Bevacizumab - Avastin; vascular endothelial growth factor monoclonal antibody, recombinant
Status: approved; marketed
Organizations involved:
Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.; Patent dispute
Hoffmann-La Roche Ltd. – Intl. mark.
Lonza Biologics plc – Manuf.
Chugai Pharmaceutical Co. Ltd. – Japan mark.
PDL Biopharma, Inc. – Tech.; Patent dispute
Celltech Group Ltd. – Tech.; Patent dispute
Columbia University. – Tech.; Patent dispute
Amgen Inc. – Tech.
Cross ref.: See the entry for VEGF aptamer (Macugen), a synthetic oligonucleotide with VEGF antibody-like binding activity. See the Monoclonal Antibodies entry (#300)
Description: Avastin in an aqueous formulation of bevacizumab, a recombinant humanized IgG1 monoclonal antibody expressed Chinese hamster ovary (CHO) cells that selectively binds to and inhibits the biological activity of human vascular endothelial growth factor (VEGF). Bevacizumab glycoprotein contains human framework regions and the complementarity-determining regions (CDRs; epitope-binding portions) of a murine antibody that binds to VEGF. Bevacizumab competitively inhibits VEGF-mediated proliferation of endothelial cells in vitro and in vivo by binding to VEGF and inhibiting binding of VEGF to its receptors, resulting in reduction of the vascularization of tumors. Blood supply is critical in tumor growth and spread. By inhibiting angiogenesis or the induction of growth of new blood vessels by VEGF, bevacizumab interferes with blood supply to tumors, inhibiting further tumor growth and metastasis. Bevacizumab has a molecular weight of approximately 149 kDa. Avastin is the first therapeutic with an antiangiogenesis-based mechanism of action.
Avastin is supplied in 100 mg and 400 mg (25 mg/mL) preservative-free single-use vials to deliver 4 mL or 16 mL, respectively, of bevacizumab by intravenous (IV) infusion. The 100 mg product is formulated in 240 mg alpha,alpha-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg alpha,alpha-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20 (Tween 20), and Water for Injection, USP. Avastin has a pH 6.2. Avastin is stored at 2-8°C (36-46°F; refrigerated).
Nomenclature: VEGF Mab, rDNA [BIO]; Avastin [TR]; bevacizumab [FDA USAN INN]; immunoglobulin G1, anti-(human vascular endothelial growth factor) (human-mouse monoclonal rhuMAb-VEGF .gamma.1-chain), disulfide with human-mouse monoclonal rhuMAb-VEGF light chain, dimer [CAS]; 216974-75-3 [CAS RN]; rhuMAb-VEGF [SY]; Anti-VEGF monoclonal antibody [SY]; vascular endothelial growth factor monoclonal antibody, recombinant [SY]; NDC 50242-060-01 and NDC 50242-060-02 [NDC]
Biological.: The two major cellular components of the vascular system are endothelial and smooth muscle cells. Endothelial cells form the lining of the inner surface of all blood vessels, and constitute a nonthrombogenic interface between blood and tissue. Endothelial cells are also an important component for the development of new capillaries and blood vessels. Endothelial cells proliferate during the neovascularization associated with tumor growth (and other diseases, including psoriasis, arthritis, and diabetic retinopathy).
Various natural polypeptides induce the proliferation of endothelial cells, including bovine vascular endothelial growth factor (VEGF), e.g., as first reported Genentech in 1989 (e.g., PCT patent. WO 90/13649; and U.S. 332,671, filed in 1989). Bovine VEGF was identified in media conditioned by bovine pituitary follicular or folliculostellate cells. DNA encoding bovine VEGF was isolated by screening a cDNA library prepared from such cells, using oligonucleotides based on the amino-terminal amino acid sequence of the protein as hybridization probes. Biochemical analyses showed that VEGF is a dimeric protein with an mitogenic specificity for vascular endothelial cells.
Human VEGF is a homodimeric, cysteine-rich glycoprotein that can occur in at least four forms due to alternative splicing of its mRNA. VEGF is a high-affinity ligand for the VEGF receptors, VEGFR-1 (Flt1) and VEGFR-1 (KDR/Flk-1 or Flk1), on the surface of endothelial cells, but does not bind or activate Flt4. The only other closely related member of the VEGF family is placental growth factor (PlGF), which has 47% amino acid identity with VEGF. Overexpression of VEGF mRNA occurs with most tumor types, and is associated with poor clinical outcomes. High levels of VEGF in eye fluids of patients with diabetic or other ischemia-related retinopathies correlate with the active proliferation of blood vessels. Tumors are critically dependent on angiogenesis and VEGF, with the resulting increase in oxygen and nutrients (due to increased blood supply) promoting tumor growth and metastasis. In vivo studies show that VEGF inhibition reduces the rate of tumor growth and metastases, overall tumor vascularity, and the permeability of tumor microvessels.
Human VEGF (hVEGF) was first obtained by Genentech by screening a cDNA library prepared from human cells, using bovine VEGF cDNA as a hybridization probe (Leung, et al., Science 246:1306,1989; and U.S. patent 5,332,671, filed in 1989). This provided the 165-amino acid human vascular endothelial growth factor (hVEGF), two hVEGF-related proteins, and hVEGF murine monoclonal antibodies produced by hybridoma clones A4.6.1 and B2.6.2. hVEGF has a greater than 95% homology to bovine VEGF. The mitogenic activity of hVEGF was confirmed by expressing the hVEGF cDNA in mammalian host cells. Media conditioned by cells transfected with the human VEGF cDNA promoted the proliferation of capillary endothelial cells, but control cells did not. Additional cDNAs were identified in the human cDNA library that encode 121- and 189-amino acid hVEGF-related proteins.
In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, reported that VEGF antibodies could suppress angiogenesis and tumor growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumor growth.
Angiogenesis is regulated in normal and malignant tissues by the balance of angiogenic stimuli and angiogenic inhibitors that are produced in the target tissue and at distant sites. VEGF is a multifunctional cytokine that is induced by hypoxia and oncogenic mutations and can be produced by a wide variety of tissues. VEGF has been shown to play a major role in diseases associated with aberrant angiogenesis, including cancer, rheumatoid arthritis, bullous diseases (including bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme), and psoriasis.
Bevacizumab binds VEGF and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells. This prevents the interaction of VEGF with its receptors, which leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice causes reduction of microvascular growth and inhibition of metastatic disease progression.
Companies.: Genentech discovered VEGF in 1989 and starting clinical trials with humanized monoclonal antibody (Avastin) in 1997. Avastin was developed and is manufactured by Genentech Inc. (CBER/FDA est. no. 1048). Genentech markets Avastin in the U.S. Note, in early 2009, Roche fully acquired the remaining portion of Genentech it did not already own, i.e., Genentech is now part of Roche.
Bulk bevacizumab drug substance was originally manufactured at Genentech facilities in South San Francisco and Vacaville, CA. In mid-2005, Genentech reported it was manufacturing bevacizumab at its Vacaville facility, and would expand manufacturing to the NIMO facility in Oceanside, CA, it acquired from Biogen Idec, with Avastin to be the primary product of this facility. With Amgen ending its contract with Genentech for manufacture of etanercept (Enbrel; see related entry), Genentech has dedicated two of eight 12,000 liter bioreactors at its South San Francisco facility to manufacture of Avastin, with approval for their use expected in 2006. Avastin supplies for clinical trials have been manufactured using two of four 10,000 L bioreactors at Genentech facilities in Porrino, Spain. Genentech has submitted a supplemental BLA seeking approval for manufacture of Avastin for U.S. marketing using all four of its 10,000 L bioreactors at Porrino. Genentech reports that it hopes to further expand Avastin (and also Rituxan) manufacture by about 50% using its currently-licensed cell line. FDA sBLA approval for related process changes is expected by early 2007.
In Nov. 2006, Lonza agreed to purchase Genentech’s manufacturing facility in Porrino, Spain, for $150 million. This facility has a biologic manufacturing capacity of 40,000 L, currently dedicated to manufacture of Avastin. Lonza will continue to produce Avastin for Genentech. Concurrently, Genentech entered into a supply agreement for the manufacture of certain its products at Lonza’s 80,000-L facility under construction in Singapore (licensing expected in 2010). Under this agreement, Genentech also receives the right to exercise an exclusive option to purchase the facility during the period from 2007 to 2012 for a purchase price of $290 million, plus an additional $70 million in milestone payments, if certain performance milestones are met.
Hoffmann-La Roche Ltd., which owns a majority of Genentech, has exclusive development and marketing rights for Avastin in all countries outside the U.S. In Dec. 2003, Roche granted Chugai Pharmaceutical Co. exclusive rights in Japan. In June 2004, Hoffmann-La Roche announced it would spend ~$640 million for construction of two new facilities in Basel, Switzerland, and Penzberg, Germany, for the manufacture of Avastin and Herceptin. Roche currently obtains Avastin from Genentech, but expected to assume manufacture for its own use by 2009.
In May 2007, Roche inaugerated a new manufacturing facility in Basel, Switzerland; and in July 2007, inaugerated a new manufacturing facility in Penzberg, Germany. EU approval for the Basel facility for manufacture of Avastin is expected in 2009. Until then, Roche will continue to market Avastin manufactured by Genentech.
In June 2007, Genentech received FDA approval for manufacture of Avastin at its Oeanside, CA, facilities. This facility can produce "96,000 liters of monoclonal antibodies a year, or about one-third of Genentech’s current production capacity."
In 2005, Genentech reported that it and Roche had jointly spent over $2.25 billion developing Avastin, including research, clinical trials and filing for regulatory approvals. In contrast, and with some groups criticizing the high cost of Avastin based on federal subsidies, Consumer Watchdog, an advocacy group, estimated that NIH had spent $44.6 million on Avastin trials and related R&D.
In Sept, 2009, Genentech/Roche exercized and option and acquired a new 80,000 liters fermentation capacity biopharmaceutical manufacturing facility in Singapore from Lonza, with it expected to be used for manufacture of Avastin. Genentech paid $290 million up front and potentially another $70 million milestones. Lonza built the cell culture facility as part of the companies’ 2006 agreement, through which Lonza paid $150 million to acquire Genentech’s mid-scale Avastin-producing mammalian biopharmaceutical plant in Porrino, Spain. [Lonza is also building its own 80,000-liter large-scale mammalian manufacturing plant in Singapore, which is scheduled to come on-stream during 2011].
