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Roche/Genentech faces significant hurdles retaining Avastin’s label in breast cancer

By Elizabeth Krutoholow
Published: June 16 2011 21:04 | Last updated: June 16 2011 21:04


This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
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Roche and Genentech are expected to conduct an additional study testing Avastin in combination with paclitaxel in metastatic breast cancer (MBC) in order to retain its current label for this indication, according to a number of oncologists interviewed by Biopharm Insight. Yet such a trial would face significant enrollment issues if the breast cancer indication remains on the label, these experts noted.

Genentech and the Center for Drug Evaluation and Research (CDER) will meet on 28-29 of June to discuss the proposal to withdraw Avastin’s breast cancer approval in the United States.

Roche did not return repeated requests for comment.

In a written summary of arguments to be presented at a June 28-29 hearing on the indication, CDER stated that maintaining approval for an indication for which a clinical benefit has not been confirmed, while the company designs and conducts additional trials is inconsistent with the accelerated approval framework and the interests of the public health.

The potential removal of the MBC indication puts trials testing agents in patients who have progressed on Avastin in real jeopardy, said Dr Bryan Schneider, assistant professor of Medicine at Indiana School of Medicine.

The FDA granted accelerated approval on the basis of the E2100 trial which was a randomized, multicenter, open-labeled trial of Avastin with paclitaxel or paclitaxel alone that had a pre-specified primary endpoint of progression-free survival (PFS) with overall response rate (ORR) and overall survival (OS) as secondary endpoints.

The addition of Avastin to paclitaxel resulted in a reduction in the risk of disease progression with an estimated 5.5-month difference in median PFS. There was no significant difference in OS between the two treatment arms.

The RIBBON-1 trial examined Avastin in combination with taxanes, anthracyclines, or capecitabine, while the AVADO trial studied Avastin with docetaxel. Post-approval trials were proposed by Genentech and agreed to by CDER - but both studies failed to confirm the magnitude of effect on PFS that was seen in the E2100 trial and instead showed increases in median PFS ranging from under one month to 2.9 months.

A review of the data on Avastin suggests that the E2100 trial result is an “outlier” - as it was the only trial that showed a “fleeting glimpse of evidence” (Lancet Oncol. 2010 Dec;11(12):1117-9.), said an oncologist and investigator.

Genentech has hypothesized that the specific chemotherapy regimen Avastin is paired with, influences the drug’s effect. The company has argued that the MBC approval for Avastin should be maintained while it conducts further studies evaluating the agent in combination with paclitaxel.

It is unclear that Avastin works with any chemotherapy partner, said Schneider. Still, Avastin appears to be markedly better with paclitaxel, over other regimens, he noted.

The E2100 trial was “rushed,” commented a second oncologist, who explained that if Genentech had enrolled twice the number of patients, then it would have provided a statistically sufficient benefit for approval.

An additional study with paclitaxel is required to understand the differences seen between the E2100 and confirmatory trials and to disprove concerns, said Dr Gloria Morris, a medical oncologist and assistant professor at Thomas Jefferson Medical College.

Enrollment in confirmatory study could be difficult

The agency review noted that Genentech does not explain how it would enroll patients in a new, blinded, controlled clinical trial studying the use of Avastin in combination with paclitaxel to treat MBC if this were to remain an approved indication, since patients generally do not enroll in trials in which an approved indication is tested against a placebo. If Genentech were able to complete new trials showing that Avastin has a favorable risk-benefit profile when used to treat a subset of HER2-negative MBC patients, this work would likely take many years, the documents stated.

There would be concerns surrounding accrual for such a study, since it would require gaining patient confidence, said Morris. Patients would need to be presented with a full disclosure of the risk/benefit of the drug, she noted.

The second oncologist said he was not sure that Genentech could enroll patients in a placebo controlled blinded study if the agent remains labeled for use in breast cancer. However, if the drug’s benefit is real, it needs to be re-established with an additional trial, he commented.

It would be difficult to accrue to this study, Schneider agreed, saying that it is not the best use of resources. The E5103 trial that examines Avastin’s efficacy as an adjuvant therapy in combination with an anthracycline and taxane-based chemotherapy regimen in patients who have undergone surgery will show what the real signal is, he said, noting that this trial is almost completed.

The E5103 trial testing Avastin in the adjuvant setting will provide additional data on the toxicity profile of the agent, said the second oncologist. This data might be presented at this year’s San Antonio Breast Cancer Symposium, but efficacy results are unlikely at this point, he said. By nature, this trial will enroll healthier and younger patients, therefore the side-effect profile may be improved, he said.

Because Avastin’s use can result in considerable toxicity, the magnitude of its effect on PFS, especially if not supported by an improvement in overall survival, should be substantial, clinically meaningful, and capable of being confirmed in additional trials, the CDER document stated.

Drug’s toxicity profile important consideration

The increase in reported Grade 3/4 toxicities was twice as high in the Avastin arm in the E2100 study, the first oncologist said.

While Avastin provides more tumor shrinkage, it does not matter for patients whether 82% or 72% of the tumor is left, said the first oncologist. Such a narrow survival benefit is “trivial” for patients who are left to deal with the agent’s toxicity, he said.

The first oncologist pointed to the fact that there are numerous studies that have evaluated Avastin in breast cancer that have never been published. Those results were likely negative, he speculated, and said that with enough studies for any drug -- one will appear positive. In particular, the data set on the combination of Abraxane and Avastin in breast cancer has never been presented at a conference. The use of Avastin in the adjuvant setting is also likely to turn out negative, he said.

Anecdotally, Avastin does benefit patients when added to chemotherapy with a magnitude of excess side effects, which is why many clinicians are disappointed to see the indication removed, said Morris. In her experience, she said there is a distinct lengthening in time to progression with no excess side effects. It is necessary to look for changes in blood pressure and thrombosis, but these effects would need to be monitored for with chemotherapy anyway, she said.

The FDA will ultimately decide if anecdotal evidence will carry at the upcoming hearing, said the first oncologist.

There is a large amount of evidence suggesting that Avastin has activity, said Dr Ricardo Alvarez, assistant professor of medicine in the Department of Breast Medical Oncology and The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at MD Anderson, who believed that an additional study is not necessary.

While an overall survival benefit has yet to be seen, it does not mean that the drug lacks activity in breast cancer, he said. Prolonged survival past progression is a significant benefit in breast cancer, he said. An overall survival benefit can be difficult to show in breast cancer, relative to other cancers as patients can receive multiple lines of chemotherapy and survival past progression is longer.

Despite the anecdotal experience, the scientific evidence supporting the use of Avastin is not there, said the oncologist and investigator. One problem with anecdotal experience is that it is unclear how well chemotherapy alone would have worked in such patients and does not factor in the possibility that chemotherapy alone would have given as great a response, the oncologist said.

Removal of the MBC indication from the label will end the use of Avastin in all breast cancer indications, said the second oncologist, who said while it could be used as an experimental agent, its cost would be prohibitive.