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Avastin (bevacizumab) may increase the risk of neural bleeding and stroke in a small population of patients with glioblastoma multiforme, according to several physicians interviewed by Pharmawire. The gravity of this side-effect should be carefully studied, they added.
The drug acts by targeting vascular endothelial growth factor (VEGF) and is thought to act by blocking the formation of new blood vessels (angiogenesis). The drug is approved by the FDA for the treatment of patients with non-small cell lung cancer, colorectal cancer and metastatic breast cancer. Avastin is currently undergoing Phase II clinical studies in patients with glioblastoma multiforme.
A significant side-effect of Avastin is that the drug’s administration may cause bleeding complications in the brain, according to Dr Steven Wong, a brain cancer expert at Harvard University. Genentech did not want to initiate clinical studies of Avastin in glioblastoma because the neural bleeding risk was so heavily feared, Wong said.
Serious bleeding complications occur in a little less than 5% of the patients who receive Avastin, Wong explained. Also, administering the drug in the time frame of four to six weeks before and after surgery could increase the risk of bleeding in the brain, he added.
A Genentech spokesperson said safety concerns did not emerge in the Phase II study of Avastin in patients with glioblastoma.
However, due to lack of data from randomized controlled clinical studies, physicians estimated that anywhere from 2% to approximately 15% of patients given the drug may experience the side-effect of bleeding. Treatment with Avastin has also caused stroke and hemorrhage in patients with colon and non-small cell lung cancers who have brain metastases, according to oncologists that treat patients with those diseases.
Dr William Leenders, who is currently studying Avastin in this indication, and an expert in the department of pathology at the Raboud University Nijmen Medical Centre, said the likelihood of experiencing a neural hemorrhage after receiving Avastin is approximately 15% (2 events in 13 patients according to one publication). Leenders said that according to another publication, 1 patient out of 35 (3%) experienced bleeding. Physicians cannot do anything to minimize patients’ potential risk of bleeding after receiving Avastin and many physicians are wary of administering the drug for glioblastoma due to this risk, Leenders said. Genentech has not seen such a high number of reported adverse events associated with Avastin in a clinical trial for any tumor type, a Genentech spokesperson noted. If this number is based on anecdotal reports from physicians, then it could be very misleading, the spokesperson said. In a Phase II trial for relapsed glioblastoma multiforme, Avastin was well tolerated and associated with low rates of bleeding, she added. Still, Dr Maria Juarez, a specialist at the Cancer Institute of Dallas noted that the rate of neural bleeding in past clinical studies of Avastin was so low, because they excluded patients with brain metastases. Avastin can increase the risk of hemorrhagic stroke, systemic stroke and blood pressure, Juarez said.
Yet Dr Henry Friedman, an investigator who has in the past received research support from Genentech, and who is also the deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University, where Avastin is currently being studied, disagreed and said that the bleeding caused by Avastin is “very rare”. It also does not appear that patients who are on anti-coagulants are at a higher risk for bleeding than those who are not, he added.
The rates of serious bleeding were in the 1-2% range in a clinical study that tested the effects of Avastin and Pfizer’s Campostar (irinotecan) compared to Avastin alone in patients with recurrent glioblastoma multiforme, said Dr Robert Mass, senior group medical director of BioOncology at Genentech. Campostar is a topoisomerase 1 inhibitor that is often administered in combination therapy with Avastin for a variety of indications. This rate of bleeding is acceptable since patients with glioblastoma are prone to experience bleeding as a result of their disease, Mass said.
“We knew that based on the way the drug works, we knew that bleeding is a complication, and there could be an increase in the risk of bleeding,” Mass said.
Patients with colon cancer who have brain metastases are at an increased risk of developing bleeding in the brain when given Avastin, added Dr Alfred Neugut, an oncologist who treats patients with colorectal cancer at Columbia University Medical Center. Physicians are especially concerned that patients given the drug may have a hemorrhagic stroke, Neugut added.
Treatment with Avastin has led to bleeding, and even death as a complication of the hemorrhage according to Dr Rakesh Jain, a brain cancer expert at Harvard University. The side-effects of the drug in this patient population have been published by the Duke University Study Group, Jain said. The drug’s adverse event profile and efficacy needs further study in Phase III clinical trials, he said. Genetech is planning on initiating a Phase III study evaluating Avastin in this patient population, a spokesperson noted. The Phase III trial will evaluate the standard of care of chemotherapy and radiation plus or minus Avastin in newly diagnosed patients with GBM.
Yet due to the lack of available treatments for patients with metastatic glioblastoma, if Avastin is shown to be an efficacious, it would be a major advantage for this patient population, said Dr Chin Wang, an oncologist at the Cancer Institute of Dallas.
Wang agreed that Avastin has been shown to be associated with an increased risk of stroke. It is not known if having glioblastoma and receiving Avastin increases your risk of a stroke even more so than receiving Avastin for other cancer indications, he added.
In addition, patients administered Avastin are at an increased risk for developing an ischemic stroke, which occurs after the formation of a blood clot in a vessel, explained Dr Leia Phioanh Nghiemphu, a specialist studying Avastin at UCLA. Higher rates of ischemic strokes have not occurred in the glioblastoma population to date, Nghiemphu said.
Still, ischemic strokes caused by Avastin could occur at a higher rate in the glioblastoma population which is comprised of older patients, she noted. Older patients receiving Avastin in the colon cancer trials were at an increased risk for developing ischemic strokes, Nghemphu added.
Several cases of cerebral hemorrhage in patients with brain metastases emerged in the studies used to gain FDA approval for Avastin for the non-small cell lung cancer indication. Future studies should investigate if Avastin increases the risk of bleeding in the brain after administering Avastin, Wang said.
The trials used to gain FDA approval for patients with non-small cell lung cancer did not enroll patients with brain metastases, Mass said. Currently Avastin is being studied in clinical trials enrolling patients with non-small cell lung cancer who have brain metastases, he said. The preliminary data that was presented of Avastin in this patient population at ASCO suggests that it is safe to give the drug in this manner, Mass said.
It is important for physicians treating patients with brain metastases to disclose the drug’s potential risk for causing bleeding and stroke, Wang advised. Physicians should also treat patients with chemotherapy or radiotherapy prior to administering Avastin, Wang said. Those treatments would potentially destroy some of the blood vessels feeding the tumor and thereby reduce circulation, Wang added. It is hoped that when the tumor is not actively growing as before, the chance for bleeding and stroke is lower, Wang said.
Nghiemphu, who has studied the drug in small clinical trial enrolling 20 patients, said that Avastin only increases the risk of bleeding by 1-3% in glioblastoma patients. Avastin’s benefits for glioblastoma patients outweigh its risks as glioblastoma is a very deadly cancer with a high risk of recurrence, she said.
Genentech is planning on conducting a randomized clinical trial of Avastin in patients with glioblastoma multiforme, based on the high tumor response rate and tumor free progression that was seen in studies to date, Mass said. “Genentech recognizes the importance of further evaluating Avastin in a randomized Phase III clinical trial in glioblastoma,” the spokesperson said. “The Phase II findings have with Avastin have exceeded our expectations, which is why we plan to submit an sBLA to the FDA for accelerated approval of Avastin,” she added.
Based on data from a Phase II clinical trial that was presented at ASCO this year, 0 out of 84 patients receiving Avastin alone and 3 out of 79 patients receiving Avastin and chemotherapy experienced a grade 3 or higher hemorrhage. A tumor response was seen in 28% of patients treated with Avastin and 38% of patients treated with Avastin in combination with chemotherapy.
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