Manufacture: Bevacizumab monoclonal antibody humanization was reported by Genentech researchers in Cancer Research, vol. 57, p. 4953-9, 1997. Murine (mouse) monoclonal antibody A.4.6.1 (VEGF Mab A.4.6.1) with specificity for VEGF was humanized by site-directed mutagenesis of a human framework. Murine residues involved in the six complementarity-determining regions (CDRs; antigen-binding sites) were converted to consensus human frameworks. Simply stated, the sequences of CDRs of the murine antibody were changed to human sequences. Also, seven framework residues in the variable heavy (VH) domain and one residue in the humanized variable light (VL) domain were changed from human to murine to achieve binding comparable to VEGF Mab A.4.6.1. The resulting humanized monoclonal antibody, bevacizumab, binds to VEGF with affinity very similar to the original antibody, and has comparable activity in vitro and in vivo.
For stable expression of the resulting humanized IgG1 monoclonal antibody, bevacizumab, Chinese hamster ovary (CHO) cells (CHO-K1 DUX B11 cell line) were transfected with dicistronic vectors designed to express both IgG1 heavy and light chains, and selected for growth in glycine/hypoxanthine/thymidine (GHT)-free culture medium. A single clone expressing a high affinity antibody was selected, expanded in T-flasks, and used to inoculate a spinner suspension culture. Suspension adapted cells, used to construct the master cell bank, were further selected and propagated. Culture of these cells in serum-free culture medium supplemented with various hormones and protein hydrolysates and containing the antibiotic gentamicin provides high purity bevacizumab.
In "High-yield expression of human vascular endothelial growth factor VEGF(165) in Escherichia coli and purification for therapeutic applications," Protein Expr Purif., May 2010, Genentech staff report developing a bacterial expression system capable of producing ~9 g of rhVEGF per liter of broth and a downstream purification process consisting of protein refolding and three chromatography steps prior to formulation of the drug substance. A high cell density (HCD) fed-batch fermentation process is used to produce rhVEGF in E. coli periplasmic inclusion bodies. The inclusion bodies are harvested from the cell lysate and subjected to a single-step protein solubilization and refolding operation to extract the rhVEGF for purification. Overall recovery yields observed during development, including refolding and chromatography, were 30 +/- 6%. Host cell impurities are consistently cleared below target levels at both laboratory and large-scale, demonstrating process robustness.
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FDA class: Biologic BLA
Approvals: Date = 20040226; BLA (no. 125085), first approval
Date = 20040810; BLA supplement; Indication = approval for manufacture of bevacizumab (bulk drug substance) at Genentech facility in Vacaville, CA
Date = 20050100; BLA supplement; Indication = added information about risk of arterial thromboembolic events (ATEs) to product insert/labeling
Date = 20050930; BLA supplement; Indication = added a note to the insert/labeling that a 1% overall response rate had been reported in the first 100 evaluable patients with metastatic colorectal cancer having received Avastin plus 5-fluorouracil/leucovorin (5-FU/LV) (i.e., the combination was not effective; see the Trials section below)
Date = 20060620; BLA supplement; Indications: = in combination with intravenous 5-fluorouracil-based chemotherapy for second-line metastatic colorectal cancer
Date = 20061011; BLA supplement; Indications: = Avastin in combination with carboplatin and paclitaxel chemotherapy for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC)
Date = 20070623; BLA supplement; Indications: = approval for manufacture by Genentech at Oceanside, CA
Date = 20080222; BLA supplement; Indications: = accelerated approval for Avastin in combination with paclitaxel chemotherapy for the first-line treatment of metastatic HER2-negative breast cancer
Date = 20090802; BLA supplement; Indications: = Avastin plus interferon-alfa for treatment of metastatic renal cell carcinoma
Date = 20090505; BLA supplement; Indications: = accelerated for glioblastoma
Date = 20090731; BLA supplement; Indications: = treatment of metastatic renal cell carcinoma in combination with interferon alfa
Date = 20101228; Indications = revised the ADVERSE REACTIONS, PostMarketing Experience subsection to add eye disorders and to update gastrointestinal reactions
Date = 20110208; BLA supplement; Indications = “Prior Approval” labeling supplement to revise the CLINICAL STUDIES, Unresectable Non-Squamous Non-Small Cell Lung Cancer subsection to include the overall survival results of study BO17704 and revises the INDICATIONS AND USAGE, Glioblastoma and the USE IN SPECIFIC POPULATIONS, Pediatric Use subsections.
Date = 20110930; BLA supplement; Indications = additions to the package insert: a new subsection, titled “Ovarian Failure” to WARNINGS AND PRECAUTIONS; a new subsection, titled “Females of Reproductive Potential” (8.6), to USE IN SPECIFIC POPULATIONS; a new subsection titled Ovarian Failure under ADVERSE REACTIONS; addition of the adverse reaction of osteonecrosis of the jaw to ADVERSE REACTIONS (6.3); inclusion of additional information to the subsection titled Venous Thromboembolic Events in ADVERSE REACTIONS; and addition of information on ovarian failure to PATIENT COUNSELING INFORMATION.
Date = 20111220; BLA supplement; Indications = “Prior Approval” labeling supplement revises the package insert to remove the metastatic breast cancer indication, to remove information based on the results of studies E2100 and AVF2119g from the DOSAGE AND ADMINISTRATION, CLINICAL STUDIES, and USE IN SPECIFIC POPULATIONS, Geriatric Use sections of labeling, and to remove subsections of the ADVERSE REACTIONS section limited to the description of adverse reactions in these studies.
Date = 20130123; BLA supplement; Indications: = in combination with fluoropyrimidine-based irinotecan or oxaliplatin chemotherapy for people with metastatic colorectal cancer (mCRC)
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 6/2012]:
Avastin is a vascular endothelial growth factor-specific angiogenesis
inhibitor indicated for the treatment of:
Status: Hoffmann-La Roche filed a MAA for European Union approval of Avastin on Dec. 5, 2003. On Jan. 14, 2005, Hoffmann-La Roche received European Union (EU) approval of Avastin for first-line treatment of colon cancer.
With the Aug. 2004 sBLA approval for manufacture of bulk Avastin at Vacaville, CA, facilities, Genentech manufactures bulk drug substance at its South San Francisco and Vacaville, CA, facilities (in addition to manufacture by Lonza).
In Jan. 2005, U.S. labeling for Avastin was modified to include discussion of increased risk of arterial thromboembolic events (ATEs) associated with the use of Avastin for first-line colorectal cancer treatment in combination with FU chemotherapy. An analysis of 1,745 patients treated in Avastin trials had showed that ATEs occurred in 4.4% of patients treated with Avastin vs. 1.9% who received chemotherapy alone. Some of these events were fatal. ATEs are defined as stroke, transient ischemic attacks (TIAs), heart attack, angina and other arterial thromboembolic events. U.S. physicians had previously been informed of this in an Aug. 2004 letter.
In Dec. 2005, Genentech submitted a supplemental BLA (sBLA) seeking approval of Avastin for treatment of relapsed metastatic colorectal cancer in combination with 5-fluorouracil (5-FU).
In Feb. 2006, Genentech submitted a supplemental BLA for Avastin for treatment of advanced non-small cell lung cancer, other than predominant squamous histology.
On April 11, 2006, Genentech filed a supplemental BLA for Avastin use in combination with platinum-based chemotherapy for first-line treatment of advanced, non-squamous, non-small cell lung cancer (NSCLC).
Also in April 2006, Chugai filed the first marketing application for Avastin in Japan, for the treatment of advanced or recurrent colorectal cancer. The application was filed early under an MHLW initiative aimed at expediting patient access to innovative medicines that are already approved in the US or EU. The application has been granted priority review status.
In May 2006, Roche submitted a supplemental BLA for Avastin plus paclitaxel for first-line treatment of locally recurrent or metastatic breast cancer. The sBLA was based on interim data from the E2100 trial.
In June 2006, FDA approved Avastin in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy for second-line metastatic colorectal cancer.
In July 2006, Roche filed a MAA for European Union approval of Avastin plus paclitaxel for the treatment of advanced breast cancer.
In Sept. 2006, FDA issued Genentech a “Complete Response Letter” requesting additional analyses from the E2100 trial (see Trials section below) to support approval of Avastin plus paclitaxel to treat chemotherapy-naive metastatic breast cancer patients. This included an independent, blinded review of patient scans for progression-free survival (PFS), the primary endpoint of the trial.
In Oct. 2006, following priority review, FDA approved Avastin for the treatment of non-small cell lung cancer (NSCLC), the most common form of the disease. A filing for the same indication was submitted to the European Union in August.
In Oct. 2006, FDA granted supplemental approval for Avastin in combination with carboplatin and paclitaxel for the first-line treatment of advanced non-small cell lung cancer (NSCLC). Approval was based on results of the Phase III E4599 trial (see Trials section below) that studied a 15 mg/kg dose of Avastin administered every three weeks. The 15 mg/kg dose was selected based on the outcome of a randomized Phase II study evaluating two different doses of Avastin in combination with carboplatin and paclitaxel chemotherapy. Avastin became the first therapy in 10 years to improve on standard first-line treatment for advanced lung cancer, and the first FDA-approved therapy ever to extend survival for these patients beyond one year in a large, randomized clinical trial.
In Feb. 2007, Japanese authorities recommended approval of Avastin from Chugai for advanced or recurrent colorectal cancer, with approval expected by mid-year.
In March 2007, Hoffmann-La Roche Inc. filed a supplemental NDA for approval of Xeloda (capecitabine; the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer) in combination with oxaliplatin (XELOX) with or without Avastin for the treatment of metastatic colorectal cancer. Study NO16966 had showed that XELOX in combination with Avastin further improved progression-free survival over XELOX alone.
On March 29, 2007, the European Union (EU) granted supplemental approval of Avastin for first-line treatment of women with metastatic breast cancer in combination with a standard chemotherapy paclitaxel.
On Aug. 24, 2007 Genentech resubmitted its supplemental BLA for Avastin plus paclitaxel for patients who have not received chemotherapy for their locally recurrent or metastatic breast cancer, with a six month review target. This was involved independed blinded review of patient scans from the pivotal E2100 Phase III trial (see the Trials section below).
On Aug. 24, 2007, Roche received European Union approval for Avastin plus platinum-based chemotherapy for first-line and also later treatment of advanced non-small cell lung cancer (NSCLC), primarily based on the U.S.AVAiL Phase III trial (see Trials section below). The new Avastin label will allow it to be used in combination with every standard fluoropyrimidine-based chemotherapy and also allows for combinations with Xeloda or oxaliplatin. Avastin formerly could only be used in combination with IV 5-FU or IV 5-FU/irinotecan-based chemotherapy regimen, where it had demonstrated an impressive survival extension of nearly 5 months. Physicians now have the flexibility to use Avastin with a broad variety of standard chemotherapy of their choice in any line of metastatic colorectal cancer. The approval was based on the results of two large international Phase III pivotal studies (NO16966 and E3200).
