Clinical UM Guideline

 

Subject: Bevacizumab (Avastin®) for Non-Ophthalmologic Indications
Guideline #: CG-DRUG-68 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

This document addresses the indications and criteria for the use of bevacizumab in the treatment of oncologic conditions and other non-ophthalmologic indications.  Bevacizumab (Avastin, Genentech, San Francisco, CA) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF).

Note: Please see the following related documents for additional information:

Clinical Indications

Medically Necessary:

  1. Breast Cancer
    1. Bevacizumab is considered medically necessary in the treatment of individuals with metastatic breast carcinoma when all of the following criteria are met:
      1. HER2-negative breast cancer; and
      2. Bevacizumab is used in first-line chemotherapy* for treatment of metastatic disease; and
      3. Bevacizumab is used in combination with paclitaxel or paclitaxel protein-bound.
        *Note: Hormonal therapy alone is not considered “chemotherapy.”
  2. Central Nervous System – Primary Tumor
    1. Bevacizumab is considered medically necessary in the treatment of individuals with a primary central nervous system tumor who have failed radiation therapy when the following criteria are met:
      1. Bevacizumab is used in a single line of therapy; and
      2. The tumor to be treated is a World Health Organization (WHO) Grade III/IV glioma (includes, but is not limited to):
        1. Anaplastic astrocytoma; or
        2. Anaplastic glioma; or
        3. Ependymoma, progressive or recurrent; or
        4. Glioblastoma; or
        5. Glioblastoma multiforme; or
        6. High-grade glioma, recurrent.
  3. Cervical Cancer
    1. Bevacizumab is considered medically necessary in the treatment of individuals with metastatic cervical cancer when all of the following criteria are met:
      1. Individual has recurrent or persistent disease that is not amenable to curative treatment with surgery or radiotherapy; and
      2. Bevacizumab is used in combination with paclitaxel and topotecan, or with paclitaxel and cisplatin chemotherapy; and
      3. Bevacizumab is used in a single line of therapy.
  4. Colon, Rectal, Colorectal and Small Bowel Adenocarcinoma
    1. Bevacizumab is considered medically necessary in the treatment of individuals with metastatic colon, rectal, colorectal, or small bowel adenocarcinoma when the following criteria are met:
      1. Bevacizumab is used in a combination with 5-fluoruracil-based chemotherapy, irinotecan or oxaliplatin; and
      2. Individual has not progressed on more than two lines of a bevacizumab-containing chemotherapy regimen.
  5. Malignant Mesothelioma
    1. Bevacizumab is considered medically necessary in the treatment of individuals with unresectable malignant mesothelioma when the following criteria are met:
      1. Bevacizumab is used in a first-line combination chemotherapy with cisplatin or carboplatin and pemetrexed; and
      2. Individual has an Eastern Cooperative Oncology Group performance status of 0-2 and no history of bleeding or thrombosis.
    2. Bevacizumab as maintenance therapy is considered medically necessary in the treatment of individuals with malignant mesothelioma when all of the following criteria are met:
      1. Bevacizumab was previously administered as an agent in a first-line combination chemotherapy regimen; and
      2. Bevacizumab is used as a single agent; and
      3. Bevacizumab is used until disease progression*.
        *Note: Once disease progression has occurred, bevacizumab is not to be re-instituted.
  6. Non-Small Cell Lung Cancer
    1. Bevacizumab is considered medically necessary in the treatment of individuals with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) when the following criteria are met:
      1. Bevacizumab is used in first-line combination chemotherapy with platinum-based therapy and a taxane or pemetrexed; and
      2. Individual has an Eastern Cooperative Oncology Group performance status of 0-1 and no history of hemoptysis.
    2. Bevacizumab as maintenance therapy is considered medically necessary in the treatment of individuals with unresectable, locally advanced, recurrent or metastatic non-squamous, NSCLS when all of the following criteria are met:
      1. Bevacizumab was previously administered as an agent in a first-line combination chemotherapy regimen; and
      2. Bevacizumab is used as a single agent; and
      3. Bevacizumab may be used until disease progression.
  7. Ovarian Cancer
    1. Bevacizumab is considered medically necessary in the treatment of individuals with recurrent, metastatic epithelial ovarian cancer, fallopian tube cancer or recurrent primary peritoneal cancer when all of the following criteria are met:
      1. Bevacizumab is used as a single agent or in combination with other chemotherapy; and
      2. Bevacizumab is used in a single line of therapy; and
      3. Bevacizumab is used for relapsed or refractory disease.
    2. Bevacizumab as maintenance therapy is considered medically necessary in the treatment of individuals with recurrent, metastatic epithelial ovarian, fallopian tube, or primary peritoneal cancer when all of the following criteria are met:
      1. Bevacizumab was previously administered as an agent in a first-line combination chemotherapy regimen; and
      2. Bevacizumab is used as a single agent; and
      3. Bevacizumab may be used until disease progression.
  8. Post-Radiation Necrosis
    1. Bevacizumab is considered medically necessary in the treatment of individuals with symptomatic post-radiation necrosis of the central nervous system.
  9. Renal Cell Carcinoma
    1. Bevacizumab is considered medically necessary in the treatment of individuals with renal cell carcinoma (RCC) when any of the following criteria are met:
      1. Bevacizumab is used in first-line treatment of metastatic clear cell RCC in combination with interferon; or
      2. Bevacizumab is used as a single agent for relapsed or medically unresectable stage IV disease with predominant clear cell histology in individuals who have progressed on prior cytokine therapy; or
      3. Bevacizumab is used as a single agent for relapsed or medically unresectable stage IV disease with non-clear-cell histology; or
      4. Bevacizumab is used for relapsed or medically unresectable stage IV non-clear cell RCC (including papillary RCC and hereditary leiomyomatosis and RCC [HLRCC]), in combination with erlotinib or everolimus.
  10. Soft Tissue Sarcoma
    1. Bevacizumab is considered medically necessary when used as a single agent for treatment of angiosarcoma.
    2. Bevacizumab is considered medically necessary when used in combination with temozolomide for the treatment of solitary fibrous tumor and hemangiopericytoma.

Not Medically Necessary:

  1. Bevacizumab is considered not medically necessary in the treatment of all other conditions when the criteria are not met, including but not limited to any of the following:
    1. Adjuvant therapy following surgery for stage II or III adenocarcinoma of the colon; or
    2. Prostate cancer; or
    3. Carcinoid tumors; or
    4. Metastatic melanoma; or
    5. Metastatic adenocarcinoma of the pancreas; or
    6. Metastatic breast cancer, second line therapy or greater, for example when progression noted following anthracycline and taxane chemotherapy; or
    7. Neurofibromatosis type 2.
  2. Treatment of a single condition with concomitant use of bevacizumab with other targeted biologic agents (including, but not limited to erlotinib, cetuximab, panitumumab, trastuzumab, lapatinib, and ziv-aflibercept) is considered not medically necessary.
  3. Bevacizumab is considered not medically necessary when used in combination with the same irinotecan-based regimen that was previously used in combination with ziv-aflibercept.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J3590

Unclassified biologics [when specified as bevacizumab-awwb (Mvasi)]

J9035

Injection, bevacizumab, 10 mg [Avastin]

 

 

ICD-10 Diagnosis

 

C17.0-C17.9

Malignant neoplasm of small intestine

C18.0-C20

Malignant neoplasm of colon, rectosigmoid junction, rectum

C21.2-C21.8

Malignant neoplasm of cloacogenic zone, overlapping sites of rectum, anus

C33

Malignant neoplasm of trachea

C34.00-C34.92

Malignant neoplasm of bronchus and lung

C45.0-C45.9

Mesothelioma

C48.0-C48.8

Malignant neoplasm of retroperitoneum and peritoneum

C49.0-C49.9

Malignant neoplasm of other connective and soft tissue [angiosarcoma, hemangiopericytoma]

C50.011-C50.929

Malignant neoplasm of breast

C53.0-C53.9

Malignant neoplasm of cervix uteri

C56.1-C56.9

Malignant neoplasm of ovary

C57.00-C57.9

Malignant neoplasm of other and unspecified female genital organs

C64.1-C64.9

Malignant neoplasm of kidney, except renal pelvis

C65.1-C65.9

Malignant neoplasm of renal pelvis

C71.0-C71.9

Malignant neoplasm of brain

C78.00-C78.02

Secondary malignant neoplasm of lung

C78.4-C78.5

Secondary malignant neoplasm of small intestine, large intestine and rectum

C79.00-C79.02

Secondary malignant neoplasm of kidney and renal pelvis

C79.60-C79.62

Secondary malignant neoplasm of ovary

C79.81

Secondary malignant neoplasm of breast

I67.89

Other cerebrovascular disease [radiation necrosis]

T66.XXXS

Radiation sickness, unspecified, sequela 

Z51.11-Z51.12

Encounter for antineoplastic chemotherapy, immunotherapy

Z85.038

Personal history of other malignant neoplasm of large intestine

Z85.048

Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

Z85.068

Personal history of other malignant neoplasm of small intestine

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

Z85.3

Personal history of malignant neoplasm of breast

Z85.43

Personal history of malignant neoplasm of ovary

Z85.528

Personal history of malignant neoplasm of kidney

Z85.841

Personal history of malignant neoplasm of brain

Discussion/General Information

Bevacizumab is a recombinant, humanized, monoclonal IgG1 antibody, a genetically engineered protein from both mouse and human antibody components developed in the laboratory, that locates and bind to VEGF and inhibits the proliferation of endothelial cells and formation of new blood vessels (Avastin Product Information [PI] Label, 2016). As a result, bevacizumab may interrupt the signals necessary for the growth of blood vessels (angiogenesis) required for the proliferation and survival of cancer cells. VEGF is a cytokine that appears to have a key role in angiogenesis and vascular permeability. Overexpression of VEGF has been found in most human tumors (Crane, 2006).

