The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. 

Metastatic Renal Cell Carcinoma (mRCC)
Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Persistent, Recurrent or Metatstatic Carcinoma of the Cervix:
Avastin, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of peersistent, recurrent or metastatic carcinoma of the cervix. 

Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Indication
Epithelial ovarian, fallopian tube, or primary peritoneal cancer:

• In combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection (1.6)
• In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens (1.6)
• In combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum sensitive recurrent disease (1.6)

Hepatoculluar carcinoma, unresectable or metastsic (Avastin only)

Avastin is indicated for the treatment of unresectable or metastatic hepatocellular carcinoma (in combination with atezolizumab) in patients who have not received prior systemic therapy.

Avastin (bevacizumab) will be approved when being used as indicated by the National Comprehensive Cancer Network (NCCN) guidelines as a grade 2A or better recommendation. All others will need to be reviewed by clinical team before approval.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

Rationale:
A recombinant, humanized, monoclonal IgG1 antibody, bevacizumab binds to VEGF and inhibits the interaction of VEGF to Flt1 and KDR receptors on the surface of endothelial cells. As a result of the binding process, the proliferation of endothelial cells and formation of new blood vessels is prevented (Product Information Label, 2013). 

Colorectal and Small Bowel Adenocarcinoma
In 2004, bevacizumab received U.S. Food and Drug Administration (FDA) approval for use in combination with 5-fluorouracil (5-FU)-based chemotherapy as initial treatment of metastatic colorectal cancer (mCRC). Bevacizumab was the first FDA approved angiogenesis inhibitor drug. The approval was based on results from two randomized controlled trials.

In June 2006, bevacizumab was approved by the FDA for the second-line treatment of individuals with metastatic colorectal cancer in combination with a 5-FU based regimen. The randomized controlled study involving 829 individuals in three study arms compared 5-FU, leucovorin (LV) and oxaliplatin (FOLFOX4) alone, FOLFOX4 plus bevacizumab, and 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. Overall survival (OS) was 13.0 months in the FOLFOX4 plus bevacizumab arm compared to the FOLFOX4 group of 10.8 months (Product Information Label, 2013).

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 have 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 progression-free survival (PFS); there was no significant difference in a key secondary outcome measure of overall response rate" (Product Information Label, 2013).

Bennouna and colleagues (2013) reported data from an open-label, randomized, phase 3 international study that investigated the continued use of bevacizumab in individuals with metastatic colorectal cancer that had progressed after receiving first-line chemotherapy which included bevacizumab. Participants were excluded if less than 3 consecutive months of first-line bevacizumab was received and if they progressed within 3 months of initiating first-line chemotherapy. The primary endpoint of the study was changed from PFS to OS when the study was expanded to additional study sites. A total of 820 participants were randomized to infusional or bolus fluorouracil, or oral capecitabine at the discretion of the investigators, plus irinotecan or oxaliplatin, with or without bevacizumab at 2.5mg/kg/week equivalent. Second-line chemotherapy was based on the first-line chemotherapy utilized. The bevacizumab plus chemotherapy group included 409 individuals and 411 were randomized to the chemotherapy alone group. The median follow-up was 11.1 months in the bevacizumab plus chemotherapy group (6.4 – 15.6) and 9.6 months (5.4 – 13.9) in the chemotherapy alone group. The median OS was 11.2 months (95% CI, 10.4 – 12.2) in the bevacizumab group compared to 9.8 months (8.9 – 10.7) for chemotherapy alone (HR 0.81, 95% CI 0.69 – 0.94; p = 0.0062). The bevacizumab group had a median PFS of 5.7 months (95% CI 5.2 – 6.2) versus 4.1 months (3.7 – 4.4) for the chemotherapy alone group (HR 0.68, 95% CI 0.59 – 0.78; p < 0.0001). Grade 3 – 5 adverse events occurred in 255 (64%) participants in the bevacizumab group and 235 (57%) participants in the chemotherapy group. Each group had 11 grade 5 events that resulted in death. Four deaths in the bevacizumab and three deaths in the chemotherapy alone group were considered treatment related.