On Dec. 19, 2007, the EU granted supplemental approval to Avastin the first-line treatment of patients with advanced renal cell carcinoma (RCC) in combination with interferon alfa. This approval was based on the Phase III AVOREN trial in which patients who received Avastin in combination with interferon lived roughly twice as long without disease progression than those who received interferon alone.
In Jan 2008, Avastin received supplemental EU approval for use in combination with any chemotherapy, including Roche's oral chemotherapy Xeloda (capecitabine), for first and later treatment lines in patients with metastatic colorectal cancer.
In Feb. 2008, FDA granted broad approval to Avastin for first-line use in breast cancer treatment (generally, in combination of paclitaxol/Taxol) in patients with HER2-negative breast cancer (not candidates for Herceptin treatment). The approval was based largely on a Phase III study (E2100) that showed that Avastin in combination with paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease progression or death compared to those treated with paclitaxel alone and a doubling in progression-free survival (PFS) (based on a hazard ratio of 0.48; p less than 0.0001), with PFS a surrogate market for improved survival. However, the trial's primary endpoint was survival, and a statistically significant improvement was not reached. Genentech's studies of Avastin essentially showed that while it halted tumor growth for more than 11 months, but breast cancer patients didn't live significantly longer than those who didn't receive the drug.Genentech had argued that stopping tumor growth benefits patients physically and psychologically, even if it doesn't increase life expectancy. The safety profile of Avastin was consistent with our previous experience and no new safety signals were observed. No real quality-of-life measurement were submitted.
The Feb. 2008 approval for breast cancer was somewhat of a surprise for many, since in Dec. 2007, the Oncologic Drugs Advisory Committee (ODAC) voted 5-4 that available data are not sufficient to establish a favorable risk/benefit analysis for the use of Avastin in combination with paclitaxel chemotherapy for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.This vote against approval for breast cancer was largely due to Avastin not having significantly lengthening survival of women with late-stage breast cancer, and quality of life data were not available. The gold standard for chemotherapy approvals has long been improvements in survival, something which Avastin did not demonstrate in its pivotal Phase III trial, E2100 (see the Trials section below). At the committee meeting, FDA staff did not take a position on approval. Updated results from trial E2100 reported in Feb. 2008 showing improvements in survival may have helped sway FDA in its later final approval. This accelerated approval is contingent on results from follow-up Phase III trials, including results from AVADO and RIBBON I, showing improvements in survival, with this not explicitly but expected to be required by FDA. Otherwise, like the drug Iressa, its approval for this indication could be revoked.
In April 2009, the Oncologic Drugs Advisory Committtee, FDA, voted 10-0 in favor of accelerated approval of Avastin for glioblastoma.
In May 2009, Avastin received FDA supplemental approval for treatment of glioblastoma, one of the most aggressive forms of brain cancer and previously considered untreatable.
In Nov. 2009, Genentech filed two supplemental BLAs for Avastin in combination with taxane-based, anthracycline-based and capecitabine chemotherapies, based on findings from the AVADO and RIBBON-1 studies. The findings were submitted to convert the accelerated approval to a full approval.
In July 2010, the Oncologic Drugs Advisory Committtee, FDA, voted 12-1 in favor of revoking Avastin's approval for breast cancer. Available data suggested that, at least for advanced breast cancer, the initial data that led to approval was not borne out by subsequent studies. The committee voted 13-0 that studies did not confirm the initial benefit that supported approval for this indication.
On Sept. 22, 2010, FDA extended by an additional 90 days the review period for a supplemental BLA for the treatment of previously untreated advanced HER-2–negative breast cancer. [Keep in mind that FDA originally approved Avastin for breast cancer in 2008 after its advisory committee had recommended against this, so FDA already had ignored the wished of its advisory committee regarding Avastin for breast cancer].
In Dec. 2010, FDA notified Genentech of a “Proposal to Withdraw Marketing Approval” of Avastin for first-line treatment of metastatic HER2 negative breast cancer in combination with paclitaxel and issued a “Notice of Opportunity for a Hearing” (NOOH). An NOOH is the mechanism FDA uses to provide a company an opportunity for a hearing on a proposal to withdraw an indication. Genentech request a hearing. Until the conclusion of these proceedings, Avastin remains FDA-approved for use in combination with paclitaxel for the first-line treatment of metastatic HER2-negative breast cancer. FDA also issued Complete Responses on the AVADO and RIBBON1 trials for the first-line use of Avastin in combination with other chemotherapies in metastatic breast cancer and a Complete Response on RIBBON2 for the second-line use of Avastin plus chemotherapy in metastatic breast cancer.The FDA’s decision does not impact Avastin’s availability for its approved uses for other cancer types. Note, as reported below, European regulators, who reviewed the same data, supported the use of Avastin in breast cancer.
[Recall, Avastin, in combination with chemotherapy (paclitaxel), was approved by FDA in Feb. 2008 under the FDA’s accelerated approval program, based on the results of a clinical trial known as “E2100,” which evaluated the drug in patients who had not received chemotherapy for their metastatic HER2-negative breast cancer. Under the accelerated approval program, a drug may be approved based on clinical data that suggest the drug has a meaningful clinical benefit, with more post-approval information being needed to confirm this. The program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted].
As of Dec. 2010 in the EU, the EMA confirmed that Avastin in combination with paclitaxel has been convincingly shown to enable women with metastatic breast cancer to live longer without their disease getting worse (progression-free survival). The EMA has also stated that “the benefits of this combination outweigh its risks and that this combination remains a valuable treatment option for patients suffering from metastatic breast cancer”. Paclitaxel is the chemotherapy most frequently used in Europe and also most frequently partnered with Avastin for the first-line treatment of metastatic breast cancer. The CHMP, which is part of EMA, recommended the removal of the combination of Avastin with docetaxel from the label based on uncertainty about the benefit of the combination and also recommended against a label extension with capecitabine. he CHMP opinion does not affect the other approved uses of Avastin in the European Union for advanced colorectal, kidney and lung cancer.
On June 30, 2011, the Oncologic Drugs Advisory Committee (ODAC), FDA, voted 6-0 that Avastin in combination with paclitaxel is ineffective for first-line HER2-negative metastatic breast cancer and in another unanimous vote stated Avastin had not been shown to be safe for this indication. The decision was expected, given that the ODAC had voted 12-1 in July 2010 to remove the breast cancer indication for Avastin in combination with paclitaxel.
On June 30, 2011, the European Commission extended Avastin metastatic breast cancer labeling to include combination with Xeloda (capecitabine), in addition to the previous approval for the paclitaxel combination.
In Nov. 2011, FDA revoked approval of Avastin plus paclitaxel for the treatment of women with HER2-negative metastatic breast cancer (MBC), concluding that this had not been shown to be safe and effective. With this, most insurers dropped coverage for this indication. The decision came nearly five months since an FDA Oncology Drug Advisory Committee (ODAC) sided with agency staff who concluded that Avastin does not prolong overall survival in patients with breast cancer or offer a benefit in slowing the progression of the disease that outweighs the drug’s risks. Recall that FDA had conditionally approved Avastin for MBC in 2008 despite an advisory panel’s 5–4 recommendation against this, citing Genentech’s E2100 study. It showed a 5.5-month increase in progression free survival (PFS) from 5.8 to 11.3 months.
In Dec. 2011, the National Institute for Health and Clinical Excellence (NICE), U.K., issued final draft guidance not recommending the use of Avastin for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy. Avastin did not meet the criteria to be considered under NICE’s special arrangements for drugs to help people facing the end of their lives.
As discussed in the "Trials" section, a head-to-head trial comparing Lucentis and Avastin for wet AMD treatment.
In early 2012, some fake/counterfeit Avastin was reported to have been distributed in the U.S. This was one of the first and most major instances of biopharmaceutical counterfeiting in the U.S.
In Dec, 2011, Avastin received EU EMA approval for treating women with newly diagnosed, advanced ovarian cancer, offering new options to sufferers previously limited to surgery and chemotherapy.
In Jan. 2013, FDA approvedl a new indication that will allow patients who received Avastin plus an irinotecan or oxaliplatin containing chemotherapy as an initial treatment (first-line) for mCRC to continue to receive Avastin plus a different irinotecan or oxaliplatin containing chemotherapy after their cancer worsens (second-line treatment). The majority of people diagnosed with metastatic colorectal cancer receive Avastin plus chemotherapy as their initial treatment. These people now have the option to continue with Avastin plus a new chemotherapy after their cancer worsens, which may help them live longer than changing to the new chemotherapy alone.
Tech. transfer: U.S. patents protecting the composition-of-matter of Avastin include 6,582,959, “Antibodies to vascular endothelial cell growth factor," June 24, 2003, assigned to Genentech. This patent has only four brief claims for the hybridoma cell line American Type Culture Collection Accession Number HB10709 (ATCC HB10709) (referred to as A4.6.1); ATCC HB10710 (referred to as B2.6.2); and the two monoclonal antibodies produced by each of the hybridomas.
See the Tech. transfer (rDNA) section of the Monoclonal Antibodies entry (#300) for information about the complex situation concerning antibody humanization patents, licensing, cross-licensing and patent disputes, including disputes over Genentech’s licensing of PDL technology for its recombinant antibody products; and Genentech’s “New Cabilly” (Cabilly II) patent. Genentech holds a strong patent position concerning humanized monoclonal antibodies through its “New Cabilly” U.S. patent, includng claims copied from a revoked Celltech Group patent, with Genentech and Celltech later cross-licensing their patents.
Genentech and Protein Design Labs. (PDL) engaged in long-running disputes over each other’s monoclonal antibody humanization design/construction patents, including Genentech having taken the stance that PDL patents do not cover Avastin. In late 2003, Genentech and PDL extended and modified their prior patent licensing master agreement under which either company may nonexclusively license the other company’s relevant technologies upon payment of a license fee of up to ~$1 million per antibody and unspecified royalties. Genentech exercised its option to license antibody humanization patents from PDL for Avastin only after its approval.
Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking further royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
In Jan. 2006, Genentech and Amgen cross-licensed their respective enabling recombinant monoclonal antibody techologies. Amgen received a nonexclusive license for use of Genentech’s Cabilly/Boss patents (see the Monoclonal Antibodies entry, #300), while neither company has disclosed what Genentech received in return.