Central Nervous System (CNS) - Primary Tumors

Some of the highest concentrations of VEGF are found in malignant gliomas. Bevacizumab has been studied as a treatment option for malignant gliomas, particularly given the overall poor prognosis with chemotherapy or radiation therapy. In May 2009, the U.S. Food & Drug Administration (FDA) announced the accelerated approval of bevacizumab as a single agent, for the treatment of glioblastoma with progressive disease following prior therapy. This approval was based on the results of initial trials in subjects with recurrent disease demonstrating dramatic responses on serial MRI studies (Kreisl, 2009; Friedman, 2009).

In 2014, the results of two similarly designed randomized trials were published that compared progression free survival (PFS) and overall survival (OS) in subjects with newly diagnosed glioblastoma multiforme randomized to receive either the standard treatment of radiotherapy and temozolomide with or without additional bevacizumab (Chinot, 2014; Gilbert 2014). The co-primary endpoints of both trials were investigator-assessed PFS and OS. In the Chinot trial of 921 subjects and the Gilbert trial of 637 subjects, there were no significant differences in the OS between the two groups. However, subjects in the standard treatment arm were allowed to cross over to the bevacizumab group if the disease progressed, thus possibly diluting a bevacizumab associated survival advantage. Both studies also reported improvements in PFS, with the Chinot trial reporting 10.6 months versus 6.2 months improvement (95% confidence interval [CI], 0.55 to 0.74; p<0.001) and the Gilbert trial reporting 10.7 months versus 7.3 months, a difference that did not meet the prespecified target. Aside from survival benefits, the outcomes of quality of life are relevant to the overall treatment of glioblastoma multiforme. This is where the two studies differed. The Chinot study reported that baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was also lower. In contrast, the Gilbert study reported that bevacizumab was associated with an increased symptom burden, a worse quality of life, and a decline in neurocognitive function. An accompanying editorial by Fine (2014) notes that these discrepant results are currently unexplained, but of vital interest in validating the role of bevacizumab in the initial therapy of glioblastoma. Specifically, if the treatment does not prolong OS, then its impact on quality of life will become the driver of treatment decisions.

Cervical Carcinoma

In August 2014, the FDA approved the use of bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer (Avastin PI Label, 2016).

GOG-240, a randomized phase III trial investigated 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. The primary endpoint of the study was OS. A total of 452 participants with squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix were randomized to one out of four possible treatment arms. The study regimens were cisplatin/paclitaxel, topotecan/paclitaxel and bevacizumab (15 mg/kg every 3 weeks) added to both regimens. The treatment cycles repeated every 21 days and continued until disease progression, unacceptable toxicity, or complete response (CR). The addition of bevacizumab resulted in an improved response rate of 48% versus 36% in the chemotherapy-only arm (p=0.0078). There was a significantly improved median OS of 17 months reported with the bevacizumab combination versus 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%) (Tewari, 2014).

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guideline (CPG) (V1.2017) for cervical cancer includes the recommendation for use of bevacizumab in combination with paclitaxel and either cisplatin or topotecan (category 1, FDA-approved indications) as first-line combination therapy for treating persistent, recurrent or metastatic cervical cancer. In addition, specialty consensus opinion suggests that bevacizumab may be used in a single line of therapy (that is, one line of therapy) in combination with either cisplatin and paclitaxel, or topotecan and paclitaxel, as treatment for metastatic or recurrent cervical cancer.

Colorectal and Small Bowel Adenocarcinoma

Based on the results of two randomized trials, bevacizumab received FDA approval in 2004 for use in combination with 5-fluorouracil (5-FU)-based chemotherapy as initial treatment of metastatic colorectal cancer.

In June 2006, bevacizumab received FDA approval for second-line treatment of individuals with metastatic colorectal cancer in combination with a 5-FU based regimen. The randomized controlled study of 829 individuals compared the outcomes of three treatment arms; Arm 1:5-FU, leucovorin (LV) and oxaliplatin (FOLFOX4) alone; Arm 2: FOLFOX4 plus bevacizumab; or Arm 3: bevacizumab as monotherapy. After interim analysis provided evidence of decreased survival in the bevacizumab monotherapy arm compared to the FOLFOX4 arm, further accrual to the monotherapy cohort was closed. OS was 13.0 months in the FOLFOX4 plus bevacizumab arm compared to the FOLFOX4 group of 10.8 months (Avastin PI Label, 2016).

In 2013, the FDA approved bevacizumab in combination with fluoropyrimidine-irinotecan-based or fluoropyrimidine-oxaliplatin-based chemotherapy as second-line treatment of individuals with metastatic colorectal cancer who had progressed on a first-line bevacizumab-containing regimen. The label notes “The addition of bevacizumab to chemotherapy resulted in a significant prolongation of survival and PFS; there was no significant difference in a key secondary outcome measure of overall response rate” (Avastin PI Label, 2016). This FDA approval was based in part on a phase III international study that randomized 820 participants to receive a fluoropyrimidine chemotherapy regimen with or without additional bevacizumab. All participants had progressive disease after receiving a first-line regimen that included bevacizumab. The primary outcome, OS, was 11.2 months (95% CI, range 10.4-12.2 months) in the bevacizumab group compared to 9.8 months (8.9-10.7 months) for chemotherapy alone (hazard ratio [HR], 0.81; 95% CI, 0.69-0.94; p=0.0062). Grade 3-5 adverse events occurred in 255 (64%) participants in the bevacizumab group and 235 (57%) participants in the chemotherapy group.

Simkens and colleagues (2015) evaluated the optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in a phase III unblinded randomized controlled trial (CAIRO3) of individuals with metastatic CRC. This Dutch Colorectal Cancer Group study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. A total of 64 hospitals in the Netherlands 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 (Interquartile range [IQR], 36-57). The primary endpoint of median PFS2 was significantly improved in participants on maintenance treatment compared to observation, 11.7 months versus 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 investigators concluded that global quality of life did not deteriorate during maintenance treatment with capecitabine plus bevacizumab after 6 cycles of CAPOX-B in individuals with metastatic CRC.

Hegewisch-Becker and colleagues (2015) performed an open-label, non-inferiority, randomized, phase III trial of 472 individuals with metastatic colorectal cancer who did not progress on induction FOLFOX/bevacizumab or CapeOx/bevacizumab. After 24 weeks of induction therapy, participants were randomized to receive either maintenance therapy with fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. The planned protocol included re-induction of primary therapy after first progression. The primary endpoint was time to failure, defined as time from randomization to second progression after maintenance, death, or initiation of further treatment with a new drug. After a medium follow-up of 17 months, the median time to failure of strategy was 6.9 months (95% CI, 6.1-8.5) for the fluoropyrimidine plus bevacizumab group, 6.1 months (95% CI, 5.3-7.4) for the bevacizumab alone group, and 6.4 months (95% CI, 4.8-7.6) for the no treatment group. Bevacizumab alone was non-inferior when compared with standard fluoropyrimidine plus bevacizumab (HR 1.08; 95% CI, 0.85-1.37; p=0.53), whereas the absence of maintenance therapy was not; however, the interpretation of these results are limited as only one-third of participants received the re-introduction therapy, In addition, OS (secondary endpoint of the trial) demonstrated no relevant difference between the arms.

Koeberle and colleagues (2015) evaluated the use of bevacizumab continuation as maintenance therapy in an open-label, non-inferiority, randomized, phase III trial (SAKK41/06) of 262 individuals with metastatic colorectal cancer without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab. Participants were randomized to continue bevacizumab at a standard dose or no treatment. The primary endpoint of time-to-progression (TTP) was not met. Median TTP was 4.1 (95% CI, 3.1-5.4) months for bevacizumab continuation versus 2.9 (95% CI, 2.8-3.8) months for no continuation; HR 0.74 (95% CI, 0.58-0.96). The median OS was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI, 0.63-1.1; p=0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Therefore, the authors concluded that based on no impact on OS, bevacizumab as a single agent “...is of no meaningful therapeutic value.”

The PI label for bevacizumab (Avastin PI Label, 2016) states that for stage II and stage III CRC, “Avastin is not indicated for adjuvant treatment of colon cancer.”

