLC (adenocarcinoma with mixed subtypes; large cell carcinoma) (4) recommends the off-label use of bevacizumab when used in combination with carboplatin and paclitaxel or pemetrexed or in combination with cisplatin and pemetrexed for recurrent or metastatic non-small-cell lung cancer in patients with a performance status 0-1, tumors of non-squamous cell histology, and no history of recent hemoptysis as (category 1 for combination therapy with carboplatin and paclitaxel; category 2A for all others, category 2B for locoregional recurrence (excluding mediastinal lymph node recurrence with prior radiation therapy with no evidence of disseminated disease):

  • Initial cytotoxic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PD-L1 <50% or unknown.
  • First-line or subsequent therapy for BRAF V600E-mutation positive tumors.
  • Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, or osimertinib therapy.
  • Subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy.
  • Subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy.
  • Subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK, ROS1, and BRAF negative or unknown and prior pembrolizumab therapy.

Continuation maintenance therapy if given first line with chemotherapy for recurrent or metastatic disease in patients with performance status 0-2, tumors of nonsquamous cell histology, and no history of recent hemoptysis who achieve tumor response or stable disease following initial cytotoxic therapy:

  • As a single agent (category 1A).
  • In combination with pemetrexed if previously used with a first-line pemetrexed/platinum chemotherapy regimen (category 2A).

Ovarian Cancer, Fallopian Tube or Primary Peritoneal Cancer

On November 14, 2014, the FDA approved bevacizumab for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant in combination with paclitaxel, pegylated liposoma doxorubicin, or topotecan or platinum-sensitive in combination with carboplatin and paclitaxel or carboplatin and gemcitabine followed by Avastin as a single agent. (1)

The FDA approval is based on the results of an international, multicenter, open-label randomized two-arm trial (AURELIA) which compared bevacizumab plus chemotherapy vs. chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum-based therapy (n=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following intravenous chemotherapies: paclitaxel (80mg/m2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin (PLD) 40mg/m2 on day 1 every 4 weeks; or topotecan 4mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25mg/m2 on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received bevacizumab monotherapy upon progression. The main outcome measure was PFS. Secondary outcome measures were ORR and OS. The median age was 61 years (range 25-84 years) and 37% of patients were ≥ age 65. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥ 2 × 1002 ULN and 31% had ascites at baseline. Seventy-three percent had a platinum-free interval (PFI) of 3−6 months and 27% had PFI of <3 months. ECOG Performance Status was 0 for 59%, 1 for 34% and 2 for 7% of the patients. The addition of bevacizumab to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. (19)

Wright and colleagues (35) reported a small retrospective study of 23 patients with epithelial ovarian carcinoma treated with bevacizumab in combination with other cytotoxic agents, a best overall response rate of progesterone resistance was noted in eight patients (35%). Ten patients had stable disease (44%) and 5 patients had progressive disease. Patients with progressive resistance had a median time to progression (TTP) of 5.6 months compared with 2.3 months for patients with stable disease. Three participants had a progression free interval greater than 6 months. Common adverse effects included proteinuria and hypertension. Thromboembolic complications occurred 9% in addition to two patients (4%) bleeding complications. Bowel obstruction occurred in five (22%) patients, with two patients (9%) experienced bowel perforations.

In 2012, Aghajanian et al. (36) reported results from the Ovarian Cancer Study comparing efficacy and safety of chemotherapy and anti-angiogenic therapy in platinum-sensitive recurrent disease. This phase III, randomized, double-blind clinical trial investigated the safety and efficacy of gemcitabine (GC) plus bevacizumab compared to GC plus placebo in women with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer. The primary endpoint was PFS. A total of 484 individuals were randomized between April 2007 and January 2010. Two hundred forty-two women (n=242) were assigned to the bevacizumab arm and 242 were assigned to the GC plus Placebo arm. With a median follow-up of 24 months, the PFS was increased in the bevacizumab arm (12.4 months) compared to the PL arm (8.4 months) with a HR 0.484 (95% CI, 0.388 to 0.605; P<0.0001). Treatment was discontinued most commonly for progressive disease 66.1% in the Placebo arm and 43.0% in the bevacizumab arm. Serious adverse events were 24.9% in the Placebo arm and 34.8% in the bevacizumab arm. The authors noted limitations of the study which included lack of quality-of-life data and specimen collection for biomarker analysis.

Burger et al. (37) reported data from a GOG phase 3 double-blind trial (GOG-0218) that randomized 1873 women with stage 3 or stage 4 epithelial ovarian cancers to 1 of 3 first-line treatment groups. All three of the cohorts included treatment with paclitaxel and carboplatin for the first 6 cycles. The control cohort included 625 individuals who received chemotherapy with the addition of a placebo in cycle 2 through cycle 22. The bevacizumab initiation-therapy group of 625 women received chemotherapy in addition to bevacizumab 15mg/kg in cycle 2 through 6, and then placebo for the duration of the treatment cycles. The third cohort included 623 individuals who received chemotherapy plus bevacizumab-throughout, with bevacizumab starting in cycle 2 and continued until cycle 22 was completed. The primary endpoint of OS was changed to PFS midway through the trial, and 19% of the participants had completed the planned treatment and 66% had prematurely discontinued from the study treatment, most commonly resulting from disease progression. There was no significant difference between the control group, the bevacizumab-initiation and the bevacizumab-throughout cohorts, with the median PFS of 10.3, 11.4 and 14.1 months respectively. The median OS did not differ significantly with 39.3, 38.7 and 39.7 months observed for the control cohort, the bevacizumab-initiation cohort and the bevacizumab-throughout cohort, respectively. The HR for progression or death compared to control treatment, the HR 0.908 (95% CI, 0.795 to 1.040; p=0.16) with bevacizumab-initiation and 0.717 (95% CI, 0.625 to 0.824; P<0.001) with bevacizumab-throughout. There was an increased rate of (22.9%) hypertension in the bevacizumab-throughout group, 16.5% in the bevacizumab-initiation group and 7.2% in the control group. Gastrointestinal disruption that required medical attention occurred in 1.2% of the control group, 2.8% of the bevacizumab-initiation group and 2.6% of the bevacizumab-throughout group. Although QOL scores were slightly lower in the bevacizumab groups during the chemotherapy phases, there were no significant differences in the mean QOL scores after chemotherapy was completed. Burger and colleagues concluded bevacizumab could be considered a frontline therapy option" but additional studies are needed to assess optimal timing and duration of therapy along with integration with other standard therapies to treat ovarian cancer.