In Aug. 2010, Genentech, then fully part of Hoffmann-La Roche, informed PDL BioPharma Inc. (now PDL Biopharma, Inc.) it believed that four of its marketed products, including Avastin, are not covered by patents that had been licensed by Genentech from PDL. Genentech/Roche plans to continue to pay patent royalties (while presumably trying to renegotiate of get out of its prior licensing agreement). PDL will surely appeal any actions by Genentech/Roche, since is receives 30% of its revenue from these licenses.
Trials: The safety and efficacy of Avastin in the initial treatment of patients with metastatic carcinoma of the colon and rectum were studied in two randomized, controlled clinical trials in combination with intravenous 5-fluorouracil-based chemotherapy. Study 1, the primary pivotal trial supporting approval, was a randomized, double-blind, active-controlled trial in 925-patients randomized to receive bolus-IFL (irinotecan 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once weekly for 4 weeks every 6 weeks; also referred to as CPT-11) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Avastin in combination with the bolus-IFL regimen was deemed acceptable. The primary endpoint of this trial was overall survival. The clinical benefit of Avastin, as measured by survival in the two principal arms, was seen in all subgroups tested. Among the 110 patients enrolled in Arm 3, median overall survival was 18.3 months, median progression-free survival was 8.8 months, overall response rate was 39%, and median duration of response was 8.5 months. This is one of the largest improvements in survival ever reported in a randomized Phase III study of patients with metastatic colorectal cancer. The most serious adverse events that occurred with Avastin included gastrointestinal perforations and wound healing complications, which were uncommon.
Study 2 was a randomized, active-controlled trial of Avastin plus 5-FU/LV for first-line treatment of metastatic colorectal cancer. Patients were randomized to receive 5-FU/LV (5-fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks) or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) or 5-FU/LV plus Avastin (10 mg/kg every 2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective response rate and progression-free survival. Progression-free survival was significantly better in patients receiving 5-FU/LV plus Avastin at 5 mg/kg, compared to those not receiving Avastin. However, overall survival and overall response rate were not significantly different. Outcomes for patients receiving 5-FU/LV plus Avastin at 10 mg/kg were not significantly different than for patients who did not receive Avastin.
In Nov. 2003, Genentech and Roche reported a Phase II study of Avastin plus 5-fluorouracil/Leucovorin chemotherapy (i.e., without irinotecan) in 209 previously untreated metastatic colorectal cancer patients not considered optimal candidates for irinotecan. The trial showed a 29% improvement in median survival, the primary endpoint, for the Avastin regimen. However, this did not achieve statistical significance. The study also showed a 67% prolongation in median progression-free survival, which was highly statistically significant, in patients treated with Avastin plus 5-fluorouracil/Leucovorin vs. 5-fluorouracil/Leucovorin alone. Results from this study were not included in the BLA filing. This Phase II trial was intended to provide comparison between Avastin/5-FU/LVand 5-FU, a comparison not included in the privotal Phase III trial.
The efficacy of Avastin monotherapy for colorectal cancer has not been established. However, in an ongoing (at time of approval) randomized study of patients with metastatic colorectal cancer having progressed following a 5-fluorouracil and irinotecan-based regimen, the arm in which patients were treated with single-agent Avastin was closed early due to evidence of an inferior survival, compared with patients treated with the FOLFOX regimen of 5-fluorouracil, leucovorin, and oxaliplatin.
The incidence of antibody development in patients receiving Avastin has not been adequately determined, because available assay sensitivity is inadequate to reliably detect low titers. During trials, enzyme-linked immunosorbant assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin. High titer human anti-bevacizumab antibodies were not detected.
In Jan. 2005, results from a Phase III study (E3200) of Avastin in combination with an oxaliplatin-containing chemotherapy regimen (FOLFOX4) for treatment of a advanced colorectal in patients having failed one chemotherapy regimen showed that the combination significantly increases survival from 10.7 months for those receiving FOLFOX4 alone to 12.5 months. In combination with other trials, this further showed that Avastin can prolong survival of colorectal cancer patients, independent of the type of chemotherapy that is administered.
In Feb. 2005, Provenge, a prostate cancer immunotherapeutic vaccine based on autologous prostate tumor antigen-sensitized antigen-presenting cells (APCs; see #242), in a Phase II trial (P-16) in combination with Avastin increased PSA doubling time (PSADT) in patients with prostate cancer having relapsed after prior surgical and radiation therapy.
In the March 2005 issue of the Journal of Clinical Oncology, results were reported from a Phase III trial showing that Avastin plus a less aggressive course of chemotherapy can significantly delay tumor progression in elderly patients with advanced colorectal cancer too sick or too old to tolerate traditional aggressive chemotherapy, delaying tumor growth by an extra four months compared to chemotherapy alone, a 67% increase in progression-free survival. Avastin will likely become the primary or a major option for such advanced patients.
In March 2005, interim results were reported from an open-label Phase III study (E4599) of Avastin in 878 patients with first-line non-squamous, non-small cell lung cancer (NSCLC), with the study meeting its primary efficacy endpoint of improving overall survival. Patients receiving Avastin plus conventional paclitaxel and carboplatin had a 30% improvement in overall survival (or a hazard ratio of 0.77; a 23% reduction in the risk of death) compared to patients who received chemotherapy alone. Final results were published in the published in the Dec. 14, 2006, issue of the New England Journal of Medicine. Median survival of patients treated with Avastin plus chemotherapy was 12.3 months compared to 10.3 months for patients treated with chemotherapy alone. One-year survival was 51% in the Avastin plus chemotherapy arm versus 44% in the chemotherapy-alone arm. This was the first time median survival has been extended beyond one year in advanced NSCLC.
In April 2005, interim results from a Phase III trial (E2100; ECOG 2100) in 722 chemotherapy-naive women with metastatic breast cancer showed that Avastin (10 mg/kg every 2 weeks) plus paclitaxel improved progression-free survival compared with paclitaxel alone (meeting the primary endpoint). This formed the basis for Genentech’s May 2005 sBLA for this indicastion. Prior therapy with Herceptin was part of the exclusion criteria, so most patients are likely HER2 negative. This endpoint was met on the first interim analysis, indicating a high level of efficacy. Median progression-free survival was 11 months for patients treated with Avastin plus chemotherapy, compared to six months for patients treated with chemotherapy alone. A 49% improvement was reported for the secondary endpoint of overall survival (hazard ratio of 0.67; 33% reduction in the risk of death). In patients with measurable disease, the overall response rate was 28% (93/330) in the Avastin plus chemotherapy arm, a 100% increase over the 14% (45/316) observed in the chemotherapy alone arm. If final results concur, this trial should support approval of Avastin for breast cancer treatment, and/or off-label sales for breast cancer may further increase. In 2002, Avastin failed to show significant efficacy in a Phase III trial for relapsed, metastatic breast cancer.
In Sept. 2005, Genentech halted a Phase II trial of Avastin in female ovarian cancer patients with tumors resistant to platinum compounds after reporting a higher rate of gastrointestinal perforations than in previous studies. Such adverse effects had been reported in various other trials for other Indications:, and the insert/labeling already includes a black box warning about this. Genentech continued its other ongoing trials with Avastin for early-stage ovarian cancer.
In Oct. 2005, Genentech and Accelerate Brain Cancer Cure (Burlingame, CA), a not-for-profit organization, formed a collaboration for a Phase II trial of Avastin for treatment of glioblastoma multiforme (GBM), a form of brain cancer. This will include study of dynamic contrast enhancement images from trial patients. The organizations will share costs.
In Oct. 2005, interim results from a double-blind, placebo-controlled, 104-patieint Phase II trial showed that adding Tarceva (marketed by OSI Pharmaceuticals Inc.) to Avastin resulted in progression-free survival and response rates similar to those achieved with Avastin alone (i.e., addition of Tarceva was not effective). Further trials with the combination were halted by Genentech in the U.S. and Roche internationally.
The Dec. 2005 sBLA seeking approval of Avastin in combination with 5-fluorouracil (5-FU)-based chemotherapy for treatment of relapsed, metastatic colorectal cancer was largely based on results from a randomized, controlled, multicenter Phase III trial (E3200) of 829 patients with advanced or metastatic colorectal cancer whose disease progressed following previous treatment with 5-FU and irinotecan. Patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25% reduction in the risk of death (hazard ratio of 0.75), the primary endpoint, which is equivalent to a 33% improvement in overall survival, compared to patients who received FOLFOX4 alone.
In Feb. 2006, a Roche-sponsored Phase III AVAiL (BO17704) study in over 1,000 NSCLC patients outside the U.S. evaluating two different doses of Avastin in combination with gemcitabine and cisplatin chemotherapy met the primary endpoint of prolonging progression-free survival (PFS) in patients with previously untreated, advanced non-squamous, non-small cell lung cancer (NSCLC), the most common form of the disease. Both doses of Avastin (15 mg/kg or 7.5 mg/kg every three weeks) significantly improved PFS compared to chemotherapy alone. Although the study was not designed to compare the Avastin doses, a similar treatment effect in PFS was observed between the two arms. No new safety concerns were reported.
In Feb. 2006, Genentech temporarily suspended enrollment in AVANT, an international Phase III study of Avastin, XELOX and FOLFOX chemotherapy regimens in early-stage colon cancer. The XELOX regimen consists of capecitabine and oxaliplatin and the FOLFOX regimen consists of oxaliplatin, 5-fluorouracil and leucovorin. A higher rate of adverse events had been observed in the XELOX/Avastin arm, compared to the other two arms of the study (FOLFOX and FOLFOX/Avastin). Also, rapid recruitment in the AVANT trial (>200 patients/month) could prevent an adequate and timely safety assessment.
In June 2006, Genentech reported that a Phase III trial (CALGB 80303) of Avastin in combination with gemcitabine chemotherapy as first-line treatment for 602 advanced pancreatic cancer patients did not meet its primary endpoint of overall survival. The trial was halted at the recommendation of an independent data monitoring board, based on an interim analysis indicating that it is very unlikely that significant differences in overall survival will be shown between treatment arms as the data mature. The study was not stopped due to safety events and no new safety concerns related to Avastin were observed in this trial. Another, ongoing Phase III study (AVITA) is examining Avastin in combination with Tarceva (erlotinib) on top of standard therapy. The AVITA trial is due to complete patient recruitment by the end of 2006,
In mid-2006, Genentech reported 130 ongoing clinical trials with Avastin involving 25 different types of cancer. Genentech has been continuing testing Avastin in Phase III studies for adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers. Some of these indications could add another incremental $1.5 billion-$2.0 billion in Avastin sales. An estimated 220,000 patients could be candidates for Avastin, if it is shown safe, effective and approved for colon, lung, breast, renal and pancreatic cancers. Ovarian cancer is cited as an example of a potential new indication for Avastin. The number of patients with ovarian cancer is relatively small, with no more than 23,000 patients affected and roughly 16,000 deaths annually in the U.S. Avastin is also being evaluated in earlier stage trials in a variety of solid tumor cancers and hematologic malignancies.
