TEC Assessment Index

Off-Label Uses of Bevacizumab: Breast and Lung Cancer Indications

Assessment Program
Volume 21, No. 8
October 2006

Executive Summary

Background
Bevacizumab (Avastin®) is a humanized recombinant antibody to vascular endothelial growth factor-A (VEGF-A). VEGF-A bound to bevacizumab cannot bind to or activate VEGF receptors (VEGF-R) on vascular endothelial and other cells. Biological consequences include inhibition of angiogenesis (growth of new blood vessels) in tumors.

Bevacizumab combined with intravenous fluorouracil-based chemotherapy is indicated as first- or second-line therapy for advanced or metastatic colon or rectal cancers. Ongoing studies investigate use of bevacizumab in adjuvant therapy regimens following surgery for operable stages of colon and rectal cancers.

Objective
This Assessment summarizes and evaluates evidence on outcomes of bevacizumab for breast cancer and non-small cell lung cancer (NSCLC). For both cancers, evidence on bevacizumab is assessed separately as second- or subsequent-line therapy for advanced or metastatic disease, as first-line therapy for advanced or metastatic disease, or as adjuvant therapy for early stage disease. Another Assessment (Vol. 21, No. 9) summarizes and evaluates evidence on health outcomes of bevacizumab for clear cell renal carcinoma and other malignancies besides colorectal cancers.

Search Strategy
MEDLINE® was searched through July 2006 using the terms "Avastin" or "bevacizumab," cross-indexed with breast or lung neoplasms, or indexed as a clinical trial NOT colon cancer. Hand-searching of reference lists and online searches of recent meeting presentations in the U.S. supplemented the search, which was limited to English-language articles on human subjects.

Selection Criteria
The Assessment includes full-length, peer-reviewed articles reporting on 10 or more patients. Also summarized are meeting presentations with slides available online showing results of phase III randomized comparative trials (RCTs).

Part I: Breast Cancer

A. Second- or Subsequent-Line Therapy for Advanced or Metastatic Disease

Main Results
One of 2 available studies was a dose-escalation trial of bevacizumab monotherapy (5–20 mg/kg; total n=75) that lacked controls managed without bevacizumab, and did not demonstrate a dose-response relationship for the clinical outcomes reported. The second was an RCT (total n=462) of capecitabine with versus without bevacizumab as second- or third-line therapy for metastatic disease that relapsed after doxorubicin and a taxane (used separately as adjuvant therapy or for relapse). The RCT reported no significant difference between arms for duration of response, progression-free survival (PFS), or overall survival (OS), and an absolute increase of 17.5% in grade 3 (treatable) hypertension.

Author's Conclusions and Comments
Neither study showed improved OS or PFS. However, ongoing trials are testing bevacizumab combined with drugs other than capecitabine. Also, results of the currently available studies may not be generalizable to patients whose disease has not separately failed regimens that used doxorubicin and a taxane.

B. First-Line Therapy for Advanced or Metastatic Disease

Main Results
An Eastern Cooperative Oncology Group (ECOG) multicenter RCT (E2100) on paclitaxel with (n=341) versus without (n=339) bevacizumab as first-line therapy for inoperable metastatic disease was presented at two national meetings but has not been published. The first interim analysis reported statistically significant improvement in overall response rate (ORR), PFS, and OS. The second interim analysis also found statistically significant improvement in ORR (30% versus 14%, p<0.0001) and PFS (11.4 versus 6.1 months; p<0.0001), but effects on OS were no longer statistically significant (28.4 versus 25.2 months; p=0.12). The only other study, a published pilot trial on inoperable locally advanced or inflammatory disease, lacked controls.

Author's Conclusions and Comments
Although the first interim analysis of E2100 found a statistically significant increase in median duration of OS for the bevacizumab arm compared with the control arm, the between-arm difference was not statistically significant in the second interim analysis. Definitive conclusions await results from the final analysis. Between-arm differences in PFS significantly favored bevacizumab in each interim analysis, but evaluation of response and progression was unblinded and without central review. Furthermore, evidence is presently unavailable to determine whether longer time to progression translated to improved health status of the patients randomized to bevacizumab.

For these reasons, the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) deferred conclusions on outcomes of first-line bevacizumab for advanced or metastatic breast cancer, pending availability of final results from the unpublished E2100 phase III RCT.

C. Adjuvant Therapy after Resection

Main Result
No evidence was found on outcomes of bevacizumab for adjuvant therapy of resected breast cancer.

Part II: Non-Small Cell Lung Cancer

A. Second- or Subsequent-Line Therapy for Advanced or Metastatic Disease

Main Results
The literature search identified one uncontrolled dose-finding study on second-line therapy (n=34) that combined bevacizumab with erlotinib. The report did not include concurrent or historical controls managed with erlotinib alone.