In 2011, the International Collaboration on Ovarian Neoplasms (ICON7) trial (38) randomized 1528 women with ovarian cancer to carboplatin and paclitaxel or to the same chemotherapy regimen with the addition of bevacizumab 7.5mg/kg every 3 weeks for 5 or 6 cycles and then for 12 additional cycles or until disease progression. Primary outcome measures were PFS and OS. In the updated analysis at a mean follow-up of 42 months, median durations of PFS was 19.8 months and 17.4 months for the bevacizumab treatment group and the chemotherapy group, respectively. The corresponding restricted means of PFS was 22.4 months for the chemotherapy control group and 24.1 months for the bevacizumab group (p=0.04). In the subset analysis, women with high risk for progression, the median PFS was 14.5 months in the control group and 18.1 months in the bevacizumab treatment group. There was a trend towards improved OS with a HR for death 0.85 (95% CI, 0.69 to 1.04; p=0.11) in the bevacizumab group when compared to the control group. The investigators noted an OS advantage in the subset of women at high-risk for progression of disease with a median of 36.6 months OS in the bevacizumab treatment group compared to 28.8 months in the control group (p=0.002). Adverse toxicities of grade 3 or higher were reported in 56% of the control group and 66% in the bevacizumab treatment group with hypertension as the most frequently occurring event. Perren et al. noted there was maximum improvement of PFS at 12 months, but the effect diminished by 24 months.

In 2014, Pujade-Lauraine et al. (39) indicated that in platinum-resistant ovarian cancer, single-agent chemotherapy is the standard treatment. The authors completed the Aurelia randomized phase III trial combining bevacizumab with chemotherapy in platinum-resistant ovarian cancer.

Eligible patients had measurable/assessable ovarian cancer that had progressed <6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected the chemotherapy (PLD, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab until disease progression, unacceptable toxicity, or patient withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end-point was PFS. Secondary end points included ORR, OS, safety, and patient-reported outcomes. The PFS HR after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < 0.001). Median PFS was 3.4 months with chemotherapy alone vs. 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% vs. 27.3%, respectively (p=0.001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P<0.174; median OS, 13.3 vs. 16.6 months, respectively). Grade ≥2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. The study concluded that adding bevacizumab to the chemotherapy regime significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

In 2015, Oza et al. (40) reported on the final OS results of the ICON7 trial. Median follow-up at the end of the trial was 48.9 months, at which point 714 participants had died (352 in the chemotherapy group and 362 in the bevacizumab group). The OS benefit of bevacizumab was not increased in the whole study population (restricted mean survival time 44.6 months [95% CI, 43.2-45.9] in the standard chemotherapy group vs. 45.5 months [44.2-46.7] in the bevacizumab group; p=0.85). In an exploratory analysis of a predefined subgroup of 502 participants with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in OS was observed between women who received bevacizumab plus chemotherapy vs. those who received chemotherapy alone (restricted mean survival time 34.5 months [95% CI, 32.0-37.0] with standard chemotherapy vs. 39.3 months [37.0-41.7] with bevacizumab; p=0.03). However, in non-high-risk participants, the restricted mean survival time did not differ significantly between the 2 treatment groups (49.7 months [95% CI, 48.3-51.1]) in the standard chemotherapy group vs. 48.4 months [47.0-49.9] in the bevacizumab group; p=0.20). An updated analysis of PFS showed no difference between treatment groups. One additional treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated participant) was noted in addition to three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated participants), and one grade 1 treatment-related event (vaginal hemorrhage, in a participant treated with standard chemotherapy) were reported. The authors concluded that Bevacizumab, added to platinum-based chemotherapy, did not increase OS in the study population as a whole. However, an OS benefit was recorded in poor-prognosis patients, which is concordant with the PFS from ICON7 and GOG-218 studies, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for ovarian cancer (4) recommends the off-label use of bevacizumab for the following indications:

  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer - epithelial with serous or endometrioid histology when:
    • Used as neoadjuvant chemotherapy in combination with paclitaxel and carboplatin for bulky stage III-IV disease or poor surgical candidates (2B recommendation). NCCN stated bevacizumab containing regimen should be used with caution before debulking surgery due to potential interference with postoperative healing.
    • Used in combination with paclitaxel and carboplatin when used as a:

      a) Primary treatment for patients with incomplete previous surgery and/or staging with suspected stage IA-IB, grade 2-3 or clear cell, or stage IC and no suspected residual disease. (2B recommendation)

      b) Primary treatment for patients with incomplete previous surgery and/or staging with stage II-IV and suspected unresectable residual disease. (2B recommendation)

      c) Primary adjuvant therapy for pathologic stage IA-IB (grade 2 serous/endometrioid or grade 3), stage IC (grades 1-3), or stage II-IV disease. (2B recommendation)