The June 2006 approval of Avastin for advanced or metastatic colorectal cancer was based on results of a randomized, controlled, multicenter Phase III trial (E3200) in 829 patients who received previous treatment with irinotecan and 5-FU as initial therapy for metastatic disease or as adjuvant therapy. Patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25% reduction in the risk of death (based on a hazard ratio of 0.75), the primary endpoint, equivalent to a 33% improvement in overall survival, compared to patients who received FOLFOX4 alone. Median survival for patients receiving Avastin plus FOLFOX4 was 13.0 months, compared to 10.8 months for those receiving FOLFOX4 alone.
In July 2006, Roche reported that an international Phase III study (NO16966) enrolling 2,035 previously untreated metastatic colorectal patients met both primary endpoints. Xeloda plus oxaliplatin (XELOX) was as effective in terms of progression-free survival (PFS) as infused 5-FU/leucovorin plus oxaliplatin (FOLFOX). The addition of Avastin to chemotherapy (FOLFOX and XELOX) significantly improved progression-free survival compared to chemotherapy alone by ~20%.
In Dec. 2006, Genentech reported interim analysis from a randomized Phase III study of Avastin in combination with interferon alfa-2a (Roferon-A from Hoffmann-La Roche) in patients with first-line metastatic renal cell carcinoma (mRCC). The trial met the primary analysis endpoint by significantly improving progression-free survival (PFS) compared to interferon alfa-2a therapy alone. A trend was observed toward improvement in overall survival in the Avastin plus interferon arm.
In Dec. 2006, interim analysis of the AVOREN Phase III trial showed that Avastin significantly improves progression-free survival when given as a first-line treatment for metastatic (advanced) renal cell carcinoma (mRCC). Patients (n = 649) randomly received standard therapy consisting of interferon alfa-2a (Roferon-A) plus either placebo or Avastin. This study is expected to form the basis for a supplemental European marketing application planned for 2007. Another study of interferon with or without Avastin in first-line mRCC with a primary endpoint of overall survival was underway, and Roche and Genentech were planning a randomized study of Avastin in combination with another targeted agent in RCC.
In Jan. 2007, Genentech reported results from a trial in 600 advanced pancreatic cancer patients showing that Avastin was not effective. Patients receiving Avastin plus standard chemotherapy lived only about six months -- the same as those who received chemotherapy alone. Earlier studies had suggested that Avastin added to chemotherapy would improve survival in this patients. Patients who took Avastin also experienced increased adverse events, including higher rates of high blood pressure and bleeding in the stomach and intestine, and were more likely to develop a tear in their intestines.
In March 2007, an academic-based trial not affiliated with Genentech was halted. The trial had tested Avastin in combination with radiation and chemotherapy on 29 patients with small-cell lung cancer, an unapproved indication for Avastin (and a much smaller market than non-small-cell lung cancer for which Avastin is approved). Some patients had developed holes in their gastrointestinal tract and windpipe, and one died. This did not affect Genentech’s Avastin development or marketing.
In early 2007, Roche initiated a Phase III first-line trial, AVEREL, evaluating Avastin in combination with docetaxel plus Herceptin (trastuzumab) in HER2-positive breast cancer patients. Additional Phase III breast cancer trials are ongoing to explore Avastin in the first-line treatment in combination with docetaxel and other commonly used chemotherapies including Roche’s own Xeloda (capecitabine).
In June 2007, results from a trial indicated that Avastin has potential for treatment of metastatic renal cell carcinoma. When Avastin was added to an interferon alfa-2a (Roferon-A), tumor growth was delayed by 10.2 months, compared with 5.4 months with interferon alone. This near-doubling of the time before disease progression suggests Avastin could significantly improve care in kidney cancer, a tough type of tumor that until recently had few attractive options.
In June 2007, a second Phase III trial (AVAiL) sponsored by Roche in over 1,000 patients with advanced, non-squamous, non-small cell lung cancer (NSCLC) showed Avastin in combination with gemcitabine and cisplatin chemotherapy has potential for treatment of advanced non-small cell lung cancer. Patients were randomized to receive cisplatin (80 mg/m2 on Day 1) and gemcitabine (1,250 mg/m2 on Day 1 and Day 8) chemotherapy every three weeks for up to six cycles plus either Avastin 15 mg/kg or Avastin 7.5 mg/kg every three weeks (until disease progression), or placebo. Physicians and patients in the study were blinded to treatment with Avastin but not dose. Avastin when used at two different doses in combination with gemcitabine and cisplatin chemotherapy significantly increased progression-free survival (PFS; the time patients lived without their disease advancing). Patients receiving 15 mg/kg of Avastin plus gemcitabine and cisplatin chemotherapy experienced a 22% improvement in PFS (based on a hazard ratio of 0.82) (p-value = 0.0301) compared to patients receiving chemotherapy alone, and patients receiving 7.5 mg/kg of Avastin plus gemcitabine and cisplatin chemotherapy experienced a 33% improvement in PFS (based on a hazard ratio of 0.75) (p-value = 0.0026) compared to patients receiving chemotherapy alone. Broadly overlapping confidence intervals (the range of plausible values that would likely contain the real effect) in the Avastin treatment arms compared to chemotherapy alone suggest the two Avastin arms had a similar treatment effect on PFS compared with the control arm. The 22% and 33% improvements in PFS, respectively, in the 15 mg/kg and 7.5 mg/kg Avastin treatment arms can also be referred to as 18% and 25% reductions in risk of cancer progression or death, as calculated by the hazard ratios. Median PFS was 6.5 months in the 15 mg/kg Avastin plus chemotherapy arm, 6.7 months in the 7.5 mg/kg Avastin plus chemotherapy arm and 6.1 months in the gemcitabine/cisplatin chemotherapy alone arm. No new safety signals for Avastin were observed in the study, and there were no clinically meaningful differences in safety between the two dosage arms. Some Genentech investors and analysts were concerned that the lower dose appeared more effective.
In Nov. 2007, Roche reported that a late-stage study in 607 patients showed that the addition of Avastin to Tarceva and chemotherapy failed to prolong the lives of patients with advanced pancreatic cancer, but did have some benefits, such as a prolonging the time patients lived without disease progression, as well as safety benefits.
Approvals: for first-line metastatic breast cancer, e.g., in the EU and the Feb. 2008 FDA approval, have largely been based on study E2100 in 722 women with previously untreated, locally recurrent or metastatic breast cancer randomized to receive treatment with paclitaxel with or without Avastin. Patients were randomized to receive weekly treatment with paclitaxel every three out of four weeks, with or without Avastin. Based on an independent, blinded review of patient scans, patients treated with Avastin plus paclitaxel experienced median progression-free survival (PFS) of 11.3 months versus 5.8 months in the paclitaxel alone arm. A secondary endpoint of overall survival was 1.7 months longer in the Avastin-containing arm (with a hazard ratio of 0.87), tending to support the primary endpoint of PFS. This improvement did not reach statistical significance (p=0.14).
In Feb. 2008, the National Cancer Institute initiated its head-to-head clinical trial in 1,200 patients to compare the relative safety and effectiveness of Lucentis (ranibizumab) and Avastin to treat advanced wet age-related macular degeneration (AMD). As discussed elsewhere in this and the Lucentis (another angiogenesis inhibitor from Genentech) entry, Avastin is often used off-label for treatment of wet AMD, with Avastin use costing much less for this indication.
In April 2008, Dr. Werk, Harvard Medical School reported results from a small trial (24 patients) showing adding Avastin to standard treatment stopped metastasis in 22 of 24 patients with rectal tumors, with the results indicating Avastin facilitated repair of blood vessels, not just halting of angiogenesis, with tumor tissue more susceptible to radiation and chemotherapy.
In April 2008, Roche reported updated results from AVAiL. The update confirmed the clinically and statistically significant improvement in the primary endpoint of progression free survival (PFS) for the two different doses of Avastin studied in the trial (15 mg/kg and 7.5 mg/kg) compared to chemotherapy alone. The study did not demonstrate a statistically significant prolongation of overall survival, a secondary endpoint, for either dose in combination with gemcitabine and cisplatin chemotherapy compared to chemotherapy alone. Median survival of patients in all arms of the study exceeded one year, longer than previously reported survival times in this indication. No new safety signals for Avastin were observed in the study, and there were no clinically meaningful differences in safety between the two doses of Avastin.
In June 2008, Roche reported results from the randomized, controlled Phase III AVF2107 study involving more than 800 previously untreated metastatic colorectal cancer patients. Avastin was combined with a standard chemotherapy – irinotecan, fluorouracil and leucovorin (IFL). Avastin significantly improved survival in patients with metastatic colorectal cancer, irrespective of K-Ras gene mutations which occur in half of colorectal cancer patients. Avastin showed an 82% increase in the time patients with normal K-Rase gene live without their disease getting worse, compared to chemotherapy alone; and a 57% increase in overall survival versus chemotherapy alone in the same patient group, while a 60% increase in the response rate was observed, compared to 37% in patients receiving chemotherapy alone. In the patient group with K-Ras gene mutations, a 69% increase in the time patients live without disease advancement was observed, compared with chemotherapy alone. Genentecn notes, "The statistically significant improvement in overall survival observed in E4599, as well as the safety and improvement in progression-free survival in AVAiL and E4599, give us confidence in Avastin's safety and efficacy for patients with advanced, non-squamous, non-small cell lung cancer. These studies reinforce our belief that Avastin is an important treatment option for patients with this most common form of lung cancer."
In April 2009, it was reported that a Phase III study (NSABP C-08) of Avastin plus chemotherapy following surgery in patients with early-stage (adjuvant) colon cancer (NSABP C-08) did not meet its primary endpoint of reducing the risk of cancer returning (improvement in disease-free survival). Resultswere from a planned final analysis of the study. This was the first trial of Avastin in early-stage cancer and the results do not affect approved indications in advanced (metastatic) disease.
In July 2009, the European Union approved broader indications for Avastin allowing combination with docetaxel for the first-line treatment of advanced (metastatic) breast cancer. Avastin can be combined with docetaxel, giving both patients and physicians more Avastin based therapy options. The standard dose of Avastin for the treatment of metastatic breast cancer remained at 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks.
