TEC Assessment Index

Off-Label Uses of Bevacizumab: Renal Cell Carcinoma and Other Miscellaneous Non-Colorectal Cancer Indications

Assessment Program
Volume 21, No. 9
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 clear cell renal carcinoma and other malignancies besides colorectal cancers. For each cancer, 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. 8) summarizes and evaluates evidence on health outcomes of bevacizumab for breast cancer and non-small cell lung cancer.

Search Strategy
MEDLINE® was searched through July 2006 using the terms "Avastin" or "bevacizumab," crossindexed with renal, pancreatic, or ovarian 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: Clear-Cell Renal Carcinoma

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

Main Results
The literature search identified one 3-arm RCT on second-line therapy, and one single-arm study without controls on a mixed patient group receiving first- or second-line therapy. The RCT enrolled patients with metastatic disease who were ineligible for (5–8%) or failed (92–95%) interleukin-2 (IL-2). They were randomized to placebo or to 3 mg/kg or 10 mg/kg bevacizumab. The median progression-free interval was significantly longer in each arm given bevacizumab than for controls (n=40; 2.5 months), with a larger increase in the high-dose (n=39; 4.8 months; p<0.001) than the low-dose arm (n=37; 3.0 months; p=0.041). Effects of bevacizumab on OS were not statistically significant, but 22 of 40 controls crossed over to bevacizumab when they progressed. An independent data safety and monitoring board stopped accrual when the second interim analysis showed that the higher-dose bevacizumab arm crossed the prespecified O'Brien-Fleming boundary (p≤0.015 in the trial's second year) for time to progression, a primary trial outcome.

The literature search found no evidence directly comparing effects of bevacizumab with those of either multi-targeted protein kinase inhibitor (sorafenib or sunitinib) recently approved to treat renal cell carcinoma. The search also found no evidence on outcomes of bevacizumab in patients who progressed after interferon alfa, sorafenib, or sunitinib. Trials are in progress on some of these comparisons and patient groups.

Author's Conclusions and Comments
An RCT showed that, compared with no second-line therapy, bevacizumab improved PFS of patients progressing after IL-2 therapy (92–95% of those randomized). However, the trial did not detect an effect of bevacizumab on OS. When this RCT was published, no alternative treatments with proven effectiveness were available for these patients. Subsequently, the U.S. Food and Drug Administration approved two new drugs for renal carcinoma, sorafenib and sunitinib. A large phase III RCT for the same indication showed that sorafenib improved OS compared with placebo. Presently, it is not possible to determine whether outcomes of bevacizumab are at least equivalent to those of sorafenib. Nor is there evidence on the outcomes of bevacizumab for patients who progress after interferon alfa, sorafenib or sunitinib. Thus, no conclusions are possible on outcomes of bevacizumab for patients with metastatic clear cell renal carcinoma that progressed after treatment with IL-2, interferon alfa, sorafenib, or sunitinib.

B. First-Line Therapy for Advanced or Metastatic Disease

Main Result
No evidence was found on outcomes of bevacizumab for first-line therapy of metastatic clear cell renal carcinoma.

C. Adjuvant Therapy after Resection

Main Result
No evidence was found on outcomes of bevacizumab for adjuvant therapy of resected clear cell renal carcinoma.

Part II: Other Non-Colorectal Malignancies

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

Main Results
The literature search identified 2 published uncontrolled studies on pancreatic cancer, 3 on ovarian cancer, and 1 published uncontrolled study each on hepatocellular carcinoma, soft-tissue sarcoma, and acute myeloid leukemia. Each study treated patients with bevacizumab plus one or more cytotoxic drugs. One study on pancreatic cancer also included radiation therapy, and another study on ovarian cancer reported results for a mixed group managed with bevacizumab alone or with added chemotherapy.

Author's Conclusions and Comments
Each study used bevacizumab as part of a combination regimen, but none provided data for comparison on concurrent or historical controls managed with the same regimen minus bevacizumab. Therefore, no conclusions are possible on the outcomes of bevacizumab as second- or subsequent line therapy for any of these (or any other) non-colorectal malignancies.

B. First-Line Therapy for Advanced or Metastatic Disease

Main Results
No evidence was found on outcomes of bevacizumab for first-line therapy of any non-colorectal malignancies other than breast or lung cancers. On June 26, 2006, the drug's manufacturer announced that, after interim analysis of a phase III RCT (n=602) comparing gemcitabine with versus without bevacizumab as first-line therapy for pancreatic cancer, the trial's data and safety monitoring board concluded it was "…very unlikely that significant differences in overall survival will be shown as the data mature." Consequently, the trial was stopped early.

Author's Conclusions and Comments
The announced results strongly suggest that adding bevacizumab to gemcitabine does not improve outcomes of first-line therapy for metastatic pancreatic cancer. However, definitive conclusions must wait for final analysis and reporting on this unpublished multicenter cooperative group trial.

C. Adjuvant Therapy after Resection

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

The Blue Cross and Blue Shield Medical Advisory Panel 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 renal cell or other non-colorectal cancers. Three indications were evaluated separately for each malignancy:

• 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 for second-line therapy of metastatic clear cell renal carcinoma after failure of interleukin-2, interferon alfa, sorafenib, or sunitinib; for first-line therapy of metastatic clear cell renal carcinoma; or as a component of adjuvant therapy for operable renal carcinoma. Also, current evidence does not permit conclusions on outcomes of bevacizumab for any stage of pancreatic, ovarian, or hepatocellular cancers; soft-tissue sarcoma; acute myeloid leukemia; or any other non-colorectal 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 any non-colorectal cancers reviewed in this Assessment; as first-line therapy or as second-line therapy after failure of interleukin-2, interferon alfa, sorafenib, or sunitinib for metastatic clear cell renal carcinoma; or as a component of adjuvant therapy for any non-colorectal malignancy reviewed in this Assessment. Consequently, it also cannot be determined whether the improvement from use of bevacizumab for any 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 first-line therapy or second-line therapy after failure of first-line interleukin-2, interferon alfa, sorafenib, or sunitinib for patients with metastatic clear cell renal carcinoma. Bevacizumab also does not meet the TEC criteria as first-line or second-line therapy for advanced or metastatic pancreatic, hepatocellular, or ovarian cancers; advanced or metastatic soft-tissue sarcoma; acute myeloid leukemia; or as a component of adjuvant therapy for any non-colorectal malignancy. 

TEC Assessment Index

KEYWORDS: Oncology (category); Pharmacotherapy/Therapy (category); acute myeloid leukemia; angiogenesis; antiangiogenesis; antibody; bevacizumab; cancer; carboplatin; chemotherapy; cisplatin; clear cell; colon cancer; colorectal cancer; combination; ECOG, Avastin; erlotinib; fluorouracil; gemcitabine; hepatocellular carcinoma; humanized; IL-2; immunotherapy; interleukin-2; ifosfamide; interferon alfa; kidney; lung; lung cancer; malignancy; metastatic; nephrectomy; NSCLC; off-label; oncology; ovarian; overall response rate; overall survival; paclitaxel; pancreatic; pancreas; polychemotherapy; posterior leukoencephalopathy syndrome; progression-free survival; recombinant; renal cell; renal; resected; soft-tissue sarcoma; sorafenib; sunitinib; vascular endothelial growth factor; VEGF; vinorelbine;