The NCCN CPGs for colon (2017) and rectal (2017) cancer state:

No data directly address whether bevacizumab should be used with chemotherapy in the perioperative treatment of resectable metastatic disease. Recent data regarding the lack of efficacy of bevacizumab in the adjuvant setting in stage II and III colon cancer have prompted some to reconsider the role of bevacizumab in the adjuvant setting of resectable colorectal metastases. However, the panel does not recommend the use of bevacizumab in the perioperative stage IV setting.

In addition, for adenocarcinoma of the small bowel or appendix, the NCCN CPG (2017) recommends “systemic chemotherapy according to the NCCN CPG for colon cancer.” These recommendations were based on 2A category of evidence and uniform consensus.

Non-small cell lung carcinoma (NSCLC)

NSCLC - First-Line Therapy

Bevacizumab in conjunction with chemotherapy has studied as a first-line treatment of locally advanced or metastatic NSCLC or as maintenance monotherapy following initial therapy with a bevacizumab-containing regimen. Bevacizumab is associated with an increased risk of hemorrhage, and the FDA PI label specifically notes that bevacizumab should not be given to individuals with a history of hemoptysis.

Bevacizumab received FDA approval in October 2006 as first-line treatment in combination with carboplatin and paclitaxel for individuals with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. This FDA approval was based in part on the ECOG4599 randomized trial that compared the OS of 878 participants who received 6 cycles of paclitaxel and carboplatin with or without bevacizumab at a dosage of 15 mg/kg (Sandler, 2006). After completion of the 6 cycles, participants in the bevacizumab arm continued to receive maintenance bevacizumab alone every 21 days. The OS of 12.3 months in the paclitaxel and carboplatin plus bevacizumab group was statistically significant compared to 10.3 months in the paclitaxel and carboplatin alone cohort. The use of bevacizumab in combination with paclitaxel and carboplatin has been recommended as the new standard of treatment (Azzoli, 2009, 2011; NCCN, V8.2017; Sandler, 2006). Reck and colleagues (2009) studied bevacizumab in combination with cisplatin and gemcitabine in a randomized study of first-line treatment of recurrent or metastatic NSCLC. While PFS was significantly higher in the bevacizumab arms, the addition of bevacizumab to cisplatin and gemcitabine chemotherapy failed to demonstrate a significant improvement in the duration of OS. The FDA labeling limits the addition of bevacizumab to regimens containing carboplatin and paclitaxel.

Zhu and colleagues (2012) linked the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) data to Medicare claims. Study criteria included individuals 65 years of age and older with stage IIIB or IV NSCLC who were diagnosed between 2002 and 2007, and received combination first-line therapy with carboplatin/paclitaxel or bevacizumab/carboplatin/paclitaxel. The primary comparison groups were comprised of individuals diagnosed between 2006-2007 and received either of the chemotherapy regimens as first-line therapy. The control group included individuals diagnosed between 2002-2005, and treated with first-line carboplatin/paclitaxel, prior to commercial availability of bevacizumab. A significant difference was not identified in OS between individuals treated with chemotherapy plus bevacizumab (2006-2007) compared to those treated only with carboplatin-paclitaxel in either group diagnosed in 2006-2007 (HR, 1.01; 95% CI, 0.88-1.15) or 2002-2005 (HR, 0.94; 95% CI, 0.83-1.06). The authors noted the data suggested the addition of bevacizumab to first-line carboplatin-paclitaxel was not associated with improved OS in older individuals and emphasized caution when bevacizumab is used in the elderly population.

A sub-group analysis of participants older than 65 years of age from a phase IV, multicenter, open-label, single-arm study of first-line bevacizumab treatment of individuals with advanced or recurrent NSCLC was reported by Laskin (2012). The Safety of Avastin in Lung (SAiL) study included 623 individuals older than 65 years of age. Individuals in the bevacizumab treatment cohort received chemotherapy and either 7.5 or 15 mg/kg of bevacizumab every 3 weeks for up to 6 cycles, followed by single-agent bevacizumab until disease progression. With a mean follow-up of 12.5 months, the median OS was 14.6 months for both older participants and younger participants. TTP was 8.2 months (95% CI, 7.5-8.7) for the elderly cohort and 7.6 months (95% CI, 7.3-8.0) in the younger cohort. Comorbidities were more common in the elderly, and the most frequent condition was baseline hypertension occurring in 39.6% of the elderly compared to 22% in the younger cohort. The authors concluded that elderly individuals can tolerate first-line bevacizumab in combination chemotherapy regimens for treatment of NSCLC and can achieve benefits similar to younger individuals.

NSCLC - Second Line Therapy

The NCCN CPG for NSCLC (V8.2017) lists the off-label use of bevacizumab in combination with a platinum-based doublet, when used as second-line of therapy if erlotinib or crizotinib was included as first-line therapy for NSCLC. This recommendation is based on a 2A category of evidence and uniform consensus.

The American Society of Clinical Oncology (ASCO) CPG on systemic therapy for stage IV NSCLC (Master, 2015) recommends:

first-line therapy include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications) (evidence quality: intermediate; strength of recommendation: moderate)...A major gap in current evidence is a lack of direct comparisons of platinum plus pemetrexed with or without bevacizumab. Given the historical lessons learned, the Update Committee does not think it would be fruitful to put valuable resources into a large RCT comparing cisplatin plus pemetrexed with carboplatin plus pemetrexed or with other historical platinum doublets.

The CPG concludes “there is insufficient evidence (for or against) to recommend pemetrexed in combination with bevacizumab plus carboplatin for patients who do not have contraindications to bevacizumab.”

NSCLC - Maintenance Therapy

The NCCN CPG for NSCLC (V8.2017) includes a category 1 recommendation to continue single-agent bevacizumab as continuance maintenance therapy if bevacizumab had been included in first-line of therapy and resulted in stable disease or achieved a tumor response.

The NCCN CPG for NSCLC (V8.2017) includes a 2A off-label recommendation for the use of bevacizumab in combination with pemetrexed and platinum-based therapy, followed by bevacizumab with pemetrexed as maintenance therapy if bevacizumab was a component of the first-line regimen. In 2009, Patel and colleagues conducted a nonrandomized, phase II trial evaluating the safety and efficacy of cisplatin, pemetrexed and bevacizumab in chemotherapy-naïve, advanced non-squamous NSCLC. Bevacizumab and pemetrexed therapy were continued until treatment failure occurred; 60% of participants received > 6 cycles. In total, 49 participants were enrolled and were available for evaluation; 55% of participants experienced an objective response. PFS and OS were 7.8 months and 14.1 months, respectively. Incidence of grade 3-4 toxicities was modest. Based on the findings of this study, a phase III trial was recommended. Patel and colleagues (2013) reported findings from a randomized, open-label, phase III trial (BreakPoint) evaluating the safety and efficacy of induction therapy with bevacizumab, carboplatin, and pemetrexed, followed by maintenance with pemetrexed plus bevacizumab (PemCBev) versus paclitaxel, carboplatin and bevacizumab, followed by bevacizumab alone (PacCBev; standard of care for first-line therapy), as treatment for individuals with advanced non-squamous NSCLC (stage IIIB or IV). The primary endpoint was OS; secondary endpoints included PFS, overall response rate (ORR), disease control rate (partial response [PR] + CR + stable disease), time-to-progression (TTP) and toxicities. In total, 939 participants were enrolled and randomized, 1:1 to the PemCBev arm (n=472) or the PacCBev arm (n=467); 292 and 298 participants were eligible for and received maintenance therapy with PemCBev and PacCBev, respectively. OS and survival at 12 and 24 months was not statistically different between the PemCBev and PacCBev study arms. Secondary endpoints of PFS (6.0 vs. 5.6 months; HR=0.83, 95% CI, 0.71-0.96; p=0.012) and TTP (7.0 vs. 6.0 months; HR=0.79, 95% CI, 0.67 to 0.94; p=0.006) were significantly better in the PemCBev arm. Grade 3-4 toxicities of neutropenia, alopecia and neuropathy were significantly lower in the PemCBev arm while thrombocytopenia, anemia and fatigue were lower in the PacCBev arm. The trial’s primary endpoint was not met, but authors concluded that the treatment options explored in this trial were comparably safe and efficacious as induction and maintenance therapies in advanced NSCLC.