In April 2012, results were published in the journal Ophthalmology from the head-to-head trial CATT(Comparison of Age-related macular degeneration Treatment Trials) sponsored by NEI/NIH at years comparing intravitreal Avastin and Lucentis for wet AMD treatment, an indication for which repackaged Avastin is often used off-label. The trial concluded that the two products were comparable in efficacy. However, there was overall significantly higher risk of serious systemic adverse events with intravitrealunlicensed bevacizumab versus Lucentis (p=0.004)
Medical: Avastin is commonly used in combination with intravenous 5-fluorouracil (5-FU) for first-line treatment of metastatic color or rectal cancer. The recommended dose of AVASTIN for first-line use is 5 mg/kg given once every 14 days as an intravenous infusion. Based on this, a 100 kg patient would receive 1,000 mg monthly. Treatment is continued until disease progression is detected. The average duration of Avastin treatment is 10-11 months (in late 2004). As mentioned above, Avastin use entails a number of potentially serious adverse effects.
For second-line treatment of colorectal cancer, Avastin has been approved at a 10mg/kg dose, twice the dosage for first-line use.
Avastin is now considered the standard of care for first-line treatment of colon/rectal cancer. By early 2006, considerable anecdotal reports indicate that physicians’ experience with Avastin, in terms of safety and efficacy, is as good as or better than reported in clinical trials, with a recent study reporting an average of 11.3 months of progression-free survival, better than the 10.6 months reported in the pivotal trial, with less frequent serious adverse events. Avastin is generally considered a breakthrough in that it significantly increases colon/rectal cancer survival without what are considered to be unacceptable safety problems (other than a low rate of bowel perforation). However, the absolute benefit to patients may be considered modest (months increase in survival), and Avastin is far from a cure for these cancers.
In Europe, physicians commonly use half the U.S.-approved dosage for second-line treatment, i.e., 5 vs. 10 mg, because Avastin is considered efficacious when given in these smaller amounts. Genentech used a 10mg/kg dose of in the ECOG E3200 trial, which supported FDA approval for the second-line metastatic colorectal cancer, with this the maximum tolerated dose found in a dose escalation study. During its clinical development, these higher doses were given to achieve maximum efficacy to increase likelihood of approval. Once the FDA approved the high doses of the drug, like most companies in this situation, Genentech has not conducted studies to examine the possibility that lower doses are equivalent to the approved doses. Critics have noted, "There is no data available on the optimal dosing of Avastin in colorectal cancer." With a definitive trial of optimal dosage likely to cost on the order of $10 million, there are insufficient incentives for Genentech to sponsor such as study. If use of half-doses becomes the norm, sales of Avastin would be reduced.
In July 2005, Dr. P. Rosenfeld, Bascom Palmer Eye Institute, University of Miami, reported dramatic positive results using very low, inexpensive doses of Avastin for treatment of wet age-related macular degeneration (AMD) in a single patient. [See the entry below for Lucentis, also from Genentech, approved for this indication]. By 2006, many ophthamologists were using Avastin for treatment of macular degeneration; and Dr. Rosenfeld and others were seeking to organize a trial with funding from Medicare (which stands to save considerable money) of low-dose Avastin for AMD. Dramatic rapid improvements have been anecdotally reported with low-dose Avastin for wet AMD. This has upset Genentech, which developed Lucentis, another VEGF inhibitor (see futher discussion and the Lucentis entry below), for this indication.
In the Feb. 2007 issue of Clinical Cancer Research, results were reported from a trial in 32 patients indicating that Avastin combined with standard chemotherapy (irinotecan) can temporarily stop growth of gliomas (brain tumors) in patients with gliomas recurring after initial treatment (a group with a very poor prognosis). The study showed 63% of patients had their tumors shrink by >50% and the tumors did not start to grow for >6 months in 38%.
In Feb. 2007, results were reported from a Roche-sponsored Phase III study (AVAiL; BO17704) in over 1,000 patients with previously untreated, advanced non-squamous, non-small cell lung cancer (NSCLC) outside the U.S. showing that two different doses of Avastin in combination with gemcitabine and cisplatin chemotherapy met the primary endpoint of prolonging progression-free survival (PFS) in patients with previously untreated, advanced non-squamous, non-small cell lung cancer (NSCLC), the most common form of the disease. Both doses of Avastin (15 mg/kg or 7.5 mg/kg every three weeks) significantly improved PFS compared to chemotherapy alone, as assessed by trial investigators. Although this study of first-line use was not designed to compare the Avastin doses, a similar treatment effect in PFS was observed between the two arms. No new safety signals related to Avastin were observed in the study. While demonstration of comparable efficacy with a lower dose is good for patients and payers, this was not good news for Genentech and Roche, since use and sales will likely decrease. These results may drive oncologists to use the half dose, particularly if this has a better side-effect profile. Genentech stated that the trial was not powered to show a statistical difference between both the treatment arms (i.e., the high and low-dose Avastin arms). However, payors may use this data to push doctors to use the half dose in lung cancer.
In Feb. 2010, results were reported from AVAGAST (AVF4200g). This Phase III study (AVAGAST) did not meet its primary endpoint of showing Avastin plus Xeloda® (capecitabine) or 5-FU and cisplatin chemotherapy extended the lives of people with inoperable or advanced stomach (gastric) cancer, compared to chemotherapy alone. Adverse events in the trial were consistent with those previously reported for Avastin . These findings did not significantly impact Avastin's approved uses or its development program.
The Aug. 2009 approval for Avastin plus interferon-alfa for metastatic renal cell carcinoma was based on results from a global, randomized, double-blind, placebo-controlled Phase III study (AVOREN) of 649 patients with previously untreated metastatic renal cell carcinoma. The study showed patients who received Avastin plus interferon-alfa had a 67% increase in the time patients lived without their disease worsening (progression-free survival or PFS), compared to those who received interferon-alfa alone (hazard ratio=0.60, 95 percent CI=0.49, 0.72). In AVOREN, median PFS was 10.2 months for patients who received Avastin plus interferon-alfa compared to 5.4 months for patients who received interferon-alfa alone, corresponding to an 89% improvement in median PFS. The study was originally designed to measure an improvement in overall survival (OS). However, in consultation with the FDA and European authorities, the primary analysis endpoint was revised to assess improvement in PFS. Secondary analysis endpoints included objective response rate and OS.
In Aug. 2009, results were reported from the first Phase III Study (RIBBON 2) showing progression-free survival benefit of Avastin plus chemotherapy as a second-line treatment for advanced breast cancer. Avastin in combination with chemotherapy increased the time women with metastatic HER2-negative breast cancer whose initial chemotherapy had stopped working lived without the disease worsening (progression-free survival or PFS), compared to chemotherapy alone. The physicians treating the women in the study chose the type of chemotherapy used in combination with Avastin and the chemotherapies were assessed together in the primary endpoint analysis. Adverse events were consistent with those previously reported for Avastin, and no new Avastin safety signals were observed in the study.
Disease: Colorectal cancer was the third most commonly reported cancer worldwide in 2000, with 945,000 new cases. It is the most common cancer in developed countries. It is estimated that over 50% of people diagnosed with colorectal cancer die from the disease According to the American Cancer Society (ACS), colorectal cancer is the second leading cause of cancer death in the U.S. and the third most frequently diagnosed cancer. ACS estimated that 147,500 new cases of colorectal cancer would be diagnosed in the U.S. in 2003.
About 10,000 patients in the U.S. currently suffer from glioblastoma, and about 2,900 are eligible for therapy with Avastin.
Market: The Avastin launch was the fastest (response) launch in Genentech’s history and one of the fastest launches in biopharmaceutical and drug history. Genentech shipped product to wholesalers within hours of approval. Avastin is now Genentech’s second-biggest-selling product behind Rituxan.
Total worldwide revenue was $6.3 billion in 2012; $6.6 billion in 2011; ~$6.5 billion in 2010, with about $1.2 billion of this attributed to breast cancer treatment (then an at-risk indication); $5.970 billion in 20009; $4.484 billion in 2008); $4.014 billion in 2007; $2.188 billion in 2006; $1.470 billion in 2005; and $554.5 million in 2004.
Roche and Genentech reported in mid-2006 that they plan to establish Avastin as the “backbone” standard of care in oncology, with emphasis on combination use. Claiming the product has “unprecedented clinical benefit,” Roche stated, “We want to establish Avastin as the fifth treatment modality…we have surgery, radiotherapy, chemotherapy, we have hormone therapy and targeted agents, and certainly anti-angiogenesis is the fifth modality,” To sustain momentum, the firms devised a comprehensive lifecycle management strategy for Avastin, with first-line and other approvals expected for multiple types of cancer.
Genentech caps yearly spending on Avastin at $57,000 for patients with incomes below $100,000. Without the cap, the wholesale price of Avastin for a typical breast cancer patient is $88,000.
In Oct. 2009, the Center for Medicare and Medicaid Services (CMS) reversed a ruling proposed earlier that month that would have resulted in physicians administering Avastin geting only about $7 per injection, not enough to cover costs. Many ophthalmologists said that measure encouraged doctors to use more-expensive Lucentis, which doesn't have such reimbursement restrictions, and estimated it could cost the federal government several hundred million dollars annually. At the time, about 50% of ophthamologists were using Avastin rather than Lucentis.
With likely approvals for other cancers in coming years, analysts project Avastin sales will eventually reach up to $10 billion/year. Roche and Genentech expect a major boost from use in combination regimens, with other therapies added to Avastin as base treatment, with other companies developing cancer therapeutics in combination with Avastin. However, it remains to be seen how receptive payers will be to combination use.
In Feb. 2007, with trials results for non-small cell lung cancer showing a half-dose (7.5 mg/kg) of Avastin as effective as a full dose, supporting use of half the amount for this indication, analysts lowered their estimates for Avastin sales in lung cancer, many assuming that ~50% of physicians will be using the low dose by 2009. While likely hurting sales in the near-term, less expensive treatment may increase the use of Avastin in combination therapies.
In Aug. 2008, the U.K. National Institute for Health and Clinical Excellence (NICE), in a preliminary ruling, stated that Avastin and 3 other advanced kidney cancer (renal cell carcinoma) therapeutics were "not effective enough to warrant their high cost and shouldn't be prescribed to new patients in Britain." Thus, the U.K. National Health Service (NHS) will not cover Avastin for renal cell carcinoma treatment. Effectively, the only option NICE would allow is interferon alfa products. NICE generally does not support use of therapeutics that cost over $30,000 per quality adjusted life year (QALY). Roche had offered to supply Avastin for 20,800 pounds ($32,300) for each patient for a year, and for free after that, and later "proposed also making a payment to the UK National Health Service for each patient beginning treatment with Avastin." NICE stated that the "proposal is 'complex' and still doesn't justify the costs of the drug."