In a prospective, observational study, known as the BRiTE trial, the safety and effectiveness of bevacizumab treatment for individuals with mCRC were reported by Grothey and colleagues (2008). Of the 1953 enrolled participants, 1445 individuals with mCRC progressive disease (PD) were categorized into three groups which consisted of: no post-PD treatment (n = 253); post-PD treatment without bevacizumab (n = 531); and bevacizumab beyond first progression (BBP) (n = 642). The median OS for the entire cohort was 25.1 months (95% confidence interval [CI], 23.4 to 27.5 months). After analyzing the data by classification, the BBP cohort had a statistically significant improved survival rate (hazard ratio [HR] 0.48; P < 0.001). The median OS rates also varied by group with 12.6 months for no post-PD treatment, 19.9 months for no-BBP group, and 31.8 months for the BBP group. Bevacizumab use varied within the 642 participants in the BBP group, with 312 individuals receiving continuous first-line to beyond first progressive disease. Prior to the first progressive disease, 132 participants had stopped bevacizumab, but restarted bevacizumab treatment within one month of PD. A total of 198 participants discontinued the use of bevacizumab prior to PD or at first PD, and resumed bevacizumab more than one month after the first PD. Bevacizumab was resumed in 71 individuals at 4 or more months after the first progressive disease. The authors noted a higher incidence of new onset or worsening of hypertension in the BBP group, which was attributed to longer bevacizumab exposure. This study has significant methodological limitations which limit the applicability of the authors' conclusion. Further study in appropriately designed randomized trials is warranted. 

The product information label (2013) states for stage II and stage III CRC, "Avastin is not indicated for adjuvant treatment of colon cancer." The National Comprehensive Cancer Network^® (NCCN) clinical practice guidelines for colon and rectal carcinoma (2012) do not recommend the use of bevacizumab outside of clinical trials, as adjuvant therapy for stage II and III disease.

The guidelines list the off-label use of bevacizumab in combination with FOLFOX; leucovorin with 5-FU and irinotecan (FOLFIRI); 5-FU plus leucovorin; or capecitabine plus oxaliplatin (CapeOx) regimens as neoadjuvant therapy for metastatic disease and initial therapy in individuals with unresectable, advanced or metastatic disease. In addition, for small bowel adenocarcinoma, the NCCN recommends "systemic chemotherapy according to the colon cancer guidelines." These recommendations were based on 2A category of evidence and uniform consensus. Additionally, NCCN notes, "There are no data to suggest activity of FOLFIRI-bevacizumab in an individual who has progressed on FOLFIRI- ziv-aflibercept, or vice versa." There is no data to support the concomitant use of bevacizumab with ziv-aflibercept.

Non-small cell lung carcinoma (NSCLC)
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. In a large study, 878 participants were randomized to receive six cycles of paclitaxel and carboplatin (PC) or, PC plus bevacizumab at 15mg/kg. After completion of the six cycles, participants in the bevacizumab arm continued to receive bevacizumab alone every 21 days. OS of 12.3 months in the PC plus bevacizumab group was statistically significant compared to 10.3 months in the PC alone cohort. The median PFS was 6.2 and 4.5 months respectively (Sandler, 2006). As a result of the Eastern Cooperative Oncology Group's (ECOG) phase II and III trials (ECOG4599), the use of bevacizumab in combination with paclitaxel and carboplatin has been recommended as the new standard of treatment (Azzoli, 2009, 2011; NCCN, 2013; Sandler, 2006).