B. First-Line Therapy for Advanced or Metastatic Disease

Main Results
Two RCTs investigated carboplatin plus paclitaxel, one of several regimens used as initial therapy for inoperable NSCLC, with versus without bevacizumab. One was a small, 3-arm phase II RCT that compared 2 dose levels of bevacizumab versus controls (n=32–34 per arm). Between-arm differences in PFS or OS were not statistically significant. The second, an ECOG multicenter RCT (E4599), was presented at a national meeting but has not been published. Interim analysis found that adding bevacizumab (n=424) to carboplatin plus paclitaxel (n=431 controls) significantly improved ORR (27% versus 10%; p<0.0001), median PFS (6.4 versus 4.5 months; p<0.0001), and median OS (12.5 versus 10.2 months; p=0.007).

Author's Conclusions and Comments
The published phase II RCT lacked sufficient statistical power to detect between-arm differences in survival outcomes, as the goal was to select a dose for and judge whether a phase III trial was warranted. Although the E4599 interim analysis found statistically significant improvement in OS and PFS, the independent data and safety monitoring board continued the trial after reviewing these interim results, and did not recommend crossing over control patients to bevacizumab.

Therefore, the MAP deferred conclusions on bevacizumab for first-line therapy of advanced, metastatic, or recurrent NSCLC, pending availability of final results from the unpublished E4599 phase III RCT.

C. Adjuvant Therapy after Resection

Main Result
No evidence was found on outcomes of bevacizumab for adjuvant therapy of resected NSCLC.

For reasons detailed above, the MAP deferred decisions on outcomes of bevacizumab as first-line therapy for advanced or metastatic breast or lung cancers, pending availability of final results from the completed ECOG E2100 (breast cancer) and E4599 (lung cancer) phase III RCTs.

For the remaining indications, the MAP made the following judgments, based on the available evidence, about whether bevacizumab meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria as therapy for breast or lung cancers. Three indications were evaluated separately for both malignancies:

• second- or subsequent-line therapy for advanced or metastatic disease;
• first-line therapy for advanced or metastatic disease; and
• adjuvant therapy for operable, early stage disease.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

The U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin®) in February 2004 as first-line therapy for metastatic carcinoma of the colon or rectum, when used in combination with intravenous fluorouracil-based chemotherapy. In June 2006, the FDA added second-line therapy for metastatic colorectal cancer as a second approved indication for bevacizumab, when used in combination with intravenous fluorouracil-based chemotherapy. Use of bevacizumab to treat patients with breast, lung, renal cell, or other non-colorectal cancers is an off-label indication, whether it is given as second- or subsequent-line therapy for advanced or metastatic disease, first-line therapy for advanced or metastatic disease, or as adjuvant therapy for an earlier disease stage.

The company's Web site (http://www.gene.com/gene/pipeline/status/oncology/avastin/index.jsp) notes that a supplemental biologics licensing application (sBLA) submitted to FDA in April 2006 was granted priority review status, which requires a final decision by 6 months from submission (i.e., by October 2006). This sBLA seeks approval for a third bevacizumab indication: first-line treatment of non-small cell lung cancer (in combination with platinum-based chemotherapy) in patients with histology other than predominantly squamous cell. In May 2006, the manufacturer submitted a sBLA for a fourth indication: first-line treatment of metastatic breast cancer. The manufacturer requested and FDA granted priority review status for this sBLA also (i.e., final decision by November 2006). However, FDA also requested more documentation from the pivotal trial supporting the sBLA on metastatic breast cancer, and the manufacturer predicts this will delay FDA's final action.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

Available evidence does not permit conclusions on outcomes of bevacizumab as second- or subsequent-line therapy of advanced or metastatic breast or lung cancers, or on outcomes of bevacizumab as a component of adjuvant therapy for either malignancy.

3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.

Since available evidence is insufficient to permit conclusions, it cannot be determined whether bevacizumab improves net health outcome as second-line therapy of patients with breast or lung cancers. Consequently, it also cannot be determined whether the improvement from use of bevacizumab for either of these indications is as beneficial as any established alternatives.

5. The improvement must be attainable outside the investigational settings.

For all indications considered here, whether bevacizumab improves health outcomes, and whether the improvement from use of bevacizumab is as beneficial as any established alternatives, has not yet been determined in the investigational setting.

Based on these findings, bevacizumab does not meet the TEC criteria as second-line therapy for advanced or metastatic breast or lung cancers or as a component of adjuvant therapy for either of these malignancies. Decisions are deferred on whether bevacizumab meets TEC criteria for first-line therapy of advanced or metastatic breast or lung cancers. 

TEC Assessment Index

KEYWORDS: Oncology (category); Pharmacotherapy/Therapy (category); angiogenesis; antiangiogenesis; antibody; bevacizumab; breast cancer; breast neoplasms; cancer; carboplatin; chemotherapy; cisplatin; colon cancer; colorectal cancer; combination; ECOG, Avastin; fluorouracil; gemcitabine; humanized; ifosfamide; lung; lung cancer; lung neoplasms; malignancy; metastatic; non-small cell lung cancer; NSCLC; off-label; oncology; overall response rate; overall survival; paclitaxel; polychemotherapy; posterior leukoencephalopathy syndrome; progression-free survival; recombinant; vascular endothelial growth factor; VEGF; vinorelbine;