  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer - epithelial with serous, endometrioid, carcinosarcoma, clear cell or mucinous histology when used as therapy for persistent disease or recurrence when used:
    • As preferred therapy if platinum-sensitive, in combination with carboplatin and gemcitabine. (2A recommendation)
    • If platinum-sensitive, in combination with carboplatin and paclitaxel. (2A recommendation)
    • As preferred therapy if platinum-resistant, in combination with liposomal doxorubicin, weekly paclitaxel, or topotecan. (2A recommendation)
    • As preferred therapy when used as a single agent. (2A recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer - epithelial with serous, endometrioid, carcinosarcoma, clear cell or mucinous histology when used as maintenance therapy for platinum-sensitive persistent disease or recurrence following response to combination therapy with:
    • Carboplatin, gemcitabine, and bevacizumab. (2A recommendation)
    • Carboplatin, paclitaxel, and bevacizumab. (2A recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer – carcinosarcoma (malignant mixed mullerian tumors) when used as a preferred adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage I-IV disease. (2B recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer – carcinosarcoma with clear cell histology when used as an adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV disease. (2B recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer – carcinosarcoma with mucinous histology when used as adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV disease. (2B recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer – carcinosarcoma with mucinous histology when used as preferred therapy if platinum-sensitive, for persistent disease or reoccurrence in combination with fluorouracil, leucovorin, and oxaliplatin. (2B recommendation)
  • Ovarian cancer, fallopian tube cancer, primary peritoneal cancer – Grade 1 serous, endometrioid epithelial carcinoma when used as adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV low-grade serous/grade 1 endometrioid epithelial carcinoma or borderline epithelial tumors with invasive implants. (2B recommendation)
  • Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer – Malignant Sex-Cord Stromal tumor when used as a single agent for clinical relapse in patients with stage II-IV disease. (2A recommendation)

Renal Cell Carcinoma-Metastatic (mRCC; Kidney Cancer-Metastatic)

In July 2009, the FDA granted approval for the use of bevacizumab in combination with interferon alfa (IFN) for the treatment of patients with mRCC. (1, 19) Patients with treatment naïve mRCC were studies in a multicenter, randomized, double-blind, international study comparing bevacizumab plus interferon alfa 2a (IFN-α2a) vs. placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg IV infusion every 2 weeks; n=327) or placebo (IV every 2 weeks; n=322) in combination with IFN-α2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS. The median age was 60 years (range 18-82), 96% were white, and 70% were male. The study 935 population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate 936 (1-2), 8% poor (3-5), and 7% missing. PFS was statistically significantly prolonged among patients receiving bevacizumab plus IFN-α2a compared to those receiving IFN-α2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value ≤0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 941 12%, p ≤0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the bevacizumab plus IFN-α2a arm and 21 months in the IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

In 2003, Yang et al. (41) conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against VEGF, in patients with mRCC. This was a randomized, double-blind, phase 2 trial comparing placebo with bevacizumab at doses of 3 and 10 mg per kg of body weight, given every 2 weeks; the TTP of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (HR 2.55; P<0.001). There was a small difference, of borderline significance, between the TTP of disease in the low-dose--antibody group and that in the placebo group (HR 1.26; p=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose--antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in OS between groups (P>0.20 for all comparisons). The study determined that bevacizumab can significantly prolong the TTP of disease in patients with mRCC.

In 2007, Escudier et al. (42) investigated the combination treatment of humanized anti-VEGF monoclonal antibody bevacizumab with IFA in a multicentre, randomized, double-blind, phase III trial. Six hundred forty-nine (n=649) patients with previously untreated mRCC were randomized to receive IFN-a2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and IFN-a2a (n=322). The primary endpoint was OS. Secondary endpoints included PFS and safety. An interim analysis of OS was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of OS data. The protocol was amended to allow the study to be unblinded at this point. Three hundred twenty-five patients in the bevacizumab plus IFN group and 316 in the placebo plus IFN group received at least 1 dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus IFN group and 275 in the control group; there were 114 deaths in the bevacizumab plus IFN group and 137 in the control group. Median duration of PFS was significantly longer in the bevacizumab plus IFN group than it was in the control group (10.2 months vs. 5.4 months). Increases in PFS were seen with bevacizumab plus IFN irrespective of risk group or whether reduced-dose IFN was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs. 25 [8%] in the control group) and asthenia (34 [10%] vs. 20 [7%]). The study determined that the combination of bevacizumab with IFN as first-line treatment in patients with mRCC results in a significant improvement in PFS, compared with IFN alone.