Reck and colleagues (2009) reported results from a multi-center phase III trial that randomized participants to first-line treatment with cisplatin and gemcitabine plus low- or high-dose placebo versus low- or high-dose bevacizumab. Treatment allocation was blinded, and therefore no crossover was allowed, and the reported data from both placebo groups were combined. Treatment was planned for six cycles of combination chemotherapy, and thereafter maintained on single agent study drug until disease progression or unacceptable toxicity. In this trial, 1043 participants were randomized, but 57 participants were ineligible to receive treatment. Progression-free survival (PFS) was significantly longer in the treatment groups containing bevacizumab compared to placebo. In 2010, Reck and colleagues reported although the initial data demonstrated a trend for improved OS, the final analysis determined there was no significant OS benefit of bevacizumab when combined with cisplatin and gemcitabine compared to the cohort treated with cisplatin and gemcitabine.

In an analysis of the impact of bevacizumab treatment in the Medicare population, Zhu and colleagues (2012) linked the NCI's Surveillance, Epidemiology, and End Results (SEER) data to Medicare claims. Study criteria included individuals 65 years of age 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 total of 26,830 individuals met inclusion criteria of which 4,168 individuals received identifiable first-line chemotherapy with carboplatin-paclitaxel with or without bevacizumab. The carboplatin-paclitaxel group included 2,666 (64%) individuals diagnosed between 2002 – 2005. Diagnoses of 1502 individuals occurred between 2006 – 2007, which included 318 (21%) individuals in the bevacizumab treatment group and 1184 (79%) individuals in the carboplatin-paclitaxel group. Zhu and colleagues did not identify a significant difference 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% confidence interval [CI], 0.88 – 1.15) or 2002 – 2005 (HR, 0.94; 95% CI, 0.83 – 1.06). The authors concluded although the observational data was extracted from the SEER-Medicare data, some clinical factors such as performance status and baseline lung function were missing. 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 (Zhu, 2012).

A sub-group analysis of participants older than 65 years of age from a phase IV, multi-center, 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 study (SAiL) study included 2212 individuals in the intention to treat (ITT) population with 623 individuals comprising the subgroup of those older than 65 years of age. Individuals in the bevacizumab treatment cohort received chemotherapy and either 7.5 or 15mg/kg of bevacizumab every 3 weeks for up to six 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 (95% CI, 13.0 – 15.4) and younger participants (95% CI, 133.7 – 15.7). Time to disease progression (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 being baseline hypertension occurring in 39.6% of the elderly compared to 22% in the younger cohort. Baseline concomitant medication use was higher (82.3%) in the elderly group versus 69.9% in the younger group. The use of cardiovascular drugs were also more frequent in the elderly (48.2%) compared to the younger participants (25.1%). Serious adverse events (SAEs) were reported in 45.3% of the elderly group and 34.7% of the younger group. Adverse events of special interest (AESIs) were noted in 441 (70.8%) of the elderly and 1085 (68.3%) of the younger participants. In both groups, majority of the AESIs were equal to or less than grade 2. The mortality rates associated with AESIs were 2.9% in the elderly and 2.5% in the younger individuals. Laskin and colleagues concluded that elderly individuals can tolerate first-line bevacizumab in combination chemotherapy regimens for treatment of NSCLC and can achieve similar benefits as younger individuals.

The NCCN Clinical Practice Guideline (2012) 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 was based on a 2A category of evidence and uniform consensus. Additionally, the guideline 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. NCCN includes the off-label use of pemetrexed in combination with bevacizumab and platinum-based first-line therapy for NSCLC.

Central Nervous System — Primary Tumors
In May 2009, the 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 an improved objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab (Product Information Label, 2013). 