In Sept. 2008, with clinical trials' results reported at ASCO and other conferences, and with competing Erbitus for colorectal cancer not shaping up as a significant competitor, many analysts raised their sales projections. For example, some projected Avastin sales would reach $9.8 billion in 2012.
In March 2008, Friedman, Billings and Ramsey (FBR) analysts projected worldwide (Genentech/U.S. and Roche/intl.) sales to be $2.870 billion in 2008, $3.155 billion in 2009, $3.409 billion in 2010, $4.157 billion in 2011, and $4.821 billion in 2012. Total Genentech (U.S.) sales are projected to be $2.620 billion in 2008, $2.995 billion in 2009; $3,199 billion in 2010; $3,945 billion in 2011; and $4.605 billion in 2012. Total Roche (ex-U.S.) sales are projected to be $250 million in 2008, $200 million in 2009, $210 million in 2010, $212 millon in 2011, and $216 million in 2012. As can be seen, Genentech/U.S. sales represent about 91% of sales (in 2008). For 2007, FBR estimated Avastin’s sales for lung cancer accounted for about 27% of total sales/
In Nov. 2009, Advo Life Sciences reported consensus projections of Avastin sales of $8.9 billion in 2013.
In early 2012, the typical U.S. cost for a box of Avastin was reported to be about $2,400.
In Dec. 2011, Roche began offering hospitals and insurers in Germany a money-back guarantee for Avastin, offering to refund the cost (which can be $4,100 to $8,200 a month, depending upon the cancer being treated), if tumors continue to worsen within three to seven months. This was prompted by a law passed last year in Germany that allows insurers to bargain over prices for new therapeutics. Roche also agreed to reimburse the cost, if patients take more than 10 grams of Avastin in a year, which is equivalent to about seven months of therapy for breast, kidney, and ovarian cancer. Some critics asserted that this encouraged bad medical practices, that only truly effective therapeutics should be used.
At a cost of nearly $5,500 per treatment cycle, Avastin is the most expensive non-small-cell lung cancer therapy on the market-nearly twice the cost of the next most expensive drug, Eli Lilly's Alimta. Avastin is widely reported (in 2007) to cost about $40,000 per 5 mg/kg treatment course for colon and rectal cancer, typically $4,400 per month (although some may pay more) for approved indications other than lung cancer, which requires twice the dosage (and costs). For lung cancer, cost estimates are much the same annually, about $43,000 per year (assuming a monthly cost of $8,800 and treating for around five months). Those receiving Avastin for second-line therapy, e.g., for colorectal cancer, receive a dose of 10 mg/kg, with this costing twice as much. However, with trial results in 2007 showing comparable efficacy for lung cancer using half this dose, some payers may soonr or later only reimburse for Avastin at this lower dosage level.
The 2007 Average Wholesale Price (AWP) $687.50/4 mL vial; and $2,750.00/16 mL, 400 mg vial (unchanged since 2004). In April 2004, Genentech reported the Wholesale Acquisition Cost (WAC) was $550 for the 100 mg vial and $2,200 for the 400 mg vial.
With non-small cell lung (NSCL) patients typically receiving 1,000 mg or more monthly, costing $6,875 or more per month (based on AWP for 400 mg vial), until their disease progresses, annual costs for Avastin can easily reach $82,500. However, newsletters and the popular press have often reported that on average Avastin treatment (U.S.) costs $4,400/month ($52,800/year; apparently, with few actually paying the AWP and/or with most using lower doses for other types of cancer). Patients are expected to remain on Avastin until they experience disease progression, which may take a year or more.
In Japan in May 2007, the government set the price for Avastin (marketed by Chugai) at Yen 50,291 per 100 mg dose, a price Chugai has accepted. Peak sales in Japan of about Yen 83 billion (~$673 million) in 2011 were projected by one analyst (although a lot will depend on the indications Avastin is approved for).
Starting in early 2006, Genentech’s pricing strategy for Avastin has been causing considerable controversy. Currently costing about $40-50,000/year for its approved colon or rectum cancer indications with double the dosage used for treatment of lung and breast cancer, the cost of treatment would effectively double to about $100,000/year for these Indications:. Genentech executives signalled that the company does not expect to moderate its prices for Avastin after approval for lung and/or breast cancer, but annual prices were capped in Oct. 2006 (see next paragraph). This pricing was based on the company’s presumption that, even at its current cost, Avastin provides considerable benefits and will save money spent on treatment of these patients, i.e., that the total costs for treatment (including disease advancement) without Avastin are greater than the projected costs of treatment with Avastin. Thus, insurers should welcome Avastin. Regarding those who cannot afford it, the Genentech CEO noted that these patients would receive it free through patient assistance programs, and he also noted that the average insurance co-pay in the U.S. is $129/month, so this will not be a significant burden for insured patients (although some insurance policies may only partially cover the cost of Avastin, leaving patients with large co-pays).
For patients receiving Avastin off-label Indications:, providers have been requesting patients sign waivers making them responsible for costs if insurers reject claims. Many are refusing to sign, causing ethical, legal and financial problems for hospitals and oncologists.
In Oct. 2006, with the supplemental FDA approval of Avastin for its non-small cell lung (NSCL) cancer, Genentech announced it would cap the annual cost of Avastin to some patients based on income limitations (about $75,000 a year). Note, this indication requires twice the dosage than for previously-approved Indications:, for which Avastin treatment is commonly reported to be $40-$50,000/year, while results from E4599 (see Trials secton above) show only an average 1.8 month improvement in survival. The typical monthly cost of Avastin at its higher dose for NSCL is approximately $8,800 and, based on median progression-free survival as measured in the E4599 trial, the average cost per course of therapy (until death) in NSCLC is ~$56,000. Overall cost was limited to $55,000/year per eligible patient using Avastin for any FDA-approved indication. The $55,000 ceiling is for total spending by all payers — Medicare, private insurers and the patient — and not just for a patient’s out-of-pocket costs. With Avastin generally used in advanced colorectal patients, not many using Avastin for this and other indications using lower/base-level doses are expected to reach the cap, while patients with advanced lung cancer (and breast cancer, upon approval) can easily reach this cap. However, ovearall sales and profits will be affected, if Avastin is approved for early-stage breast and other cancer indications requiring higher dosages, with these patients presumably living much longer. Genentech began the program in Jan. 2007. Also, the company announced that it would double its contribution to independent charities that provide co-pay assistance to a total of $50 million.
In Aug. 2006, the National Institute for Health and Clinical Excellence (NICE), U.K., which rules on the cost-benefits of pharmaceuticals to be paid for by the U.S. National Health Service (NHS), decided the high cost of Avastin was not “compatible with the best use of NHS (National Health Service) resources.” This angered patient groups and others, since Avastin (and Erbitux) is widely available in the U.S. and much of Europe.
In April 2009, NICE published a Final Appraisal Determination rejecting the use of Avastin, Nexavar and Torisel for first-line use for renal cell carcinoma by the NHS in England and Wales. NICE considered the products too expensive.
In Nov. 2009, the National Institute for Health and Clinical Excellence (NICE), U.K., which rules on the cost-benefits of pharmaceuticals to be paid for by the U.S. National Health Service (NHS), ruled that for the first-line treatment of metastatic colorectal cancer Avastin in combination with oxaliplatin-containing regimens "gave a modest benefit in terms of effectiveness compared with regimens without bevacizumab." NICE found this benefit was not enough to justify the expense to the National Health Service. NICE noted that the acquisition cost of Avastin (excluding VAT and assuming wastage) for a patient weighing 70kg is £924.40 at a dosage of 5mg/kg every two weeks and £1409.72 at a dosage of 7.5 mg/kg every three weeks, and that even taking a patient access scheme proposed by Roche into account the cost of the drug equates to £36,400 per QALY gained, overshooting NICE's usual £30,000 threshold.
In Dec. 2010, NICE issued final guidance, rejecting Avastin in combination with chemotherapy (oxaliplatin and either fluorouracil or capecitabine) for treating metastatic colorectal cancer.
Largely due to the cost of Avastin and other biopharmaceuticals, colon cancer treatment is often cited as an example of the rising costs for cancer treatment. For example, 10 years ago the therapeutics used to treat colon cancer cost about $500, while the current cost is about $250,000. Over the same 10-year period, the average life expectancy for colon cancer patients increased from 11 months to a little more than two years.
In Jan. 2005, it was reported that Hoffmann-La Roche had set a European price for Avastin 20% below that charged in the U.S., to be more consistent in pricing and better compete with other therapeutics in Europe. Upon its launch in Germany shortly after Jan. 2005 EU approval, Avastin was reported to cost ~3,000 euros ($3,931) per month or $47,120/year.
Avastin is covered by most insurers and Medicare for its approved indications:. Various analysts have reported that Avastin sales for colon cancer have largely achieved their likely sales limit (market saturation), while off-label use has been less than expected. In early 2006, it was reported that many insurance companies were refusing to pay for Avastin use for breast and lung cancer, then both unapproved/off-label Indications:, primarily due to cost, and that some oncologists and patient activists were fighting this. With Avastin and cancer therapeutics administered intravenously and generally purchased by oncologists/clinics for resale and administration to patients, their profit margins are squeezed by the high prices paid for therapeutics and the limits on reimbursement by insurance companies.
Avastin could achieve a much larger market, up to $7 billion/year according to some analysts, if approved (or extensively used off-label) for other Indications:, including breast cancers.
In Oct. 2007, Genentech announced it would no longer allow sales of Avastin directly from authorized wholesale distributors to pharmacies custom compounding the product for ophthalmic/AMD Indications:. This elicited protests about restricting access. In Dec. 2008, Genentech announced a change and that "physicians can prescribe Avastin and purchase it directly from authorized wholesale distributors, and wholesalers can ship to the destination of the physician's choice, including to hospital pharmacies, compounding pharmacies or directly to the physician's office." This essentially removed patients from filling custom compounded Avastin prescriptions, while not interfering with physicians and pharmacy access, while halting sales by Genentech or wholesalers to compounding pharmacies.
In Feb. 2010, after seeing a sales decline trend in late 2009, Roche "beefed up [Avastin] marketing by assigning the sales team responsible for the Herceptin [trastuzumab] breast cancer drug to also promote Avastin, while the group that sells the Xeloda [capecitabine] therapy will promote it for use against colorectal cancer."