In 2014, Rini et al. (43) performed a phase III, open-label, randomized trial, where the combination of bevacizumab and temsirolimus was compared with bevacizumab and IFN to treat previously untreated metastatic RCC. The primary endpoint was PFS assessed by independent reviewers. A total of 791 individuals were randomized to the treatment arms. The median PFS was 9.1 months for individuals treated with temsirolimus and bevacizumab compared to 9.3 months in individuals treated with IFN and bevacizumab (p=0.8). The study concluded the combination of temsirolimus and bevacizumab was not superior to IFN and bevacizumab as a first-line of therapy for metastatic RCC.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for kidney cancer (4) recommends the off-label use of bevacizumab for tumors with clear cell and non-clear cell histology for relapse or surgically unresectable stage IV kidney cancer when used:

  • In combination with interferon alfa-2b as first-line therapy for predominant clear cell histology. (1 recommendation)
  • As preferred single-agent subsequent therapy for predominant clear cell histology. (2B recommendation)
  • As single-agent systemic therapy for non-clear cell histology. (2A recommendation)
  • In combination with erlotinib or everolimus for select patients with advanced papillary renal cell carcinoma including hereditary leiomyomatosis and renal cell cancer. (2A recommendation)

Soft Tissue Sarcoma

In 2011, Park et al. (44) retrospectively analyzed the records of 14 patients with confirmed hemangiopericytomas and malignant solitary fibrous tumors. All patients were treated with temozolomide 150 mg/m2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg IV on days 8 and 22, repeated at 28-day intervals. Computed tomography assessment of tumor size and density (Choi criteria) was used to determine the best response to therapy. The Kaplan-Meier method was used to estimate PFS. Median follow-up period was 34 months. Eleven patients (79%) achieved a Choi partial response, with a median time to response of 2.5 months. Two patients (14%) had stable disease as the best response, and 1 patient (7%) had Choi progressive disease as the best response. The estimated median PFS was 9.7 months, with a 6-month progression-free rate of 78.6%. The most frequently observed toxic effect was myelosuppression. The authors determined that combination therapy utilizing temozolomide and bevacizumab is a generally well-tolerated and a clinically beneficial regimen for these select subgroup of patients.

In 2013, Agulnik M, et al. (45) sought to determine the safety and efficacy of bevacizumab in the treatment of metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas. This single-arm phase II trial, enrolled 32 patients that received bevacizumab 15 mg/kg IV infusion in 21-day cycles. These patients had disease that was deemed unresectable, had a ECOG performance status of ≤1, adequate organ function and the patients did not have a history of any radiation treatment within the prior 28 days. Of the 30 patients evaluated for efficacy and toxic effect, 4 (2 angiosarcoma and 2 epithelioid hemangioendothelioma; 17%) had a partial response, 15 patients (11 angiosarcoma and 4 epithelioid hemangioendothelioma; 50%) showed stable disease with a mean time to progression of 26 weeks. Bevacizumab was well tolerated with only 1 grade IV adverse event. Expected known toxic effects of the drug were manageable. The authors noted that bevacizumab is an effective and well-tolerated treatment for metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for soft tissue sarcoma (4) recommend the off-label use of bevacizumab as a single agent therapy for angiosarcoma. Combination bevacizumab with temozolomide was recommended for the treatment of solitary fibrous tumor and hemangiopericytoma. These recommendations were based on 2A category of evidence

Pancreatic Adenocarcinoma

Bevacizumab, a VEGF-specific angiogenesis inhibitor, is used in the treatment of a variety of cancers. Because VEGF appears to play a role in pancreatic cancer, bevacizumab was considered a promising therapy. The results of 2 older phase 2 trials seemed to indicate a potential benefit. (46, 47) Approximately 89% to 93% of pancreatic cancer patients have a VEGF variant, which is associated with early recurrence after surgery, liver metastases, and poor prognosis. A VEGF variant in tumors also correlates with tumor size. (48)

Systematic Reviews

Five studies were identified as part of a 2009 Blue Cross Blue Shield (BCBSA) Technology Evaluation Center (TEC) Assessment that tested the use of bevacizumab in patients with advanced adenocarcinoma. (49) These studies consisted of 2 Phase 3 trials, 2 Phase 2 trials, and 1 Phase 1 trial. In all trials, bevacizumab was added to gemcitabine, the latter which is considered the current standard of care. Some trials also included other agents as well, including cisplatin and erlotinib.

Randomized Controlled Trials

The 2 phase 3 trials, by Kindler et al. (2010) and by Van Cutsem et al. (2009) provided the strongest evidence because of their designs and are the primary focus of the BCBSA TEC Assessment. (50, 51) Neither trial demonstrated that the addition of bevacizumab resulted in a statistically significant difference in the primary outcome of OS. For the secondary outcome of PFS, the Van Cutsem study (51) showed benefit, while the Kindler study (50) did not.

In 2005, Kindler et al. (52) randomized 590 patients with advanced pancreatic cancer (local or metastatic) to gemcitabine with or without bevacizumab. This study demonstrated sufficient activity to proceed to the phase 3 trial reported by Kindler et al. in 2010 (50). The latter trial was stopped early when it was determined that combination gemcitabine plus bevacizumab could not achieve longer survival than gemcitabine alone.

Van Cutsem et al. randomized 607 patients with metastatic adenocarcinoma of the pancreas to gemcitabine plus erlotinib, with or without bevacizumab. (51) There was no statistically significant difference between the 2 groups in the primary outcome of OS. Median OS was 7.1 months for the treatment group and 6.0 months for the control group HR, 0.89; 95% confidence interval [CI], 0.74 to 1.07; p=0.21). The trial reported a statistically significant difference in PFS of 4.6 months in the treatment arm and 3.6 months in the control group (HR=0.73; 95% CI, 0.61 to 0.86; p<0.001). Although this secondary outcome was significant, few details were given on the methods used to assess PFS, which might have been subject to greater measurement error than OS.