Similarly, Barlesi and colleagues (2013) conducted a randomized, open-label, phase III trial evaluating the safety and efficacy of maintenance therapy with pemetrexed, with and without bevacizumab in advanced non-squamous NSCLC. In total, 376 individuals were enrolled and received four cycles of induction therapy with pemetrexed, cisplatin and bevacizumab. The study’s primary endpoint was OSPFS. If a CR, PR or stable disease was achieved (n=253; 72%), participants were randomized 1:1 to receive bevacizumab (n=125) or bevacizumab+pemetrexed (n=128) as maintenance therapy. Investigators found that bevacizumab+pemetrexed (7.4 months) achieved a superior PFS to bevacizumab alone (3.7 months) as maintenance therapy (HR=0.48, 95% CI, 0.35-0.66; p=0.001); however, OS was not significantly different between the two study arms. Investigators concluded that bevacizumab+pemetrexed did not demonstrate improved clinical benefit when compared to bevacizumab alone in the maintenance treatment of advanced NSCLC in those who had achieved disease control with pemetrexed, cisplatin and bevacizumab. Barlesi and colleagues (2014) continued this investigation in a subsequent analysis evaluating OS in this same clinical trial cohort (Barlesi, 2013) and found that after a median follow-up of 14.8 months from randomization, individuals in the bevacizumab+pemetrexed arm continued to have statistically longer PFS; however, 1-year and 2-year OS differences did not reach statistical significance. There was an increase in grade 3 and grade 4 adverse events in the bevacizumab+pemetrexed arm, and a separately published study from the same cohort noted that health-related quality of life (HRQOL) was not improved in the combination bevacizumab+pemetrexed arm (Rittmeyer, 2013). Consequently, there is a lack of evidence in the peer-reviewed literature supporting the efficacy of this chemotherapy combination as maintenance therapy in NSCLC.

However, based on the published data and specialty consensus input, the use of single agent bevacizumab as maintenance therapy may be allowed if bevacizumab was initially used in the first-line of therapy to treat NSCLC.

Ovarian Carcinoma

In December 2016, the FDA approved bevacizumab, either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by bevacizumab as a single agent, for the treatment of individuals with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (Avastin PI Label, 2016). The expanded approval is based on results from two randomized, controlled phase III studies: Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy In Platinum-Sensitive Recurrent Disease (OCEANS; Aghajanian, 2012) and the Gynecologic Oncology Group (GOG) 0213 study.

According to the FDA label (Avastin PI Label, 2016), GOG 0213 was a randomized, controlled, open-label trial sponsored by the NCI that studied bevacizumab plus chemotherapy (carboplatin and paclitaxel) versus chemotherapy (carboplatin plus paclitaxel) alone in the treatment of individuals (n=673) with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who had not received more than one prior chemotherapy regimen. Participants were considered to have platinum-sensitive disease if a relapse occurred 6 months or longer following the last treatment with a platinum-based chemotherapy. Participants were a median age of 60 years (range, 23-85 years) and 33% were ≥ age 65. At baseline, 81.3% (274 of 337) of participants assigned to the bevacizumab plus chemotherapy group and 85.1 % (286 of 336) of participants assigned to the chemotherapy alone group had measurable disease. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 for 99% of the participants. A total of 69 (10.3%) participants received prior bevacizumab; 26% had a platinum-free interval (PFI) of 6-12 months and 74% had a PFI of > 12 months. Participants were randomized (1:1) to receive carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenously [IV] over 3 hours) every 3 weeks for 6 to 8 cycles (n=336) or carboplatin (AUC5) and paclitaxel (175 mg/m2 IV over 3 hours) and concurrent bevacizumab (15 mg/kg) every 3 weeks for 6 to 8 cycles, followed by bevacizumab (15 mg/kg every 3 weeks) as a single agent (n=337) until disease progression or unacceptable toxicity. The primary efficacy endpoint was OS; secondary efficacy endpoints were investigator-assessed PFS and ORR. The study demonstrated that adding bevacizumab plus chemotherapy followed by continued use of bevacizumab alone showed an OS difference of 5 months compared to chemotherapy alone (median OS, 42.6 months vs. 37.3 months; HR 0.84, 95% CI, 0.69-1.01 and HR 0.82, 95% CI, 0.68-0.996). Study participants survived a median of 3.4 months longer without disease progression with the addition of bevacizumab to chemotherapy followed by single agent bevacizumab compared to chemotherapy alone (median PFS, 13.8 months vs. 10.4 months; HR 0.61, 95% CI, 0.51-0.72). Grade 3 or 4 adverse events occurred at a higher frequency (≥ 2%) in 325 participants treated with bevacizumab plus chemotherapy compared to 332 participants treated with chemotherapy alone: hypertension (11.1% vs. 0.6%), fatigue (7.7% vs. 2.7%), febrile neutropenia (6,2% vs. 2.7%), proteinuria (8.0% vs. 0.0%), abdominal pain (5.8% vs. 0.9%), hyponatremia (3.7% vs. 0.9%), headache (3.1% vs. 0.9%) and pain in extremity (3.4% vs. 0.0%). There were no grade 5 adverse events occurring at a higher frequency (≥ 2%) in the bevacizumab plus chemotherapy arm compared to the chemotherapy alone arm.

Aghajanian and colleagues (2012) conducted an industry-sponsored phase III, randomized, placebo-controlled clinical trial evaluating the safety and efficacy of gemcitabine and carboplatin plus bevacizumab compared to gemcitabine and carboplatin plus placebo in 484 women with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer. The median age of participants was 61 years (range 28-87 years) and 37% of participants were ≥ age 65. All participants had measurable disease at baseline. The PFI was 6-12 months in 42% of participants and > 12 months in 58% of participants. The ECOG performance status was 0 or 1 for 99.8% of the participants. Participants were randomized (1:1) to receive carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent placebo (n=242) every 3 weeks for 6 to 10 cycles followed by placebo alone until disease progression or unacceptable toxicity, or carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent bevacizumab (15 mg/kg Day 1) every 3 weeks for 6 to 10 cycles followed by bevacizumab (15 mg/kg every 3 weeks) as a single agent (n=242) until disease progression or unacceptable toxicity. The primary efficacy endpoint was PFS. With a median follow-up of 24 months, the PFS was significantly improved in the bevacizumab arm compared to the placebo arm (12.4 vs.8.4 months, respectively, HR 0.484; 95% CI, 0.388 to 0.605; p<0.0001). Treatment was discontinued, most commonly for progressive disease, in 66.1% in the placebo arm and 43.0% in the bevacizumab arm. Serious adverse events, including blood and lymphphatic disorders, were reported at 24.9% in the placebo arm and 34.8% in the bevacizumab arm. The investigators cited some limitations of the study, including lack of quality-of-life data and specimen collection for biomarker analysis.

Aghajanian and colleagues (2015) reported the final results of the OS and safety data from the phase III OCEANS study. A Cox proportional hazards model was used to compare OS between the two treatment arms. A total of 353 participants (72.9%) had died at the cutoff date of mid-July 2013. Median follow-up for OS was 58.2 months in the gemcitabine and carboplatin plus bevacizumab arm and 56.4 months in the gemcitabine and carboplatin plus placebo arm. Median OS was consistent across all examined participant subgroups, but not significantly improved with the addition of bevacizumab to chemotherapy (gemcitabine and carboplatin plus bevacizumab, 33.6 months; gemcitabine and carboplatin plus placebo, 32.9 months; HR 0.95; 95% CI, 0.77-1.18; log rank, p=0.65). The frequency and severity of adverse events were consistent with the previous analysis (Aghajanian, 2012). No new safety concerns were identified.

In November 2014, the FDA approved bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of individuals with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens (Avastin PI Label, 2016).

AURELIA was an international, phase III randomized, open-label study evaluating bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) in combination with standard chemotherapy (either weekly paclitaxel or topotecan or pegylated liposomal doxorubicin) (BEV-CT) compared to standard chemotherapy alone (CT) as a treatment for women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer (Pujade-Lauraine, 2014). Participants were considered to have platinum-resistant disease if a relapse occurred less than 6 months after the last treatment with a platinum-based chemotherapy. The primary efficacy endpoint of the study was PFS. A total of 361 women were randomized to 1 of 3 chemotherapy agents (paclitaxel, topotecan or liposomal doxorubicin) alone, or in combination with bevacizumab. Interim data reported an improved median PFS of 6.7 months with the addition of bevacizumab compared to 3.4 months with chemotherapy alone. The authors reported a significantly higher ORR of 30.9% with bevacizumab compared to 12.6% (p=0.001) with chemotherapy alone. With a median duration of follow-up of 13.9 months in the CT arm and 13.0 months in the BEV-CT arm, the authors reported updated data from the AURELIA trial in 2014 and the ORR remained statistically significant for CT (11.8%) compared to BEV-CT (27.3%; p=0.001). Despite the improved ORR and statistically significant PFS, the improved OS was not statistically significant between the BEV-CT group (16.6 months) compared to the CT group (13.3 months) (p<0.174). The authors noted because the trial included crossover to the bevacizumab arm, the trial was not designed to detect a difference in OS. The trial did not include an arm to study the effect of bevacizumab as a single agent.

First-Line of Therapy – Ovarian Carcinoma

Burger (2011) reported data from a GOG phase III double-blind trial (GOG 0218) that randomized 1873 women with stage 3 or stage 4 epithelial ovarian cancers to one of three first-line treatment groups. All 3 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 with the addition of bevacizumab 15 mg/kg in cycle 2 through cycle 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 hazard ratio for progression or death compared to control treatment was 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 a higher rate (22.9%) of hypertension in the bevacizumab-throughout group, 16.5% in the bevacizumab-initiation group and 7.2% in the control group. Gastrointestinal-wall 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 quality of life (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 (2011) 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.

