Medication
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Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, hepatocellular carcinoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).
Common side effects when used for cancer include nose bleeds, headache, high blood pressure, and rash. Other severe side effects include gastrointestinal perforation, bleeding, allergic reactions, blood clots, and an increased risk of infection. When used for eye disease side effects can include vision loss and retinal detachment. Bevacizumab is a monoclonal antibody that functions as an angiogenesis inhibitor. It works by slowing the growth of new blood vessels by inhibiting vascular endothelial growth factor A (VEGF-A), in other words anti–VEGF therapy.
Bevacizumab was approved for medical use in the United States in 2004. It is on the World Health Organization's List of Essential Medicines.
Medical uses.
Colorectal cancer.
Bevacizumab was approved in the United States in February 2004, for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment). In June 2006, it was approved with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer.
It was approved by the European Medicines Agency (EMA) in January 2005, for use in colorectal cancer.
Bevacizumab has also been examined as an add on to other chemotherapy drugs in people with non-metastatic colon cancer. The data from two large randomized studies showed no benefit in preventing the cancer from returning and a potential to cause harm in this setting.
In the EU, bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adults with metastatic carcinoma of the colon or rectum.
Lung cancer.
In 2006, the US Food and Drug Administration (FDA) approved bevacizumab for use in first-line advanced nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy. The approval was based on the pivotal study E4599 (conducted by the Eastern Cooperative Oncology Group), which demonstrated a two-month improvement in overall survival in patients treated with bevacizumab (Sandler, et al. NEJM 2004). A preplanned analysis of histology in E4599 demonstrated a four-month median survival benefit with bevacizumab for people with adenocarcinoma (Sandler, et al. JTO 2010); adenocarcinoma represents approximately 85% of all non-squamous cell carcinomas of the lung.
A subsequent European clinical trial, AVAiL, was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck, et al. Ann. Oncol. 2010). An overall survival benefit was not demonstrated in patients treated with bevacizumab; however, this may be due to the more limited use of bevacizumab as maintenance treatment in AVAiL versus E4599 (this differential effect is also apparent in the European vs US trials of bevacizumab in colorectal cancer: Tyagi and Grothey, Clin Colorectal Cancer, 2006). As an anti-angiogenic agent, there is no mechanistic rationale for stopping bevacizumab before disease progression. Stated another way, the survival benefits achieved with bevacizumab can only be expected when used in accordance with the clinical evidence: continued until disease progression or treatment-limiting side effects.
Another large European-based clinical trial with bevacizumab in lung cancer, AVAPERL, was reported in October 2011 (Barlesi, et al. ECCM 2011). First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles, and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10.2 vs 6.6 months). Maintenance treatment with bevacizumab/pemetrexed did not confer a significant increase in overall survival vs bevacizumab alone on follow up analysis.
In the EU, bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations.
Breast cancer.
In December 2010, the US Food and Drug Administration (FDA) notified its intention to remove the breast cancer indication from bevacizumab, saying that it had not been shown to be safe and effective in breast cancer patients. The combined data from four different clinical trials showed that bevacizumab neither prolonged overall survival nor slowed disease progression sufficiently to outweigh the risk it presents to patients. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label, although insurance companies are less likely to approve off-label treatments. In June 2011, an FDA panel unanimously rejected an appeal by Roche. A panel of cancer experts ruled for a second time that Avastin should no longer be used in breast cancer patients, clearing the way for the US government to remove its endorsement from the drug. The June 2011 meeting of the FDA's oncologic drug advisory committee was the last step in an appeal by the drug's maker. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates, no improvement in quality of life, and significant side effects.
In the EU, bevacizumab in combination with paclitaxel is indicated for first-line treatment of adults with metastatic breast cancer. Bevacizumab in combination with capecitabine is indicated for first-line treatment of adults with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate.
Kidney cancer.
In certain kidney cancers, bevacizumab improves the progression free survival time but not survival time. In 2009, the FDA approved bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer). following earlier reports of activity EU approval was granted in 2007.
In the EU, bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of adults with advanced and/or metastatic renal cell cancer.
Brain cancers.