Phase 2 trials have evaluated bevacizumab alone or in combination with cytotoxic chemotherapy for metastatic pancreatic cancer; they are briefly described.

In 2011, Fogelman et al. reported on a phase 2 trial of bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer. (53) Eligible patients had stage III (n=14) or IV (n=36) pancreatic cancer and had received no prior gemcitabine. Treatment cycles were repeated every 2 weeks, and computed tomography was performed every 6 weeks. Fifty patients were enrolled: 14 had stage III disease, the remainder, stage IV. Median age was 59 years. The overall response rate was 36%; 34% demonstrated stable disease. Median PFS was 4.9 months; median survival was 11.9 months; 1-year survival was 42%. Patients with locally advanced disease lived 12.8 months; patients with metastatic disease lived 10.2 months. The authors concluded that the regimen did not meet the objective of a 14-month median survival and that the toxicity was significant.

Ko et al. (2012) conducted a phase 2 randomized trial of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for advanced pancreatic adenocarcinoma. (54)

Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab plus cetuximab, either with (arm A; n=30) or without (arm B; n=31) gemcitabine. Tumor assessments were performed every 8 weeks. The primary study end point was PFS. Median treatment duration was 9 weeks in arm A and 8 weeks in arm B (range, 2.0-40.4 weeks). Patients in arm A had median PFS and OS values of 3.55 months and 5.41 months, respectively, compared with 1.91 months and 4.17 months in arm B. The trial closed early due to lack of sufficient efficacy in both treatment arms. The authors concluded that the combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine and suggested that a strategy of dual epidermal growth factor receptor and VEGF inhibition in pancreatic cancer did not warrant further development.

In 2011, Astsaturov et al. reported on a phase 2 randomized, open-label trial for patients with metastatic pancreatic cancer. (55) Patients were randomized to bevacizumab alone or in combination with docetaxel cytotoxic therapy. The primary end-point was PFS. At 4 months, only 2 and 3 patients were stable, respectively, and the trial was discontinued on the study-defined grounds of the futility of less than 25% PFS in the 2 groups.

Noncontrolled Trials

Martin et al. (2012) investigated the safety and efficacy of bevacizumab combined with gemcitabine followed by infusional 5-fluorouracil in patients with advanced pancreatic cancer in a phase 2 trial. (56) The primary end-point was the proportion of patients with PFS at 6 months from initiation of therapy. If PFS at 6 months was 41% or more, the regimen would be considered promising. Of the 42 patients enrolled in the study, 39 were evaluable for the primary end-point. PFS at 6 months was 49% (95% CI, 34% to 64%). Median PFS was 5.9 months (95% CI, 3.5 to 8.1 months), and median OS was 7.4 months (95% CI, 4.7 to 11.2 months). Partial response and stable disease occurred in 30% and 45% of patients, respectively. Grade 3 and 4 toxicities included fatigue (14%), hypertension (5%), and venous thrombosis (5%). The authors concluded that the study met its primary end-point and that further investigation of anti-VEGF therapy in combination with fluoropyrimidine-based therapy was warranted in advanced pancreatic cancer.

Ko et al. (2010) reported partial results of a phase 2, noncontrolled study of gemcitabine-refractory metastatic pancreatic cancer patients treated with bevacizumab and erlotinib. (57) Recruitment stalled after the publication of the relative ineffectiveness of bevacizumab in the phase 3 trials previously described. Of the 36 patients followed in this study, 8 (22%) reached the primary end-point of 6-month survival. This survival rate for bevacizumab-treated patients was inferior to published rates of cytotoxic regimens.

Observational Studies

Single-arm case series published both before and after the phase 3 studies reported by Kindler et al. and Van Cutsem et al. have reported on outcomes for pancreatic cancer after treatment with bevacizumab. Given the availability of phase 2 and 3 clinical trials, the case series data do not provide significant additional data on efficacy. Examples of single-arm observational studies include: Crane et al. (58), Javle et al. (59), Tai et al., (60) and Phillip et al. (61).

National Comprehensive Cancer Network (NCCN)

The NCCN clinical practice guidelines for pancreatic adenocarcinoma (v.3.2017) state that gemcitabine is recommended for pancreatic cancer patients with locally advanced or metastatic disease. (7) While phase 2 studies have suggested some benefit from adding another chemotherapy agent (e.g., bevacizumab or cetuximab), phase 3 studies have shown that the only new targeted drug for which there is evidence of a statistically significant increase in survival when combined with gemcitabine is erlotinib.

Prostate Carcinoma

In 2008, Di Lorenzo et al. (62) studied the combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer. Typically, the taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), although most patients eventually progress while receiving taxane-based treatments. No agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure. Twenty highly pretreated patients with HRPC received bevacizumab (10mg/kg) and docetaxel (60mg/m2) every 3 wk. All patients had bone metastases and 8 had measurable lesions. Eleven patients (55%) had major prostate-specific antigen (PSA) responses, and 3 (37.5%) had objective responses. Seven major PSA responses were recorded in the same patients who had reported a >50% PSA decrease after first-line docetaxel. However, four major PSA responses were observed in patients previously nonresponsive to docetaxel alone. The treatment was well tolerated. The study concluded that the combination of bevacizumab and docetaxel is active and well tolerated. Continued investigation of bevacizumab with cytotoxic chemotherapy is warranted in HRPC.