The International Collaboration on Ovarian Neoplasms (ICON7) trial randomized 1528 women with ovarian cancer to carboplatin and paclitaxel or to the same chemotherapy regimen with the addition of bevacizumab 7.5 mg/kg every 3 weeks for five or six cycles and then for 12 additional cycles or until disease progression. Primary outcome measures were PFS and OS. In the updated analysis (Perren, 2011) at a mean follow-up of 42 months, median durations of PFS were 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 at 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 hazard ratio 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 and colleagues (2011) noted there was maximum improvement of PFS at 12 months, but the effect diminished by 24 months.

Oza and colleagues (2015) 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 noted between women who received bevacizumab plus chemotherapy and 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 further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated participant), 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 ICON7 and GOG 0218 trials were acknowledged in the NCCN CPG for the treatment of ovarian cancer. The use of bevacizumab in combination with paclitaxel and carboplatin as first-line therapy followed by maintenance bevacizumab therapy is a category 2B off-label recommendation in the NCCN CPG. The category 2B recommendation is “Based upon lower-level evidence there is NCCN consensus that the intervention is appropriate” (NCCN, V3.2017). “Data from these 2 phase III randomized trials (i.e., GOG 0218, IOCN7) have not shown a statistically significant increase in overall survival in the whole study population and/or improved quality of life.” The NCCN panel category 2B recommendation states:

…if bevacizumab is used with upfront chemotherapy followed by maintenance therapy, then either the GOG 0218 or ICON7 regimens should be used…The only GOG 0218 regimen that is recommended (2B) is the prolonged bevacizumab regimen (upfront with carboplatin/paclitaxel followed by maintenance bevacizumab) (Burger, 2011).

The NCCN panel encourages participation in ongoing clinical trials to study the use of bevacizumab in the treatment of ovarian cancer, “both in the upfront and recurrence settings” (NCCN, V3.2017).

The NCCN CPG (V3.2017) has a category 2A off-label recommendation for single agent bevacizumab to treat recurrent or persistent epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer if bevacizumab was not previously used (Burger, 2007; Cannistra, 2007). The NCCN CPG (V3.2017) also includes a category 2A recommendation for use of bevacizumab in combination chemotherapy with carboplatin and paclitaxel as potentially active agents for platinum-sensitive disease to treat recurrent epithelial ovarian cancer (excluding ovarian borderline epithelial tumors [LMP])/fallopian tube/primary peritoneal cancer if bevacizumab was not previously used. In addition, specialty consensus opinion suggests that bevacizumab, as a single agent or in combination with chemotherapy, may be used in one line of therapy.

Ovarian Cancer: Safety Issues

A high frequency of often fatal bowel perforation and gastrointestinal hemorrhage related to bevacizumab therapy documented in this population must be considered in the context of the availability of alternative disease controlling treatments for which similar harm has not been observed.

Sex Cord-Stromal Tumors

Granulosa cell tumor is the most common of the sex cord-stromal tumors (NCCN, 2017). The NCCN CPG for ovarian cancer (V3.2017) includes a category 2A recommendation for use of bevacizumab for these rare stage II-IV tumors that have relapsed or recurred. Tao and colleagues (2009) reported on a series of 8 individuals with recurrent granulose tumors. At a median follow-up of 23.6 months, the median PFS was 7.2 months; however, the OS was not reached.

Renal Cell Carcinoma (RCC) - Metastatic

According to the National Cancer Institute (NCI, 2017), renal cell cancer, also called renal adenocarcinoma, or hypernephroma, may be cured if it is diagnosed and treated when localized to the kidney and to the immediately surrounding tissue. RCC is the predominant form of primary renal malignancies and includes a group of tumors, each with distinct genetic landscapes resulting in a heterogeneous group of disease processes. The most common RCC is clear cell RCC, which accounts for 75%-80% of all primary kidney malignancies. The remainder of the most prevalent histologies include papillary (10%-15%), chromophobe (5%), collecting duct/medullary carcinomas (1%-2%), translocation associated RCC (< 1%), and unclassified (approximately 5%). Hereditary leiomyomatosis and RCC (HLRCC) is a rare autosomal dominant condition which is associated with early-onset and highly-aggressive RCC, typically papillary carcinoma type II (Sankin, 2015).

In July 2009, bevacizumab was approved by the FDA in combination with interferon alfa as treatment for metastatic RCC. Data from a phase III randomized, multi-center, double-blind clinical trial compared bevacizumab plus interferon alfa-2a (IFN-α2a) versus placebo plus interferon alfa-2a as first-line treatment for metastatic clear cell RCC. PFS was prolonged and statistically significant for participants receiving bevacizumab and IFN-α2a compared to controls (10.2 months vs. 5.4 months; p<0.0001). Although there were objective response rates noted in participants, there was no improvement in OS between the cohorts (median OS of 23 months for bevacizumab plus IFN-α2a compared to 21 months for the control arm) (Escudier, 2007).

In a phase III, open-label, randomized trial, the combination of bevacizumab and temsirolimus was compared with bevacizumab and interferon alfa (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). Rini and colleagues (2014) concluded the combination of temsirolimus and bevacizumab was not superior to IFN and bevacizumab as a first-line of therapy for metastatic RCC.

According to the NCCN CPG for kidney cancer (V1.2018), “Clinical trials of targeted agents for RCC have predominantly focused on patients with clear cell histology versus non-clear cell due to the high prevalence of the clear cell RCC.” The NCCN Panel recommends enrollment in clinical trials as the preferred strategy for the treatment of non-clear cell RCC (nccRCC). However, the NCCN states that “There are data indicating that targeted therapies approved for clear cell RCC may have benefit for non-clear cell RCC, as well.”

The NCCN CPG for kidney cancer (V1.2018) includes a category 2A recommendation for use of bevacizumab as single-agent systemic therapy for relapsed or surgically unresectable RCC, non-clear cell histology. The recommendation is “based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.” The NCCN cites the results of a small, unpublished phase II trial (Irshad, 2011; NCT00601926) where bevacizumab at a dose of 15 mg/kg IV was administered every three weeks to individuals with metastatic or unresectable papillary RCC. Participants were required to have measureable disease, ECOG performance status 0 or 1, and adequate organ function. Treatment was stopped for progression, toxicity, or withdrawal of consent. The primary endpoint was the proportion of participants free of progression at 12 months following initiation of bevacizumab. Sample size was based on intention-to-treat analysis, and was determined to be 41 participants for a study period of 2 years. The study closed early due to slow accrual of only 5 participants, in which 3 participants had undergone a prior nephrectomy, 1 participant had resection of a liver metastasis, and 1 participant had prior treatment with temsirolimus. The PFS was reported as 25, 15, 11, 10, and 6 months for each of these participants. Drug toxicities were reported as grade 1-2, including hypertension, creatinine elevations, and proteinuria.

In a phase II study (NCT01399918), Voss and colleagues (2016) evaluated the use of every 2-week bevacizumab plus daily everolimus (10 mg oral) in treatment-naive individuals with metastatic nccRCC. The primary endpoint was PFS at 6 months. A total of 35 participants were enrolled with the following histologic subtypes: chromophobe (n=5), papillary (n=5), and medullary (n=2) RCC, and unclassified RCC (uRCC, n=23). The majority of participants had papillary growth as a major component (n=14). For the 34 evaluable participants, the median PFS, OS, and ORR were 11.0 months, 18.5 months, and 29%, respectively. PFS varied by histology (p<0.001), and ORR was higher in participants with significant papillary (7 of 18) or chromophobe (2 of 5) elements than for others (1 of 11 of 11). The presence of papillary features were associated with benefit, including uRCC, where it correlated with ORR (43% vs. 11%), median PFS (12.9 vs. 1.9 months), and OS (28.2 vs. 9.3 months; p<0.001).

The NCCN CPG for kidney cancer (V1.2018) includes a 2A recommendation for use of bevacizumab in combination with erlotinib or everolimus for select individuals with relapsed or surgically unresectable stage IV papillary RCC including HLRCC subtypes. The use of bevacizumab in combination with erlotinib is being studied in a phase II study of individuals with advanced HLRCC or sporadic papillary RCC (NCT01130519). The study is currently recruiting participants with an estimated primary completion date of January 1, 2018.

Off-Label Indications

Breast Cancer – Initial Treatment of Metastatic Disease

In February 2008, the FDA announced the accelerated approval for bevacizumab in conjunction with paclitaxel for the treatment of individuals who have not received chemotherapy for their metastatic HER2 negative breast cancer. The approval was based on a phase III, Eastern Oncology Cooperative Group (E2100) trial analysis of 722 participants that demonstrated first-line bevacizumab, in combination with paclitaxel, had a 52% reduction in disease progression (PFS) versus paclitaxel alone. A clinically significant median PFS (11.3 months compared with 5.8 months; p<0.001) was noted in the cohort receiving bevacizumab with paclitaxel versus paclitaxel alone. Although objective PR rates were two times higher in individuals treated with bevacizumab plus paclitaxel, there were no observed complete responses and no statistically significant improvement to OS (Miller, 2007).

