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Avastin: Roche’s `Brilliant Concept’ Fades After Studies Make Cancer Doctors Pause

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By Dermot Doherty – Feb 23, 2011

The Avastin medicine has largely lived up to its billing as an innovative way to attack tumors, along the way generating the most revenue for any cancer drug while being Roche Holding AG’s best-selling treatment with 6.46 billion Swiss francs ($6.88 billion) in sales last year.

Only now are the limitations of Avastin, introduced in 2004, becoming clear to doctors. Even before U.S. regulators in December moved to revoke the drug’s conditional approval for treating breast cancer, Kent Osborne, a Texas oncologist, said in an interview that he was reducing use of the drug, citing its “huge” costs, disappointing benefits and frequent side effects.

“We’re talking about breast cancer that has spread and our job here, since we can’t cure patients yet, is to palliate them,” said Osborne, director of Baylor College of Medicine’s cancer center in Houston. “If you have a drug that makes their quality of life worse, you haven’t accomplished that goal.”

Avastin, developed by Roche’s Genentech unit, is the first commercial medicine to capitalize on a theory, first proposed 40 years ago, that tumor growth can be stopped by turning off a cancer cell’s access to blood. Studies show Avastin, in combination with chemotherapy, can extend life about five months in patients with advanced colorectal tumors. Still, the drug has failed to live up to early expectations that it would forestall death for years in patients with cancer that has spread.

Peak Sales

In 2009, Bill Burns, then the head of pharmaceuticals at Basel, Switzerland-based Roche, said the drug’s annual sales might reach as much as 9 billion Swiss francs by this year. Three weeks ago, however, Roche Chief Executive Officer Severin Schwan said the drug’s sales may now only reach 7 billion francs.

Avastin’s failure to win full U.S. Food and Drug Administration approval against breast cancer — a market estimated by researcher GlobalData to have been valued at $8.7 billion in 2009 — is muting enthusiasm for Avastin, which works by deactivating a chemical known as vascular endothelial growth factor, or VEGF, which spurs blood-vessel growth. The drug’s poor record against early-stage cancers, and survival gains of only a few months for most patients with advanced cancer, are additional reasons for the slowing sales growth.

‘Brilliant Concept’

“The last time Avastin appeared to be a ‘revolutionary’ treatment was when it was a laboratory idea,” Leonard Saltz, a research oncologist at Memorial Sloan-Kettering Cancer Center in New York, said in an interview. “Stopping the blood supply to a tumor is a brilliant concept, but in my opinion we have not really succeeded in bringing it to fruition in clinical trials.”

As doctors get a better sense of Avastin’s limits, governments in Europe and U.S. insurers are questioning its annual cost of as much as $100,000. The U.K.’s National Institute for Health and Clinical Excellence in London has refused to recommend the drug for any tumor type. The agency, which advises the U.K. National Health Service on cost-effective treatments, is carrying out additional reviews of the drug.

“Scientifically it’s a very important discovery, but in the clinic it hasn’t been as significant as we thought it would be,” said Lee Newcomer, an oncologist and vice president at Minnetonka, Minnesota-based UnitedHealth Group Inc., the biggest U.S. health insurer by revenue. Newcomer said his view of the drug is based on journal studies and on the FDA’s statements.

‘Removal of Growth’

Roche shares have fallen 9.2 percent since July 16, when an FDA staff review concluded the follow-up trials of Avastin against breast cancer weren’t as positive as earlier tests. The stock rose 60 centimes, or 0.4 percent, to 137.6 francs at 10:33 a.m. in Zurich trading.

“Clearly a lot of the premium that Roche had attracted was based on Avastin growing and the removal of that growth does put the consensus ‘buy’ case much more at risk,” said Amit Roy, an analyst at Nomura International in London. “It removes the critical driver for the stock and from an investment point of view, people are struggling to get excited about this story.”

Sales of Avastin may have peaked in 2010 and may fall to about 5.7 billion francs by 2013, according to Roy, who has a price target of 130 francs.