In 2012 Kelly and colleagues (63) completed a randomized, placebo-controlled study that evaluated the potential role of VEGF in prostate cancer. Patients with chemotherapy-naive progressive metastatic castration-resistant prostate cancer (mCRPC) with ECOG performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m2 IV over 1 hour for 21 days plus prednisone 5 mg orally twice per day with either bevacizumab 15 mg/kg IV every 3 weeks or placebo. The primary end-point was OS, and secondary end-points were PFS, 50% decline in prostate-specific antigen, ORR, and toxicity. In total, 1,050 patients were randomly assigned. The median OS for patients given docetaxel and prednisone + bevacizumab was 22.6 months compared with 21.5 months for patients treated with docetaxel and prednisone (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank p=0.181). The median PFS time was superior in the docetaxel and prednisone + bevacizumab arm (9.9 vs. 7.5 months, stratified log-rank P<0.001) as was the proportion of patients with ORR (49.4% vs. 35.5%; p =0.0013). Grade 3 or greater treatment-related toxicity was more common with docetaxel and prednisone + bevacizumab (75.4% vs. 56.2%; P≤0.001), as was the number of treatment-related deaths (4.0% vs 1.2%; p=0.005). The authors concluded that despite an improvement in PFS and ORR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was also associated with greater toxicity.

In 2015, Patel et al. (64) investigated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) with the use of bevacizumab in patients. Patients with mCRPC were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses. Of 1008 randomized patients, the odds of experiencing grade ≥3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥3 VTE (odds ratio, 0.60; p =0.08). In the multivariable analysis, bevacizumab treatment HR, 3.00; p=0.01) and age (HR, 1.06; p=0.02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; p=0.01) and VTE risk score (HR, 1.83; p=0.03) were significantly associated with the risk of VTE. Bevacizumab was significantly associated with a greater risk of ATE in patients with mCRPC, but not significantly associated with the risk of VTE.

In 2016, Mckay et al. (65) aimed to investigate the efficacy and toxicity of short-course androgen deprivation therapy (ADT) with or without bevacizumab in men with hormone-sensitive prostate cancer. Eligible patients had an increasing PSA of ≤50 ng/mL and PSA doubling time of <18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes <3 cm and 5 or fewer bone metastases). Patients were randomly assigned 2:1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end-point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). This randomized phase II trial concluded that ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and can remain off ADT for prolonged periods.

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for prostate cancer (4) does not indicate bevacizumab as a treatment modality for prostate cancer.

Uterine Neoplasms - Endometrial Carcinoma (Endometrioid Adenocarcinoma; Serous or Clear Cell Carcinoma; Undifferentiated/dedifferentiated Carcinoma; Carcinosarcoma)

National Comprehensive Cancer Network (NCCN)

The 2018 NCCN Drugs and Biologics Compendium (7) and the 2018 NCCN clinical practice guideline for prostate cancer (4) states Bevacizumab can be used as single-agent therapy for uterine neoplasms that has progressed on prior cytotoxic chemotherapy. (2A recommendation)

Summary of Evidence

The safety and effectiveness of bevacizumab for the treatment of additional off-label indications including, but not limited to carcinoid, melanoma, pancreatic and prostate cancer continue to be investigated. In addition, there are studies combining bevacizumab with other targeted chemotherapeutic agents. To date the evidence is inadequate to determine the effects of bevacizumab on health outcomes as there is insufficient data to support the safety and efficacy of bevacizumab outside of the FDA approved labelled indications and the off-label indications supported by a National Comprehensive Cancer Network 1, 2A, and 2B recommendation.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

C9257

HCPCS Codes

J9035

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position on at least 1 of the conditions addressed in this policy. Coverage may be subject to local carrier discretion.

National coverage positions for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

  1. FDA – Highlights of prescribing information: Avastin® (bevacizumab) (2004, revised February 5, 2017). Available at: <www.accessdata.fda.gov> (accessed April 4, 2018).
  2. NIH – Staging (March 19, 2015). National Cancer Institute of the National Institutes of Health. Available at: <https://www.cancer.gov> (accessed April 7, 2018).
  3. ECOG Performance Status (2017). Available at: <http://ecog-acrin.org> (accessed April 7, 2018).
  4. Bevacizumab. Microdex®2.0 (Healthcare Series). Thomson Reuters (Healthcare) Inc. (April 5, 2018). Available at: <www.micromedexsolutions.com> (accessed April 4, 2018).
  5. National Comprehensive Cancer Network (NCCN) - Bevacizumab (Avastin). NCCN Drugs and Biologics Compendium® (2018). Available at: <https://www.nccn.org> (accessed July 15, 2016).
  6. National Comprehensive Cancer Network (NCCN) - Patient and caregiver resources: Terms and definitions (2018). Available at: <https://www.nccn.org> (accessed April 7, 2018).
  7. National Comprehensive Cancer Network (NCCN) - NCCN Clinical Practice Guideline in Oncology.
  • AIDS related Karposi Carsoma (V1.2018). Available at: <https://www.nccn.org> (accessed January 17, 2018).
  • Breast Cancer (V1.2018). Available at: <https://www.nccn.org> (accessed April 11, 2018).
  • Central Nervous System Cancers (V1.2017). Available at: <https://www.nccn.org> (accessed January 17, 2018).
  • Cervical Cancer (V1.2018). Available at: <https://www.nccn.org> (accessed January 17, 2018).
  • Colon Cancer (V2.2018). Available at: <https://www.nccn.org> (accessed April 16, 2018).
  • Kidney Cancer (V2.2018). Available at: <https://www.nccn.org> (accessed January 17, 2018).
  • Non-Small Cell Lung Cancer (V2.2018). Available at: <https://www.nccn.org> (accessed April 16, 2018).
  • Ovarian Cancer (V2.2018) including Fallopian Tube Cancer and Primary Peritoneal Cancer. Available at: <https://www.nccn.org> (accessed February 2, 2016).
  • Pancreatic Adenocarcinoma (V3.2017). Available at: <https://www.nccn.org> (accessed April 24, 2018).
  • Prostate Cancer (V2.2018). Available at: <https://www.nccn.org> (accessed April 25, 2018).
  • Rectal Cancer (V1.2018). Available at: <https://www.nccn.org> (accessed April 24, 2018).
  • Soft Tissue Sarcoma (V1.2018). Available at: <https://www.nccn.org> (accessed January 17, 2018).