Bevacizumab slows tumor growth but does not affect overall survival in people with glioblastoma. The FDA granted accelerated approval for the treatment of recurrent glioblastoma multiforme in May 2009. A 2018 Cochrane review deemed there to not be good evidence for its use in recurrences either.
Macular degeneration.
In the EU, bevacizumab gamma (Lytenava) is indicated for the treatment of neovascular (wet) age-related macular degeneration (nAMD).
Ovarian cancer.
In 2018, the US Food and Drug Administration (FDA) approved bevacizumab in combination with chemotherapy for stage III or IV of ovarian cancer after initial surgical operation, followed by single-agent bevacizumab. The approval was based on a study of the addition of bevacizumab to carboplatin and paclitaxel. Progression-free survival was increased to 18 months from 13 months.
In the EU, bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adults with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adults with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.
In May 2020, the FDA expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.
Cervical cancer.
In the EU, bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in people who cannot receive platinum therapy, is indicated for the treatment of adults with persistent, recurrent, or metastatic carcinoma of the cervix.
Adverse effects.
Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.
The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. Fatigue and infection are also common.
In advanced lung cancer, less than half of patients qualify for treatment. Nasal septum perforation and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.
In 2013, Hoffmann-La Roche announced that the drug was associated with 52 cases of necrotizing fasciitis from 1997 to 2012, of which 17 patients died. About 2/3 of cases involved patients with colorectal cancer, or patients with gastrointestinal perforations or fistulas.
These effects are largely avoided in ophthalmological use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.
Neurological adverse events include reversible posterior encephalopathy syndrome. Ischemic and hemorrhagic strokes are also possible.
Protein in the urine occurs in approximately 20% of people. This does not require permanent discontinuation of the drug. Nonetheless, the presence of nephrotic syndrome necessitates permanent discontinuation of bevacizumab.
Mechanism of action.
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A is a growth factor protein that stimulates angiogenesis in a variety of diseases, especially in cancer. By binding VEGF-A, bevacizumab should act outside the cell, but in some cases (cervical and breast cancer) it is taken up by cells through constitutive endocytosis. It also is taken up by retinal photoreceptor cells after intravitreal injection.
Chemistry.
Bevacizumab was originally derived from a mouse monoclonal antibody generated from mice immunized with the 165-residue form of recombinant human vascular endothelial growth factor. It was humanized by retaining the binding region and replacing the rest with a human full light chain and a human truncated IgG1 heavy chain, with some other substitutions. The resulting plasmid was transfected into Chinese hamster ovary cells which are grown in industrial fermentation systems.
History.
Bevacizumab is a recombinant humanized monoclonal antibody and in 2004, it became the first clinically used angiogenesis inhibitor. Its development was based on the discovery of human vascular endothelial growth factor (VEGF), a protein that stimulated blood vessel growth, in the laboratory of Genentech scientist Napoleone Ferrara. Ferrara later demonstrated that antibodies against VEGF inhibit tumor growth in mice. His work validated the hypothesis of Judah Folkman, proposed in 1971, that stopping angiogenesis might be useful in controlling cancer growth.
Approval.
It received its first approval in the United States in 2004, for combination use with standard chemotherapy for metastatic colon cancer. It has since been approved for use in certain lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain.
In 2008, bevacizumab was approved for breast cancer by the FDA, but the approval was revoked on 18 November 2011 because, although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging.
In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA's advisory panel had recommended against approval. In July 2010, after new studies failed to show a significant benefit, the FDA's advisory panel recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA ruled to withdraw the breast cancer indication in November 2011. FDA approval is required for Genentech to market a drug for that indication. Doctors may sometimes prescribe it for that indication, although insurance companies are less likely to pay for it.
The drug remains approved for breast cancer use in other countries, including Australia. It has been funded by the English NHS Cancer Drugs Fund, but in January 2015 it was proposed to remove it from the approved list. It remains on the Cancer Drugs Fund as of March 2023.
Society and culture.
Use for macular degeneration.
In 2015, there was a fierce debate in the UK and other European countries concerning the choice of prescribing bevacizumab or ranibizumab (Lucentis) for wet AMD. In the UK, part of the tension was between on the one hand, both the European Medicines Agency and the