In November 2011, the FDA revoked the labeled indication of bevacizumab used in combination with paclitaxel as first-line treatment of metastatic HER2-negative breast cancer that resulted from the accelerated approval process. The FDA cited the lack of clinical benefit in terms of delay in tumor growth compared to the risk of serious and potentially life-threatening risks, and the PI label was updated in December 2011.

In a phase III, randomized, double-blinded multicenter trial, Miles (2010) reported results from the AVADO trial which studied bevacizumab in either 7.5 mg/kg or 15 mg/kg in combination with docetaxel versus placebo plus docetaxel as a first-line treatment for HER2-negative metastatic breast cancer. The primary endpoint of the study was PFS from randomization to disease progression or death. Best overall response, duration of response, time-to-treatment failure (TTF), safety and OS were secondary endpoints. A total of 736 individuals were randomly assigned in a 1:1:1 manner. Median follow-up was 25 months. In the unstratified data analysis, the median PFS in the placebo arm was 8.2 months, and 9.0 months in the bevacizumab 7.5 mg arm (HR, 0.86; p=0.12) and 10.1 months in the bevacizumab 15 mg arms (HR, 0.77; p=0.006). In the analysis of stratified data, the median PFS in the placebo arm was 8.1 months, 9.0 and 10.0 months in the bevacizumab 7.5 mg and 15 mg arms, respectively. There was no significant difference in the OS between groups, with a median OS of 31 months (HR 1.05, bevacizumab 7.5mg; HR 1.03, bevacizumab 15mg). Adverse events occurred more frequently in the bevacizumab cohorts compared to the placebo group. Grade 3 or greater adverse events were 78% in the bevacizumab 7.5mg group, 75% in the bevacizumab 15mg group, and 67% in the placebo group. The authors concluded the data suggest the combination of taxane chemotherapy with bevacizumab should be considered an option for the first-line treatment of HER2-negative metastatic breast cancer (Miles, 2010).

The Regimens in Bevacizumab for Breast Oncology (RIBBON-1), phase III, double-blind, placebo-controlled trial compared first-line chemotherapy with or without bevacizumab as a treatment for HER2 negative locally recurrent or metastatic breast cancer (Robert, 2011). The primary endpoint was PFS. A total of 1237 enrolled participants were randomized to a chemotherapy regimen consisting of capecitabine (Cape), taxane (Tax)-based or anthracycline (Anthra)-based regimen with or without bevacizumab (BV). There were 615 participants in the Cape group with a median follow-up of 15.6 months, and 622 participants in the Tax/Anthra group with a median follow-up of 19.2 months. The median PFS in the Cape cohort increased from 5.7 months in the placebo arm to 8.6 months in the BV arm (HR, 0.69; 95% CI, 0.56 to 0.84; p<0.001). The median PFS for the Tax/Anthra cohort in the placebo arm was 9.0 months and 9.2 months in the BV 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 OS for either cohort. The incidence of grade 3 to 5 adverse events (AEs) was higher in all of the BV-containing arms versus the placebo-containing arms. Regardless of the type of chemotherapy, hypertension and proteinuria were consistently increased in the BV-containing arms of the treatment cohorts. There were higher rates of discontinuation related to the incidence of AEs in the BV-containing arm compared to the placebo arm (Tax: 24.1% with BV versus 7.8% placebo; Anthra: 14.3% with BV versus 4.0% placebo). However, in the Cape cohort, there was no difference in rates of discontinuation (11.9% for both arms). The authors concluded first-line BV combined with chemotherapy increased PFS in individuals with HER2-negative metastatic breast cancer.

There remain significant questions regarding the combinations of chemotherapy with bevacizumab which produce improvements in net health outcome. It is notable that the NCCN CPG for breast cancer (2017) includes a category 2A off-label recommendation for use of bevacizumab in combination with paclitaxel as a treatment for recurrent or metastatic human epidermal growth factor receptor 2-negative (HER2-neg) breast cancer. This was based on modest improvement in response rate and TTP, but bevacizumab did not improve OS.

Malignant Mesothelioma

The NCCN CPG (2.2017) includes a category 1 off-label recommendation for use of bevacizumab as first-line combination chemotherapy with pemetrexed and cisplatin followed by single agent maintenance therapy until disease progression for the treatment of unresectable malignant pleural mesothelioma. The recommended dose of bevacizumab is administered every 3 weeks for 6 cycles followed by maintenance bevacizumab every 3 weeks until disease progression. The evidence cited with this category 1 recommendation includes data from a multicenter phase III randomized clinical trial conducted in France (Zalcman, 2016). A total of 448 participants aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumor solid thickening) lesion confirmed by computerized tomography scan, and a life expectancy of > 12 weeks were randomly allocated 1:1 to receive IV 500 mg/m² pemetrexed (day 1) plus 75 mg/m² cisplatin (n=225 PC; day 1) or PC plus 15 mg/kg bevacizumab (n=233 PCB; day 1) in 21-day cycles for up to six cycles, until progression or toxic effects. The PCB group was allowed maintenance bevacizumab after the six cycles until disease progression or toxic effects. For grade 2 or higher cisplatin-induced renal toxic effects, participants were allowed a switch to a carboplatin. Growth factor support was not recommended as primary prophylaxis against neutropenia in the first cycle; however, it was allowed as secondary prophylaxis if the participant developed grade 3-4 neutropenia. Second-line treatment could be used at the discretion of the investigators, but crossover and use of second-line bevacizumab in participants in the PC group was not allowed. The primary outcome was OS in the intention-to-treat population. OS was reported as significantly extended in the PCB arm (median OS 18.8 months [95% CI, 15.9-22.6]; 164 [74%] of 223 died) than in the PC arm (median OS 16.1 months [14.0-17.9]; 178 [79%] of 225 died; HR 0.77 [0.62-0.95]; p=0.0167). PFS was also significantly improved with PCB (median PFS 9.2 months [8.5-10.5]; 198 [89%] of 223 died) compared to the PC arm (7.3 months [6.7-8.0]; 217 [96%] of 225 died; adjusted HR 0.61 [0.50-0.75]; p<0·0001). More participants stopped first-line treatment for disease progression in the PC arm (189 [87.1%] of 217) than in the PCB arm (137 [62.8%] of 218; difference 24.3% [16.3-31.9]; p<0.0001). Grade 3-4 adverse events were reported in 158 (71%) of 222 participants in the PCB arm and 139 (62%) of 224 participants in the PC arm. Non-hematological adverse events in both groups included asthenia or fatigue, anorexia, constipation, and nausea or vomiting. There were more grade 3 or higher hypertension (51 [23%] of 222 vs. 0) and thrombotic events (13 [6%] of 222 vs. 2 [1%] of 224) in the PCB arm than in the PC arm. Limitations of this trial include the open label design and whether OS survival would improve if individuals received curative-intent surgery compared to medical treatment for malignant mesothelioma.

Based on the 2.7 month OS improvement rate reported in this large multicenter phase III randomized trial, the NCCN considers combination therapy with bevacizumab, cisplatin, and pemetrexed as an acceptable chemotherapy option for individuals with unresectable malignant mesothelioma. However, based on specialty consensus opinion, once disease progression has occurred, bevacizumab should not be reinstated for the treatment of unresectable malignant mesothelioma.

Radiation Necrosis

Results from a randomized, double-blind, placebo-controlled study evaluating the use of bevacizumab as a treatment for symptomatic central nervous system radiation necrosis was reported by Levin and colleagues (2011). A total of 14 participants with evidence of radiation necrosis by magnetic resonance imaging (MRI) or surgical biopsy were enrolled. Seven participants were randomized to Group A and treated with bevacizumab 7.5 mg/kg at 3-week intervals for two treatments. Another 7 participants were randomized to Group B and received placebo on the same treatment schedule. MRIs were planned at baseline prior to initiation of treatment and 6 weeks after study entry (i.e., 3 weeks after the second dose). The trial allowed for those with treatment failure to cross over to the other group. The primary endpoint was the difference in volume of edema from baseline MRI to the MRI at 6 weeks. Treatment ended after 4 cycles, and participants were followed with MRIs every 3 months. At 6 weeks, the volume of edema for those in the placebo arm increased with a median change in volume of 14%. Those treated with bevacizumab had a median decrease of -59% in edema volume. Five participants (38%) were being treated with dexamethasone and 4 individuals had a dose reduction after bevacizumab treatment. Adverse events occurred in 6 of 11 participants treated with bevacizumab, and 3 events were serious (pneumonia, embolus and thrombosis). There were no adverse events in the placebo group. The data shows improvement in the edema; however there are limitations to the study. The sample size was small and the median follow-up was 10 months. The authors noted the “Results should be interpreted cautiously as the study was likely underpowered to detect statistically significant changes in neurocognitive function and symptoms.” However, based on the lack of available therapies, specialty consensus opinion recommends the use of bevacizumab to treat symptomatic radiation necrosis of the central nervous system. The appropriate dosage and interval for bevacizumab treatment is not yet standardized.