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       22. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21(1):60-5. PMID 12506171
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       24. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. ASCO Annual Meeting. 2005. PMID 17442997
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       27. Martin RC, Scoggins CR, Schreeder M, et al. Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis. Cancer. Oct 15 2015; 121(20):3649-58. PMID 26149602
       28. Haller DG, O'Connell MJ, Cartwright TH, et al. Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized, controlled trials. Ann Oncol. Apr 2015; 26(4):715-24. PMID 25595934
       29. Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. May 9 2015; 385(9980):1843-52. PMID 25862517
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       33. Langer CJ1, Socinski MA, Patel JD, et al. Isolating the Role of Bevacizumab in Elderly Patients with Previously Untreated Nonsquamous Non-Small Cell Lung Cancer: Secondary Analyses of the ECOG 4599 and PointBreak Trials. Am J Clin Oncol. Oct 2016; 39(5):441-7. PMID 25628268
       34. Karayama M, Inui N, Fujisawa T, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Eur J Cancer. May 2016; 58:30-7. PMID 26922170
       35. Wright J, Hagemann A, Rader JS, et al. Bevacizumab combination therapy in recurrent, platinum- refractory, epithelial ovarian carcinoma. Cancer 2006; 107(1):83-9. PMID 16736514
       36. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer. J Clin Oncol. 2012; 30(17):2039-2045. PMID 22529265
       37. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. New Engl J Med. 2011; 365(26):2473-2483. PMID 22204724
       38. Perren TJ, Swart AM, Pfisterer J, et al. ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. New Engl J Med. 2011; 356(26):2484-2496. PMID 22204725
       39. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. May 1 2014; 32(13):1302-8. PMID 24637997
       40. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. Aug 2015; 16(8):928-36. PMID 26115797
       41. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. New Engl J Med. 2003; 349(5):427-34. PMID 12890841
       42. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized double-blind phase III trial. Lancet. 2007; 370(9605):2103-11. PMID 18156031
       43. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014; 32(8):752-759. PMID 24297945
       44. Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer. Nov 1 2011; 117(21):4939-47. PMID: 21480200
       45. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013; 24(1):257-263. PMID 22910841
       46. Ko AH, Tempero MA. Treatment of metastatic pancreatic cancer. J NCCN. 2005; 3(5):627-36. PMID 16194454
       47. Ducreux M, Boige V, Malka D. Treatment of advanced pancreatic cancer. Semin Oncol 2007; 34(2 Suppl 1): S25-30. PMID 17449349
       48. Borja-Cacho D, Jensen EH, Saluja AK et al. Molecular targeted therapies for pancreatic cancer. American Journal of Surgery 2008; 196(3):430-41. PMID 18718222
       49. Off-label use of bevacizumab: advanced adenocarcinoma of the pancreas. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center Assessment Program (2009) 24:4
       50. Kindler HL, Niedzwiecki D, Hollis D et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010; 28(22):3617-22. PMID 20606091
       51. Van Cutsem E, Vervenne WL, Bennouna J et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009; 27(13):2231-7. PMID 19307500
       52. Kindler HL, Friberg G, Singh DA et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005; 23(31):8033-40. PMID 16258101
       53. Fogelman D, Jafari M, Varadhachary GR et al. Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial. Canc Chemother and Pharmacol. 2011; 68(6):1431-8. PMID 21479635
       54. Ko AH, Youssoufian H, Gurtler J, et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Invest New Drugs. Aug 2012; 30(4):1597-1606. PMID 21629990
       55. Astsaturov IA, Meropol NJ, Alpaugh RK et al. Phase II and coagulation cascade biomarker study of bevacizumab with or without docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma. Am J Clin Oncol. 2011; 34(1):70-5. PMID 20458210
       56. Martin LK, Li X, Kleiber B, et al. VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA. Ann Oncol. Jul 5 2012; 23(11):2812-2820. PMID 22767582
       57. Ko AH, Youssoufian H, Gurtler J et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Invest New Drugs. 2012; 30(4):1597-606. PMID 20130876
       58. Crane CH, Winter K, Regine WF et al. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. J Clin Oncol. 2009; 27(25):4096-102. PMID 19636002
       59. Javle M, Yu J, Garrett C et al. Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study. British Journal of Cancer. 2009; 100(12):1842-5. PMID 19491904
       60. Tai CJ, Huang MT, Wu CH, et al. Two targeted medications (bevacizumab plus cetuximab) improve the therapeutic response of pancreatic carcinoma. Medicine (Baltimore). Apr 2016; 95(15):e3259. PMID 27082562
       61. Phillip V, Zahel T, Bartl K, et al. Influence of sorafenib and bevacizumab on pancreatic volume - A monocentric CT based analysis. Pancreatology. Jul-Aug 2016; 16(4):621-624. PMID 26968257
       62. Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol. Nov 2008; 54(5):1089-94. PMID 18276061
       63. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. May 2012; 30(13):1534-40. PMID 22454414
       64. Patel JN1, Jiang C, Hertz DL, Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer. Apr 1 2015;121(7):1025-31. PMID 25417775
       65. McKay RR, Zurita AJ, Werner L, et al. A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy with or without Bevacizumab for Patients with Recurrent Prostate Cancer After Definitive Local Therapy. J Clin Oncol. June 1 2016; 34(16):1913-20. PMID: 27044933
       66. Bevacizumab in advanced adenocarcinoma of the pancreas. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (November 2017) Prescription Drug 5.01.18.

