Bevacizumab in Recurrent Glioblastoma: US and Europe Disagree

Zosia Chustecka

March 22, 2010

March 22, 2010 — The same data that led to the accelerated approval of bevacizumab (Avastin, Genentech/Roche) for use in recurrent glioblastoma in the United States was rejected by the European Medicines Agency.

"It seems that the Europeans saw the glass as half empty, while the Americans saw it as half full," Henry Friedman MD, deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University in Durham, North Carolina, told Medscape Oncology in an interview.

But he pointed out that the Europeans are now testing bevacizumab in newly diagnosed patients with glioblastoma in a randomized trial, which indicates confidence in the fact that the drug has merit.

"I find this to be hypocritical nihilism," Dr. Friedman said. "You don't have enough confidence in the drug to approve it for use in recurrent disease, but you have enough to use it in a front-line setting, which by definition means that you have confidence in the drug or you shouldn't be using it."

Dr. Friedman was approached by Medscape Oncology for a reaction to criticisms from European researchers published online March 8 in a letter to the Journal of Clinical Oncology, in which they claim that the accelerated American approval of bevacizumab for recurrent glioblastoma — on the basis of uncontrolled trials — has led to missed "opportunities to adequately test this promising agent."

The lead author of that letter, Wolfgang Wick, MD, from the Department of Neurooncology at the National Center for Tumor Disease and the German Cancer Research Center in Heidelberg, told Medscape Oncology that the uncontrolled trials with bevacizumab have left many questions unanswered. He wonders why this drug was granted accelerated approval on the basis of "uncontrolled, though interesting, data " from a phase 2 trial, and why the same American regulatory authorities have demanded a "proper controlled phase 3 trial" for a very similar agent, cediranib (under development by AstraZeneca, not yet marketed).

Bevacizumab Phase 2 Data

Dr. Friedman was the lead investigator of a phase 2 clinical trial of 167 patients (J Clin Oncol. 2009; 27:4733-4740) that formed the basis, along with other studies, of the approval by the US Food and Drug Administration (FDA). But all of these studies were uncontrolled — the benefit of bevacizumab was shown only by comparing it with historic controls.

"There was some concern that the FDA was going to demand a comparator trial, but the totality of the data, . . . and the overall clinical improvement in the patients, plus the lack of any other options, proved to be compelling," Dr. Friedman said last year when the drug was approved. "The benefit to the patient was real and unchallengeable," he added.

The Oncological Drugs Advisory Committee, of which Dr. Friedman is a member, obviously agreed with these sentiments; they voted unanimously to recommend accelerated approval.

Different Perspective in Europe

But the European authors of the letter have a different opinion. In an interview, Dr. Wick emphasized that he believes that bevacizumab is an important drug for recurrent glioblastoma; indeed, he has used it in about 200 such patients. "But we think that from a scientific standpoint, there are not sufficient data to say that bevacizumab is warranted in recurrent glioblastoma."

This is the basis of the different approaches of Europe and the United States, he explained. The FDA reviewed the data for responses and overall survival from an uncontrolled phase 2 study and compared these outcomes with historic controls, whereas in Europe, "we would rather like to see data from a true comparator," Dr. Wick said.

A trial with a real comparator would allow outstanding questions to be resolved, such as the dosing (5 mg/kg or 10 mg/kg) and scheduling of administration (every 2 weeks or 3 weeks). "These types of questions are hard to answer when approval is already given," he added.

Also, the accelerated approval based on an uncontrolled phase 2 trial sets a bad example for future drug development, say the authors of the letter. "It encourages cheap(er) drug development strategies based on phase 2 protocols, promoting preregistration widespread clinical use rather than conclusive phase 3 trials with well-considered end points showing clear clinical benefit," they write.

Questioning End Points

Among the criticism that the European researchers direct at the phase 2 data used for the accelerated approval is the question of the end points that were used. The rate of patients alive and free of progression at 6 months is a surrogate end point, they note, and although it is considered valuable for cytotoxic agents, it is inappropriate when studying antiangiogenic agents (such as bevacizumab), because these drugs "modify vascular permeability and thus the imaging response assessment based on contrast enhancement."

This makes it difficult to assess objective responses to the drug, which is another primary end point, the European researchers note. This difficulty is illustrated by the substantial differences in the response rates reported by different groups of assessors, they say. For example, in the Friedman trial of 167 patients, the response rates for bevacizumab alone and for bevacizumab plus irinotecan were reported as 39% and 46%, respectively, when independently assessed by the investigators; as 28% and 38% in a sponsor-mandated central radiological review; and as 20% and 26% by the FDA.

Then, there is the "disappointing disparity" between the high response rates reported for bevacizumab in recurrent glioblastoma and the "modest, at best, survival benefit," the European researchers note. "The obvious question is whether the effects of bevacizumab by and large resemble those of dexamethasone and should therefore be named a pseudoresponse," they add.

However, Dr. Friedman said this is "nonsense", adding that there is a detailed response to these claims in a letter that he coauthored with several other American experts, which has been submitted to the Journal of Clinical Oncology. "We do not agree," he added.

We believe that the activity is so profound.

"There is agreement among experts in the United States that bevacizumab has activity in recurrent glioblastoma, the likes of which we have never seen before," Dr. Friedman explained. In fact, at their center at Duke, the drug is used off protocol in patients with recurrent glioblastoma and also in those with newly diagnosed glioblastoma who are not in clinical trials, because "we believe that the activity is so profound."

However, he added, "I do not believe that there is agreement yet that using it upfront in newly diagnosed patients will improve survival."

The European researchers agree that the drug has a place in the treatment of this disease. "Bevacizumab is without doubt a useful drug in recurrent glioma," they write. In particular, it shows benefit and improves quality of life in patients with symptomatic peritumoral edema that causes deficits and requires steroids. But they maintain that uncontrolled trials have left many questions unanswered. "We lack properly designed trials to determine how best and most economically to use this agent," they conclude.

More Data Are Coming

Dr. Wick noted that there is a trial planned that aims to answer some of these questions. The EORTC 26101 trial in recurrent glioblastoma is designed to answer whether it is best to use bevacizumab at first recurrence or second recurrence, using lomustine as additional recurrence treatment for comparison. This trial is due to start this summer, and results should be available in 2012.

In the meantime, the European denial of approval for bevacizumab in recurrent glioblastoma (in November 2009) has caused problems for clinicians. While the approval process was still underway, clinicians could use the drug in such patients if they had "good reason," Dr. Wick explained, adding that he and colleagues in Germany, France, and Italy have done so. But now that the regulatory decision has been made, this is no longer possible, and the drug is not reimbursable, he added.

Dr. Wick said it was unlikely that the company will refile for approval in Europe for this indication; it is now putting its efforts into investigating the drug in first-line treatment in the ongoing phase 3 AVAGLIO trial, from which results are expected in 2015.

Dr. Friedman reports acting as a consultant for and receiving research funding and honoraria Genentech. Dr. Wick reports serving as an advisor for Genentech/Roche.

J Clin Oncol. Published online March 8, 2010. Abstract

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