Bevacizumab
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 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.
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, 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. In June 2006, it was approved with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer.It was authorized by the European Union 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 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, which demonstrated a two-month improvement in overall survival in patients treated with bevacizumab. A preplanned analysis of histology in E4599 demonstrated a four-month median survival benefit with bevacizumab for people with adenocarcinoma ; 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. 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. 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. 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. 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 activating mutations.
Breast cancer
In December 2010, the US Food and Drug Administration 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 US Food and Drug Administration approved bevacizumab for use in metastatic renal cell cancer. Following earlier reports of activity, European Union 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 is indicated for the treatment of neovascular age-related macular degeneration.Ovarian cancer
In 2018, the US Food and Drug Administration 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 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.