Some of the highest concentrations of VEGF are found in malignant gliomas. The overall prognosis for grade III (anaplastic astrocytoma, anaplastic oligoastrocytoma and anaplastic oligodendroglioma) — grade IV glioma (glioblastoma multiforme [GBM]) is grim and treatment options are limited. In 2007, Vredenburgh reported results of a phase II prospective trial investigating the efficacy of irinotecan combined with bevacizumab for recurrent gliomas in adults. Individuals requiring therapeutic anticoagulation were excluded from the study as a safety precaution. Of 32 participants, 23 individuals had grade IV GBM and 9 individuals had grade III gliomas (7[22%] with anaplastic astrocytoma, and 2[6%] with anaplastic oligoastrocytoma). Twenty (63%) had radiographic responses noted on magnetic resonance imaging (MRI). The overall 6 month PFS was 38%. A difference in PFS was noted by severity of disease between participants with grade III versus grade IV PFS of 56% compared with 30%, respectively. Median PFS of 23 weeks (95% confidence interval [CI], 15 – 30 weeks) with an overall 6 month survival is 72% (95% CI, 58 – 89%). Eight participants (25%) continued therapy with bevacizumab and irinotecan for more than 48 weeks after initiating therapy. The response data did not stratify responses by types of grade III gliomas. There were two treatment related events, arterial ischemic stroke and thromboembolic complications resulting in death. Vredenburgh and colleagues (2007b) contrasted results to data from another trial utilizing other chemotherapy regimens with a 6 month PFS of 15% and median PFS of 9 weeks. Another multicenter phase II trial is currently in progress to validate the results. Despite the natural disease progression of high grade glioma, the early trial results demonstrated improved PFS with the use of bevacizumab in combination with irinotecan.

There are multiple clinical trials studying the effectiveness of off-label bevacizumab used as first-line therapy for newly diagnosed GBM, but the data have not been published.

Metastatic renal cell carcinoma (RCC)
In July 2009, bevacizumab was approved by the FDA in combination with interferon alfa as a treatment for metastatic renal cell carcinoma. 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 renal cell carcinoma. Progression free survival 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 (ORR) 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).

Appendix:

Dose modifications: There are no recommended dose reductions for bevacizumab. Bevacizumab should be discontinued in the following clinical situations:

Bevacizumab should be temporarily suspended in the following clinical situations:

Drug Availability: Bevacizumab is supplied as a 100 mg/4 mL single-use vial and a 400 mg/16 mL single use vial.

PRECAUTIONS:
Boxed Warning

Precautions/Warnings:

References:

1. Hurwitz, H, Fehrenbacher, L, Novotny, W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. PMID: 15175435
2. Giantonio, BJ, Catalano, PJ, Meropol, NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. PMID: 17442997
3. Saltz, LB, Clarke, S, Diaz-Rubio, E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. PMID: 18421054
4. NCCN Clinical Practice Guidelines in Oncology™. Colon Cancer v.3.2011. [cited June 2, 2011]; Available from: http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
5. Friedman, HS, Prados, MD, Wen, PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. PMID: 19720927
6. NCCN Clinical Practice Guidelines in Oncology™. Central Nervous System Cancers v.2.2011. [cited June 2, 2011]; Available from: http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf 
7. Sandler, A, Gray, R, Perry, MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. PMID: 17167137
8. Reck, M, von Pawel, J, Zatloukal, P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. PMID: 19188680
9. NCCN Clinical Practice Guidelines in Oncology™. Non-Small Cell Lung Cancer v.3.2011. [cited 06/02/2011]; Available from:http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.
10. Rini, BI, Halabi, S, Rosenberg, JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. PMID: 18936475
11. Escudier, B, Pluzanska, A, Koralewski, P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. PMID: 18156031
12. NCCN Clinical Practice Guidelines in Oncology™. Kidney Cancer v.2.2011. [cited June 2, 2011]; Available from:http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf 
13. NCCN Drugs and Biologics Compendium (NCCN Compendium™). [cited June 2, 2011]; Available from: http://www.nccn.org/clinical.asp
14. Avastin® [package insert]. South San Francisco, CA: Genentech, Inc.; February 2011
15. Bennouna J, Sastre J, Arnold D, et al.; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013; 14(1):29-37.
16. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol. 2009; 27(8):1227-1234.
17. Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: status and perspectives. Acta Pharmacol Sin. 2007; 28(9):1476-1493.
18. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006; 24(12):1898-1903.
19. Zhu J, Sharma DB, Gray SW, et al. Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancer. JAMA. 2012; 307(15):1593-1601.

Coding Section

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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