Policy History:

Date Reason
11/1/2018 Document updated with literature review. Entire document significantly revised. Coverage section revision was based on the Food and Drug Administration label and/or National Comprehensive Cancer Network guidelines. Added references 2, 3, 5-9, 11-15, 18, 19, 30-34, 39, 40, 44, 45, 60-63.
3/1/2017 Document updated with literature review. Entire document significantly revised. Coverage section revision was based on the FDA label and/or NCCN guidelines.
3/15/2015 Reviewed. No changes.
12/14/2014 Document updated with literature review. The following changes were made to the coverage section: Bevacizumab may be considered medically necessary 1) as a single agent for the treatment of angiosarcoma; 2) For endometrial cancer (endometrioid, papillary serous or clear cell) for members who have progressed on prior cytotoxic chemotherapy; 3) For the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent; 4) Single agent treatment for disease progression for adult intracranial and spinal ependymoma cancer (excluding subependymoma); 5) Treatment of recurrent disease or salvage therapy for anaplastic gliomas, glioblastoma either as a single agent or in combination with irinotecan, carmustine, lomustine, temozolomide, or carboplatin; 6) For persistent or recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; 7) For relapsed granulosa-cell tumors of the ovary (sex cord-stromal tumors); 8) when used in combination with temozolomide for the treatment of solitary fibrous tumor and hemangiopericytoma; 9) For treatment of persistent, recurrent, or metastatic carcinoma of the cervix as first line therapy in combination with either paclitaxel and cisplatin or paclitaxel and topotecan, or second-line therapy as a single agent. Note added to refer to Policy RX503.001 for additional off-label indications. Entire rationale revised. Added “For Oncology Indications” to title.
5/15/2013 Document updated with literature review. The following was added to coverage: Bevacizumab may be considered medically necessary in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin-based chemotherapy for patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.
9/1/2012 Document updated with literature review. Coverage changed to conditionally allow Bevacizumab as medically necessary for non-small-cell lung cancer when used: 1) as a single agent maintenance therapy in the absence of disease progression, and 2) in combination with platinum-based doublet chemotherapy as second-line treatment of patients with non-squamous non-small cell lung cancer who have experienced disease progression during or after first-line treatment with erlotinib or crizotinib. Rationale was revised. All information on VEGF inhibitors for use in the eye were removed from this policy and transferred to OTH903.020.
1/1/2011 Document updated with literature review. The following was added: Bevacizumab may be considered medically necessary as a non-FDA labeled indication for second-line therapy as a single agent for treatment of metastatic squamous cell carcinoma of the cervix, for local or regional recurrence of cervical cancer in patients who have received prior radiation therapy, and for distant metastases of cervical cancer.
7/15/2010 Document updated with literature review. The following was added: Bevacizumab (Avastin™) may be considered medically necessary as a non-FDA labeled indication in combination with oxaliplatin and capecitabine (oral 5-fluorouracil-based chemotherapy) for patients with metastatic colorectal cancer for first-line treatment.
9/15/2009 Coverage change, the continuation of Avastin for breast cancer as a single agent once the approved combination agent has been discontinued is now considered experimental, investigational and unproven. Coverage revised as the FDA has approved Avastin for the treatment of glioblastoma of brain with progressive disease following prior therapy as a single agent and metastatic renal cell carcinoma, in combination with interferon alfa. Additional off-label indications for Avastin for intravitreal injection have been added to the policy: Choroidal Neovascular Membrane (CNVM), or Subretinal Neovascular Membrane (SRNVM), Proliferative Retinopathy, Macular Edema.
7/1/2009 Coverage revised. Added continuation of Avastin for breast cancer as a single agent once the approved combination agent has been discontinued is considered experimental, investigational and unproven.
2/1/2009 New medical document originating from RX502.029

Archived Document(s):

Title:Effective Date:End Date:
Bevacizumab (Avastin) For Oncology Indications03-01-201710-31-2018
Bevacizumab (Avastin) For Oncology Indications.03-15-201502-28-2017
Bevacizumab (Avastin) For Oncology Indications.12-15-201403-14-2015
Bevacizumab (Avastin)05-15-201312-14-2014
Bevacizumab (Avastin)09-01-201205-14-2013
Bevacizumab (Avastin)01-01-201108-31-2012
Bevacizumab (Avastin)07-15-201012-31-2010
Bevacizumab (Avastin)09-15-200907-14-2010
Bevacizumab (Avastin)07-01-200909-14-2009
Bevacizumab (Avastin)02-01-200906-30-2009
Bevacizumab (Avastin) for Oncologic Indications12-01-200801-31-2009
Bevacizumab (Avastin) for Oncologic Indications07-15-200811-30-2008
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