In July 2010, the National Institute for Health and Clinical Excellence (NICE) recommended against use of Avastin in combination with a taxane, e.g., paclitaxel, for patients with metastatic breast cancer. NICE found that bevacizumab does not significantly improve or extend the lives of breast cancer patients whose tumours have spread elsewhere in the body. So patients in the U.K. receiving care from the National Health Service have no access to Avastin for this indication.
In Sept. 2011, the U.K. National Institute for Health and Clinical Excellence (NICE) issued new draft guidance not recommending the use of Avastin for the treatment of metastatic colorectal cancer that has progressed after first-line therapy.
In late 2011, with the approval of Eylea, Lucentis had about 40% market share for wet AMD treatment, with off-label Avastin having about 60%.
In Jan. 2012, the National Institute for Health and Clinical Excellence (NICE), U.K., issued final guidance not recommending the use of Avastin for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy.
In April 2012, the National Institute for Health and Clinical Excellence (NICE), U.K., refused use of Avastin for patients with advanced breast cancer because of uncertainties over survival and quality of life benefits. The published draft guidance bars women with metastatic breast cancer access to funding for first-line treatment with Avastin in combination with the chemotherapy Xeloda (capecitabine). Despite clinical evidence showing that the drug is able to increase progression-free survival by just under three months compared with capecitabine alone, its effect on overall survival was considered much less clear, nor is there any data on its impact on quality of life, the Institute said. With an average monthly price tag of £3,689, Avastin has an incremental cost that is estimated to be above £82,000 per QALY. NICE's appraisal committee concluded that they could not recommend the treatment as an effective use of NHS resources.
In July 2012, the National Institute for Health and Clinical Excellence (NICE), U.K., finalized its refusal of Avastin, noting that while using Avastin with the chemotherapy treatment Xeloda delayed the progression of breast cancer than chemotherapy alone, there was insufficient evidence that patients ultimately lived longer.
In July 2012, NICE published its draft final guidance, turning down the NHS use of Avastin in combination with capecitabine (Xeloda) for women with advanced breast cancer for whom treatment with other chemotherapy options is not appropriate. According to NICE's independent appraisal committee, while the evidence does suggest that the Avastin/capecitabine combo may delay disease progression for longer than capecitabine on its own, the impact on overall survival was not clear. With regard to its actual cost-effectiveness, there seems to be some dispute over which patients the treatment is most beneficial for. Roche responded, noting that the move is "all the more disappointing as it means that women in England with advanced breast cancer who have limited treatment options available to them will instead have to rely on their clinicians’ successful application to the Cancer Drugs Fund in order to receive treatment with Avastin. However, there is no similar access to Avastin for patients in Wales, Scotland and Northern Ireland as yet".
In Aug. 2012, as NICE was considering Avastin at a 15 mg/kg dose approved by the EU for ovarian cancer, it was reported that Avastin costs in the U.K. are £30,800 ($48,300) per year at the 15 mg/kg dose.
In Aug. 2012, NICE rendered its final decision, formalizing it rejection, regarding Avastin in combination with capecitabine (Xeloda) for women with advanced breast cancer for whom treatment with other chemotherapy options is not appropriate. Other treatments options that are NICE-approved for metastatic disease including Roche's Herceptin and Xeloda.
In Dec. 2012, National Institute for Health and Clinical Excellence (NICE) published draft guidance for he use of Avastin for treatment for women with advanced ovarian cancer. The draft guidance dies not recommend the use of Avastin with paclitaxel and carboplatin for people with advanced disease, as a cost-effective treatment for the NHS. In early 2013, Avastin remained not NICE-approved for any of its five European indications for NHS funding.
In April 2013, NICE again concluded that Avastin - when used with the chemotherapy drugs, Lilly’s Gemzar (gemcitabine) and carboplatin - does not represent good value for money for the NHS. Sir A. Dillon, NICE’s chief executive, explained: “Although the independent appraisal committee acknowledged that bevacizumab may help to delay a person’s cancer from spreading for a few months, it noted that clinical trial data was unavailable for around one in three trial participants, possibly due to discontinuation of treatment, side-effects or because they had been lost to follow-up, making it difficult to know what effect this had on progression-free survival rates. The committee also couldn’t be sure the drug would help people live longer. The current evidence of benefit for patients does not support the cost of the treatment, which the manufacturer estimates to be just over £25,000 for one course for an average patient.” Avastin remains the most commonly funded drug via England’s Cancer Drugs Fund, which injects an extra £200 million a year into the NHS to pay for new oncology treatments that have not been recommended by the watchdog, or are under assessment. But this is set to April 2014.
Competition: Avastin has been successfully competing and gaining market share from Erbitux. See the Erbitux entry for further discussion.
In March 2005, Novartis reported its colorectal cancer drug, PTK787, had not meet its primary endpoint of progression-free survival in first-line colorectal cancer. This removed the only other potential near-term competition to Avastin for first-line colorectal cancer treatment.
Genentech is in the situation of one of its products, Avastin, used off-label cannibalizing and potentially destroying the market for another of its products, Lucentis, another VEGF monoclonal antibody (see the entry below). Unlike bevacizumab, which is a full-sized monoclonal antibody, Lucentis uses a VEGF monoclonal antibody fragment, which is believed to be safer and more effective in the eye for its approved acute macular degeneration (AMD) indication. Lucentis was approved in late June 2006. Avastin supporters report that it appears to be as effective as Lucentis for AMD, while costing about 1% as much.
Avastin is commonly reported to cost $4,400/month for colon cancer and twice as much for its lung cancer indications:, largely because patients require large amounts. However, very much less Avastin dosage is used to treat macular degeneration. One 100 mg vial of Avastin can be split into 40± doses for treatment of macular degeneration. Because of markups by the compounding pharmacy, which must package Avastin into vials or syringes, the cost of an injection ends up ranging only $35-$75. Avastin injections for macular degeneration are given every 2-4 months. At this low cost and with Avastin anecdotally reported safe and effective for wet AMD, it is easy to understand why Avastin is a serious competitor with Lucentis.
The American Academy of Ophthalmology has called for clinical trials of Avastin for macular degeneration, but Genentech has stated that it has no plans for this. Several 1,000 patients with AMD have been treated with Avastin. Besides Lucentis, Macugen (see related entry) from Pfizer Inc. and Eyetech Pharmaceuticals Inc. is also used for treatment of macular degeneration, with this costing about $1,000 injection.
In Feb. 2006, the National Eye Institute, National Institutes of Health (NIH), initiated a large clinical trial to compare AMD treatment with Avastin vs. Lucentis (see the Lucentis entry).
Genentech claims it started work on Lucentis in the late 1990s after research indicated that Avastin would not work in the eye. Two animal studies indicated that a large antibody, e.g., Avastin, could not penetrate the retina to reach the all of the affected blood vessels behind the eye. Lucentis also has a much shorter in vivo half-life than Avastin, important to avoid systemic adverse effects. Intravenous Avastin can cause high blood pressure and potentially fatal holes in the bowel, and Genentech has already had to cancel a trial due to adverse effects. However, critics note that no such systemic effects have been reported with the low doses of Avastin being used for macular degeneration. Critics also claim this research was faulty, because Genentech did not experiment with Avastin itself, rather it tested an earlier version of Avastin, not the currently-marketed product. Genentech has defended itself, stating that Avastin was not available when the tests were performed.
Genentech notes that Lucentis was designed for use in the eye, is 10 times more potent than Avastin, and does not contain a preservative. Genentech asserts that repackaging of Avastin increases the risk of contamination, while critics report that they know of no infections related to Avastin.
Companies involvement:
Full monograph
275 VEGF Mab, rDNA
• Metastatic colorectal cancer, with intravenous 5-fluorouracil–based
chemotherapy for first- or second-line treatment.
• Non-squamous non-small cell lung cancer, with carboplatin and paclitaxel
for first line treatment of unresectable, locally advanced, recurrent or
metastatic disease.
• Glioblastoma, as a single agent for adult patients with progressive disease
following prior therapy.
-Effectiveness based on improvement in objective response rate. No data
available demonstrating improvement in disease-related symptoms or
survival with Avastin.
• Metastatic renal cell carcinoma with interferon alfa
Nomenclature:
VEGF Mab, rDNA [BIO]
Avastin [TR]
bevacizumab [FDA USAN INN]
immunoglobulin G1, anti-(human vascular endothelial growth factor) (human-mouse monoclonal rhuMAb-VEGF .gamma.1-chain), disulfide with human-mouse monoclonal rhuMAb-VEGF light chain, dimer [CAS]
216974-75-3 [CAS RN]
anti-VEGF monoclonal antibody [SY]
rhuMAb-VEGF [SY]
vascular endothelial growth factor monoclonal antibody, recombinant [SY]
NDC 50242-060-01 and NDC 50242-060-02 [NDC]
molecular weight (kDa) = 149
FDA Class: Biologic BLA
Year of approval (FDA) = 2004
Date of 1st FDA approval = 20040226
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2019 (based on 7,169,901, reported by Genentech) |
U.S. Patent Expiration Year: | 2019 |
U.S. Biosimilars Data Exclusivity Expiration: | 2016 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2011 |
U.S. Biosimilars Launchability Year: | 2019 |
U.S. Biobetters Launchability Year: | 2019 (based on EP 0971959 and EP 1325932) |
Biosimilars/biobetters-related EU Patents: | 2018 (based on EP 0971959 and EP 1325932) |
EU Patent Expiration Year: | 2018 |
EU Biosimilars Data Exclusivity Expiration: | 2015 |
EU Biosimilars Orphan Exclusivity Expiration: | 2015 |
EU Biosimilars Launchability Year: | 2018 |
EU Biobetters Launchability Year: | 2018 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blepharospasm
exempt from CBER lot release requirements
growth factors
hamster source materials
monoclonal antibodies, recombinant
monoclonal antibodies, recombnant, humanized
recombinant DNA
rodent source materials
A375 cells
ATCC HB-8483
autologous cells, human
bioreactors, spinner culture
Chinese hamster ovary (CHO) cells, CHO-K1
chlortetracycline
glycine
media, serum-based
monoclonal antibody hP67.6
rodent cells <!-- rodentcells -->
varicella-zoster virus strain Oka/Merck
vegetable oil extraction
gentamicin (gentamycin)
polysorbate 20 (Tween 20)
sodium phosphate, dibasic
sodium phosphate, monobasic
trehalose dihydrate
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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