The FDA said on Dec. 16 that it was starting the process to rescind Avastin’s accelerated approval granted in 2008 for use against breast tumors. That provisional clearance was based on a study that showed Avastin, combined with chemotherapy, slowed the spread of breast cancer cells to other tissue by 5.5 months.

Study Failures

Two follow-up studies were unable to show a similar effect. In one trial, Avastin kept cancer at bay for 0.9 months, while the comparable figure in another study was 1.2 months. Neither trial showed that Avastin prolonged the lives of the patients.

The FDA said patients given the medicine alongside chemotherapy had more side effects than those on the traditional cancer drugs alone. Two studies showed a trend toward an increased rate of death among patients given Avastin, the FDA said.

“They didn’t show that adding Avastin to a variety of chemotherapeutic regimens improved or prolonged the life of women with metastatic breast cancer,” Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland, said on a conference call in December.

What the drug did do was add “many serious side effects,” Woodcock said. “That’s sort of the bottom line.”

Appeal

Roche last month appealed the FDA’s decision to withdraw marketing permission in breast cancer, saying the agency should wait for results of a new study of Avastin with paclitaxel chemotherapy. The Swiss drugmaker said Jan. 18 it requested a hearing and that it expects to hear back from the FDA within 30 to 60 days.

“Since the introduction of Avastin we have seen that more patients live longer without their disease getting worse, and in some cancers Avastin prolongs survival,” Annette Walz, a spokeswoman at Roche, said. The company continues to “stand by” Avastin’s data in metastatic breast cancer, she said. The drug can keep breast cancer under control for a certain time and so the patient may benefit longer, Walz said.

“Avastin is and will forever be in the history books of Roche one of the biggest success stories of this company,” Roche’s CEO Schwan said in an interview Feb. 2. “It has revolutionized the treatment of cancer. There’s already a million patients who have been treated with Avastin — that’s what I call a real success story.”

Works in Some

The drug does work for some people, and that’s why doctors prescribe it, said Larry Norton, an oncologist who specializes in breast tumors at Sloan-Kettering.

“There are some individuals who are getting enormous benefit from Avastin even though on average the treatment advantage is small,” Norton said. By “enormous,” Norton said he means “many months of disease control” or even more than a year for patients who benefit the most.

Sandy Walker, 62, is an example of the kind of success that has encouraged doctors to keep trying the drug. Walker took part in a clinical trial of Avastin after she was diagnosed with advanced ovarian cancer in 2007. She took Avastin for 22 months, keeping the tumor at bay. The cancer returned after she stopped taking the drug at the end of the trial, and she has been back on Avastin ever since. She says she hasn’t experienced any side effects, though she’d be willing to accept them.

‘Worth Any Risk’

“When I stopped Avastin and the cancer came back and then went away again, it was worth any risk,” Walker said in an interview from her home in Greensboro, North Carolina. “I’m going on four years now and when I was first diagnosed I didn’t know if I’d have another six weeks.”

Roche reported Feb. 8 that Avastin, combined with chemotherapy, delayed progression of ovarian cancer for a longer time than chemotherapy alone. The company didn’t disclose exactly how much more time the treatment provided before the tumor began growing again, saying it would release the full results at a science meeting.

The drug in all has received regulatory approval for treating cancers of the colon, lung, kidney, breast and brain. Avastin has failed to work in trials in gastric and prostate cancer.

“When they’ve tried Avastin with first-line chemotherapies outside the U.S., it has failed to boost survival in any cancer,” Nomura’s Roy said. “When they’ve tried it in early- stage cancers it’s failed in all tumors and the clinical data in the current indications don’t support full penetration outside the U.S. Avastin just isn’t as good as it appeared five years ago.”

No Improvement

Avastin initially won approval in 2004 against colon cancer that had spread to other organs after a study showed the drug added about five months of life — a record survival time –when paired with a chemotherapy. In a 2006 follow-up trial, researchers looked for similar improvement in survival. Instead, they found that the addition of Avastin to two newer types of chemotherapy, called Folfox and Xelox, checked growth for just 1.4 months and offered no significant improvement in survival.