Gonzalez (2007) reported a retrospective, uncontrolled case series of 8 individuals diagnosed with radiation necrosis from a group of 15 individuals treated with bevacizumab for malignant brain tumors. The novel application of bevacizumab to decrease the symptoms of radiation necrosis needs to be studied in a randomized controlled trial to determine the efficacy and safety for this indication.

Soft Tissue Sarcoma

Hemangiopericytoma (HPC) is a vascular soft tissue tumor of fibroblastic cell origin that is characterized by Zimmerman’s pericytes. Soft fibrous tumors (SFT) and HPC have over-lapping clinical and morphologic features. HPC and SFT are viewed as a spectrum of a single entity and can be referred to as HPC/SFT (Park, 2009). A retrospective study of 14 individuals with HPC/SFT treated with combined temozolomide and bevacizumab resulted in median PFS of 8.6 months with a median follow-up of 20 months (Park, 2009).

The NCCN CPG (2017) lists 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 (Agulnik, 2013) and uniform consensus. In addition, specialty consensus opinion suggests bevacizumab to treat these specific soft tissue sarcomas.

Other Off-Label Uses

Breast Cancer - Neoadjuvant Chemotherapy

In an international, multicenter study of HER2-negative primary breast cancer, 1948 participants were randomized to neoadjuvant treatment with epirubicin, cyclophosphamide followed by docetaxel (EC-T) or to ECT plus bevacizumab. The GeparQuinto phase III study had subtype specific stratifications for individuals with HER2-negative primary breast cancer (group 1); HER2-negative disease that did not respond to four cycles of neoadjuvant chemotherapy (group 2) and HER2-positive primary breast cancer (group 3). Von Minckwitz (2012) reported outcomes from group 1 of the GeparQuinto study. A pathological complete response (pCR), defined as pathologic stage T0N0, was achieved in 144 (14.9%) of the participants who received ECT and 176 (18.4%) of the participants who were treated with combination bevacizumab and ECT (p=0.04). When the definition of pCR included nodal involvement (pathological stage T0N0/+), the addition of bevacizumab increased the response rate to 20.5%. The pCR was higher at 21.7% when the definition of pCR included noninvasive residual disease in the breast (pathological stage T0/isN0/+). From the initial 956 participants in the ECT plus bevacizumab treatment group, 150 (15.7%) did not have a tumor response by cycle 4, compared to 221 (22.7%) participants from the ECT group. In a subset analysis, participants with triple-negative breast tumors (n=663) attained pCR of 27.9% in the ECT group and 39.3% (p=0.003) in the ECT plus bevacizumab treatment group. For both treatment groups, the rate of breast-conserving surgery was identical at 66%. The investigators noted the pCR rates were better for a subset of participants with triple-negative disease and the long term effects and benefits after completion of 24 weeks of neoadjuvant bevacizumab need to be determined.

In a phase III trial, Bear and colleagues (2012) 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. A total of 1206 participants with operable HER2-negative breast cancer 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 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 three 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 (2012) 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.”

Carcinoid Tumors

In a phase II study of 44 individuals with carcinoid tumors on stable doses of octreotide, participants were randomly assigned to 18 weeks of treatment with either bevacizumab or PEG interferon alfa-2b. At the end of 18 weeks, or upon disease progression, participants received the combined bevacizumab and PEG interferon alfa-2b until progression of disease. Twenty-four individuals consented to functional computerized tomography (CT) scans. A statistically significant decrease in tumor blood flow was noted in participants treated with bevacizumab versus PEG interferon alfa-2b. However, a clinical correlation between decreased blood flow and treatment could not be made. The PFS rate at week 18 in participants treated with bevacizumab was 95% and 68% for the individuals treated with PEG interferon. The overall median PFS for all 44 participants was 63 weeks. There is currently insufficient data to validate the role of bevacizumab therapy for carcinoid tumors.

Hereditary Hemorrhagic Telangiectasia (HHT)

Individuals with a rare genetic mutation with HHT (also known as Osler-Weber-Rendu syndrome) develop inappropriate blood vessel growth resulting in visceral arteriovenous malformations (AVMs) and more frequently small AVMs in the mucosal lining of the nose which are prone to bleeding (epistaxis). In addition to the negative impact on quality of life (that is, fatigue), severe epistaxis may require blood transfusions or cauterization. Case series have reported results of intranasal submucosal, topical and IV bevacizumab treatment for moderate to severe epistaxis (Guldmann, 2012; Karnezis, 2012) that have reduced the frequency of epistaxis for a period of time. An open-label series involving 6 evaluable participants treated with low-dose IV bevacizumab had reduced episodes of epistaxis and improved quality of life surveys (SF-36), but there was no significant improvement in hemoglobin or hematocrit levels (Thompson, 2014). Despite the published results that suggest improved rates of epistaxis, the studies are limited by the small numbers of participants. In addition, there are still outstanding questions regarding the appropriate route, timing, dose, frequency and long term efficacy and safety of bevacizumab treatment for HHT that have not been confirmed in randomized controlled trials.

Riss and colleagues (2015) reported results from a randomized, double-blind, placebo-controlled trial of a single dose of injected submucosal bevacizumab. A total of 15 participants were randomized with 9 individuals assigned to bevacizumab therapy and 6 randomized to placebo. Visual analog scale (VAS; range 0-100) was used to rate epistaxis recorded in a diary beginning a month before treatment and for 3 months after treatment. The average daily VAS post-treatment was not statistically significant compared to pre-treatment VAS (p=0.57) for the bevacizumab group compared to the placebo group. The authors noted the study was underpowered and there was high variation of epistaxis episodes in both bevacizumab and placebo groups. The authors concluded there was a trend of reduced epistaxis with bevacizumab submucosal injection, but larger randomized controlled studies are needed to confirm the efficacy and long-term safety for this treatment.

Metastatic Melanoma

A phase II trial enrolled 53 participants with unresectable metastatic melanoma treated with bevacizumab, paclitaxel and carboplatin. The primary endpoint of the trial was an 8 week event free survival (EFS) rate. A median of 5 cycles were administered. Treatment was discontinued in 39 participants due to tumor progression, 5 participant refusals, and 9 with adverse events. One death was attributed to hemorrhaging related to a brain metastasis. The 8 week EFS rate was 74% (90% CI, 62%-83%). A minimum follow-up of 8.5 months or until death resulted in an estimated median PFS of 6 months and a median OS of 12 months (Perez, 2009). The current NCCN CPG for melanoma (V1.2017) does not recommend off-label use of bevacizumab to treat metastatic melanoma.

Neurofibromatosis Type 2

An inherited genetic condition with a prevalence of 1 in 25,000 births, neurofibromatosis type 2 is characterized by benign tumors that develop from the Schwann cells in the eighth cranial nerve. Progressive tumor growth results in progressive loss of hearing. Surgery or radiation is standard therapy for unilateral schwannomas. However, the procedures may impair hearing in the affected ear. Therefore, medical interventions are being studied in a variety of clinical trials.

Plotkin and colleagues (2009) reported results from bevacizumab treatment in a retrospective series of 10 consecutive participants with neurofibromatosis type 2 and growing vestibular schwannomas. The participants were not candidates for surgery and radiation or had refused the therapies. Median duration of treatment was 12 months and follow-up at a minimum of 1 year occurred for 6 participants. There was 1 case of progressive disease despite 8 months of therapy, and 1 death after meningioma resection. Seven out of 10 participants were eligible for a hearing response. Four participants had improved word-recognition scores that were durable for 11 to 16 months. Although there was evidence of tumor-volume reduction and some improvement in hearing, the follow-up is short term. The authors noted additional long-term research is needed to determine the optimal dosing and duration along with adverse events.

Pancreatic Carcinoma

Kindler (2010) reported the results of a phase III trial randomizing 602 participants to receive gemcitabine with or without bevacizumab. There was no statistically significant difference in median OS. Those treated with gemcitabine and bevacizumab had a median OS of 5.8 months compared to 5.9 months for the control group treated with gemcitabine and placebo (p=0.95).

The NCCN CPG for pancreatic adenocarcinoma (V3.2017) states that “Several targeted therapies besides erlotinib have been assessed in combination with gemcitabine, but none have been shown to significantly impact outcomes. Agents assessed in phase III trials include bevacizumab (an anti-vascular endothelial growth factor [VEGF] inhibitor)…”

Bevacizumab in Combination with Other Targeted Biologic Agents

Herbst and colleagues reported results from a randomized phase III, double-blind trial of individuals with recurrent or refractory NSCLC. Individuals were randomized in the BeTa trial to the treatment group which included erlotinib plus bevacizumab or the placebo group that received erlotinib plus placebo. The primary endpoint of the trial was OS which did not differ between the two cohorts. The bevacizumab group had a median OS of 9.3 months and the control group had a median OS of 9.2 months (HR 0.97; 95% CI, 0.80-1.18; p=0.7583).