“We all hoped and thought that the first study would be the starting point,” said Saltz of Sloan-Kettering, who was the lead investigator for the second clinical trial. “What we didn’t realize was, it was about as good as it was going to get.”

Tests with two types of chemotherapy against lung cancer resulted in an outcome similar to that of the colorectal cancer study: Avastin boosted overall survival and progression-free survival when combined with carboplatin chemotherapy. When combined with the slightly more powerful cisplatin chemotherapy, which is more widely prescribed in Europe, Avastin didn’t improve overall survival and had a smaller effect on progression-free survival, a study found.

Not Relevant

“I don’t think Avastin is clinically all that relevant in lung cancer,” said Robert Pirker, a professor at the Medical University of Vienna. “The problem with Avastin is you don’t have a proven survival benefit in patients given optimum chemotherapy such as cisplatin-based chemotherapy.”

The study results have fueled speculation about how the drug really works. The theory that Avastin kills tumors by cutting off the blood supply is open to question because there’s little evidence to indicate it works on its own, Saltz said. Avastin may change the permeability of blood vessels, allowing improved delivery of chemotherapy into the tumor, he said.

Axel Grothey, an oncologist who specializes in colorectal cancer at the Rochester, Minnesota-based Mayo Clinic, describes Avastin as a “chemo equalizer,” saying it makes older chemotherapies work better. There may be a limit to what can be achieved by adding Avastin to the traditional treatments, he said.

“If you have a weak chemotherapy backbone and you add Avastin to it, the increase in effectiveness is quite pronounced,” Grothey said. “If you already have a strong chemotherapy backbone, like modern combination regimens, the added benefit of Avastin is not as great anymore.”

Avastin in combination with chemotherapy compared with chemotherapy alone, was associated with increased treatment-related mortality

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Posted 07 Feb 2011 — by James Street
Category antiangiogenesis, Avastin, Avastin, Drug Interactions, Drug Testing

Treatment-Related Mortality With Bevacizumab in Cancer Patients
A Meta-analysis

1. Vishal Ranpura, MD;
2. Sanjaykumar Hapani, MD;
3. Shenhong Wu, MD, PhD

[+] Author Affiliations

1.
Author Affiliations: Department of Medicine (Dr Ranpura), Division of Hematology and Medical Oncology (Drs Hapani and Wu), Stony Brook University Medical Center, Stony Brook, New York.

Abstract

Context Fatal adverse events (FAEs) have been reported in cancer patients treated with the widely used angiogenesis inhibitor bevacizumab in combination with chemotherapy. Currently, the role of bevacizumab in treatment-related mortality is not clear.

Objective To perform a systematic review and meta-analysis of published randomized controlled trials (RCTs) to determine the overall risk of FAEs associated with bevacizumab.

Data Sources PubMed, EMBASE, and Web of Science databases as well as abstracts presented at American Society of Clinical Oncology conferences from January 1966 to October 2010 were searched to identify relevant studies.

Study Selection and Data Extraction Eligible studies included prospective RCTs in which bevacizumab in combination with chemotherapy or biological therapy was compared with chemotherapy or biological therapy alone. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models.

Data Synthesis A total of 10 217 patients with a variety of advanced solid tumors from 16 RCTs were included in the analysis. The overall incidence of FAEs with bevacizumab was 2.5% (95% CI, 1.7%-3.9%). Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs, with an RR of 1.46 (95% CI, 1.09-1.94; P = .01; incidence, 2.5% vs 1.7%). This association varied significantly with chemotherapeutic agents (P = .045) but not with tumor types (P = .13) or bevacizumab doses (P = .16). Bevacizumab was associated with an increased risk of FAEs in patients receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% vs 1.0%) but was not associated with increased risk of FAEs when used in conjunction with other agents (RR, 0.85; 95% CI, 0.25-2.88; incidence, 0.8% vs 0.9%). The most common causes of FAEs were hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal tract perforation (7.1%).

Conclusion In a meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone, was associated with increased treatment-related mortality.