In a phase III, open-label trial, 755 individuals with metastatic, unresectable colon or rectal carcinoma were randomized to receive treatment with capecitabine-bevacizumab (CB) and oxaliplatin, or capecitabine-bevacizumab-cetuximab (CBC) with oxaliplatin. A total of 732 individuals initiated treatment, with an equal distribution of 366 individuals in each group. The CBC cohort had a significantly decreased median PFS of 9.4 months compared to the CB group of 10.7 months (p=0.01). Overall quality of life and global health status in 532 individuals (276 in the CB group, 256 in the CBC group) improved significantly more in the CB group (p=0.007) compared to the CBC cohort (p=0.03). The investigators concluded the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab “resulted in a significant decrease in progression-free survival and a poorer quality of life” (Tol, 2009). Tol and colleagues (2009) noted the results from the combination of anti-VEGF and anti- epidermal growth factor receptor (EGFR) antibodies in the phase III trial were unexpected and differed from results in earlier phase II studies such as the BOND-2 (Saltz, 2007) trial.

The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study (Hecht, 2009) is a phase IIIb randomized, open label clinical trial evaluating cohorts of a chemotherapy regimen including bevacizumab, with and without panitumumab, an anti- EGFR, as first-line treatment of individuals with previously untreated metastatic colorectal carcinoma. Investigators chose a 5-FU, leucovorin and oxaliplatin-based regimen (Ox-CT; n=823) or a 5-FU, leucovorin and irinotecan-based regimen (Iri-CT; n=230), each with bevacizumab. Individuals were randomized to receive the selected regimen, or chemotherapy with the addition of panitumumab. A statistically significant difference in PFS in favor of the control arm (without panitumumab) was unveiled at the first planned interim analysis (Zhu, 2007) which resulted in a discontinuation of panitumumab. In the final analysis (Hecht, 2009) median PFS was 10.1 months for panitumumab and 11.7 months for the control group (HR, 1.19; 95% CI, 0.79 to 1.79). In a safety analysis of 804 individuals in the Ox-CT cohort and 224 individuals in the Iri-CT cohort, both groups had more adverse events (AEs) of grade 3 or higher in the panitumumab cohorts compared to the control groups (Ox-CT 367 [90%] versus 305 [77%], respectively; Iri-CT 100 [90%] versus 71 [63%] respectively). Serious AEs included diarrhea, infections and pulmonary embolism. Seven (1%) deaths were attributed to be panitumumab-related. The authors concluded the decreased PFS and increased serious AEs do not support panitumumab in combination with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy as a treatment for metastatic colorectal cancer (Hecht, 2009).

Citing lack of improved outcomes and increased toxicities from combination therapies used in these two phase III randomized trials, the NCCN CPGs for colon (2017) and rectal cancer (2017) strongly recommend against concurrent use of anti-EGFR agents cetuximab (Tol, 2009) or panitumumab (Hecht, 2009) with bevacizumab. In addition, the NCCN CPGs for colon (2017) and rectal cancer (2017) do not recommend capecitabine/irinotecan (CapeIRI) plus bevacizumab for the first-line treatment of metastatic colorectal cancer because of concerns with toxicity with the CapeIRI combination. Finally, the NCCN CPG for colon cancer (2017) states “There are no data to suggest activity of FOLFIRI- ziv-aflibercept or FOLFIRI-ramucirumab in a patient who has progressed on FOLFIRI-bevacizumab, or vice versa.” There is no data to support the concomitant use of bevacizumab with ziv-aflibercept.

Adverse Events and Safety of Bevacizumab

A systematic review and meta-analysis of 15 randomized controlled trials (RCTs) consisting of 7956 individuals was published by Nalluri and colleagues (2008). The goal of the study was to evaluate the occurrence of venous thromboembolism resulting from treatment with bevacizumab for oncologic indications. The studies enrolled individuals with various solid tumor types such as colorectal, breast, lung, and renal cell carcinomas. An all-grade venous thromboembolism incidence of 11.9% (95% CI, 6.8% to 19.9%) was noted in an analysis of 6 studies with 2279 individuals. In an analysis of 3795 individuals in 13 studies, high-grade venous thromboembolism (grades 3-5) had an incidence of 6.3% (95% CI, 4.8%-8.3%). The authors noted significant morbidity and mortality is associated with high-grade venous thromboembolism. The overall relative risk (RR) of all-grade and high-grade venous thromboembolism in all tumor types was 1.33 (95% CI, 1.13-1.56; p<0.001) compared to controls. Individuals treated with low dose (2.5 mg/kg/week) and high dose (5 mg/kg/week) bevacizumab had a significantly increased risk of venous thromboembolism with a RR of 1.31 for both dosing schedules. The authors concluded venous thromboembolism continues to be an emerging adverse complication of anti-angiogenic agents and additional trials are needed to study the prevention and management of venous thromboembolism.

A meta-analysis by Ranpura and colleagues (2011) included 16 randomized controlled trials. The overall incidence of fatal adverse events (FAEs) with bevacizumab was increased with the addition of bevacizumab versus chemotherapy alone with an RR of 1.46 (95% CI, 1.09-1.94; p=0.01). The overall incidence of FAEs with bevacizumab was 2.5% (95% CI, 1.7%-3.9%) which varied with chemotherapy regimen combinations, but did not have a significant variation by tumor type. Overall, hemorrhage (23.5%) was the most common cause of FAEs, followed by neutropenia (12.2%) and gastrointestinal tract perforation (7.1%). The authors noted “Risk reduction includes selecting appropriate patients for therapy, prophylactic granulocyte colony-stimulating factor, early assessment of toxic effects, and adequate management of serious adverse events” (Ranpura, 2011).

FDA Boxed Warnings and Product Information (PI) for Bevacizumab

Black box warnings from the FDA PI Label for bevacizumab (Avastin PI Label, 2016):

Additional Warnings and Precautions (Avastin PI Label, 2016):

Additional warnings and precautions, drug interactions, and use in specific populations are available on the current PI label for bevacizumab (Avastin PI Label, 2016).

Definitions

5FU-based: A treatment regimen that includes fluorouracil (5-FU) or capecitabine.

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure. May include chemotherapy, radiation, hormone, or biological therapy.

Anaplastic astrocytoma (WHO grade III): A tumor which may arise from a diffuse astrocytoma or may arise de novo without indication of a less malignant precursor. Also known as malignant astrocytoma and high-grade astrocytoma.

Angiogenesis: Blood vessel formation; in tumors, angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor.

Capecitabine (Xeloda®, Roche Laboratories, Inc., Nutley, NJ): A pro-drug that is enzymatically converted into 5-fluorouracil (5-FU) in vivo.

Complete response (CR): The disappearance of all signs of cancer as a result of treatment. May also be called complete remission. This does not indicate the cancer has been cured.

Cytokine: A substance that is made by cells of the immune system and can also be made in the laboratory. Some cytokines can boost the immune response and others can suppress it. Cytokines can be used in the treatment of various diseases, including cancer. Examples include interferon (IFN), interleukin-2 (IL2).

Eastern Cooperative Oncology Group (ECOG) performance status (PS): A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

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

Ependymoma: A slow-growing tumor of children and young adults that originates from the wall of the cerebral ventricles or from the spinal canal and is composed of neoplastic ependymal cells.

Fluoropyrimidine:  One of a group of substances used to treat cancer. A fluoropyrimidine is a type of antimetabolite. Examples are capecitabine, floxuridine, and fluorouracil (5-FU). 

Glioblastoma multiforme: Stage IV glioblastoma, which includes WHO recognized variants, giant cell glioblastoma and gliosarcoma.

Hormonal therapy: Treatment that adds, blocks, or removes hormones. Agents that slow or stop the growth of certain cancers, synthetic hormones or other drugs may be given to block the body’s natural hormones.

Human epidermal growth factor receptor 2 (HER2)-negative is defined as:

If a single test (or both tests) performed show:

Line of therapy:

Metastasis: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment. May also be called partial remission.

Refractory disease: Illness or disease that does not respond to treatment.

Single line of therapy: One line of therapy.

Targeted biologic agent: A newer type of drug developed specifically to target genetic changes in cells that cause cancer. It works differently than standard chemotherapy drugs, often with different side effects.

Vascular endothelial growth factor (VEGF): A substance made by cells that stimulates new blood vessel formation.

References

Peer Reviewed Publications:

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Government Agency, Medical Society, and Other Authoritative Publications:

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Websites for Additional Information
  1. American Cancer Society (ACS). Available at: http://www.cancer.org/. Accessed on September 27, 2017.
  2. National Cancer Institute (NCI). Available at: http://www.cancer.gov/publications/pdq/information-summaries/adult-treatment. Accessed on September 27, 2017.
Index

Monoclonal Antibody
VEGF

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development. Moved content of DRUG.00038 Bevacizumab (Avastin®) for Non-Ophthalmologic Indications to new clinical utilization management guideline document with the same title. Added MN criteria for off-label use of bevacizumab in non-clear cell renal cell carcinoma and subtypes when criteria are met.