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February 25, 2008 — Bevacizumab (Avastin, Genetech) has received accelerated approval from the US Food and Drug Administration (FDA) for use in metastatic breast cancer in combination with paclitaxel chemotherapy. The approval was granted despite the fact that an Oncologic Drugs Advisory Committee voted narrowly (5 to 4) against recommending approval for this use in December 2007.
Bevacizumab is already marketed for use in colorectal and lung cancer, and this additional indication for use in metastatic breast cancer was approved in the European Union in March 2007.
The FDA accelerated approval was based on results from the E2100 phase 3 study conducted in 722 patients, which was published in December 2007 (N Engl J Med 2007;357;2666-2676). This showed that bevacizumab added to paclitaxel nearly doubled median progression-free survival (PFS), to 11.3 months with the combination, compared with 5.8 months with paclitaxel alone (hazard ratio [HR], 0.48; P < .0001). The secondary end point of overall survival in this trial did not reach statistical significance (P = .14), although it was extended by 1.7 months in the combination group. Overall survival was 26.5 months with bevacizumab and paclitaxel, compared with 24.8 months for paclitaxel alone (HR, 0.87).
The manufacturer, Genentech, also submitted recent results from a second positive trial, known as AVADO (BO17708), in which bevacizumab plus docetaxel chemotherapy was shown to prolong PFS, compared with docetaxel alone. The finding from this study was announced very recently (on February 12), and these data were not included in the approval application or discussed at the FDA advisory hearing. The company said it shared these results with the FDA "to assist the agency in assessing the risk and benefit in this patient population."
A third company-sponsored phase 3 study of bevacizumab in breast cancer, known as RIBBON I, is still in progress, with results expected in late 2008. "A full review of the AVADO and RIBBON I data by the FDA will be required for the accelerated approval to be converted into a full approval," the company said. There are also 3 other trials in progress or planned. If these trials do not show a survival benefit, then the accelerated approval for breast cancer could be revoked or curtailed; this sort of action was taken against gefitinib (Iressa, AstraZeneca) when subsequent results failed to show survival benefit in lung cancer after initial data showed tumor shrinkage.
Decision Seen as Controversial
The FDA's decision to grant accelerated approval on the basis of PFS data is seen by some commentators as controversial — cancer drugs are usually required to show a significant affect on overall survival before they are approved. However, breast cancer experts contacted by Medscape Oncology argued that PFS is an important end point.
"We believe they have lowered the bar," said Fran Visco, president of the patient-advocacy group National Breast Cancer Coalition Fund. "Our goal is to get the best treatments out to patients that really will be effective and safe," she commented to the New York Times, adding that "this particular circumstance will not advance that goal."
FDA official Richard Pazdur told the newspaper that the agency had approved other drugs in the past using PFS data, although overall survival is still the standard. "We wanted to have the regulatory flexibility to approve effective drugs where there isn't overall survival," he said, adding that delaying the progression of a life-threatening disease "may be a direct clinical benefit in itself."
"I think it's just a matter of time before a survival benefit is documented," said Amy Tiersten, MD, associate professor at New York University. She told the newspaper that she has been routinely using bevacizumab off-label for breast cancer patients, and it appears that many other physicians do too. Genentech has previously estimated that about 9000 breast cancer patients in the United States have been treated with off-label bevacizumab.
"As a clinician investigator, I believe that PFS is an important end point for patients," commented Edith Perez, MD, director of the Multidisciplinary Breast Clinic at the Mayo Clinic, in Jacksonville, Florida. "Now we need to also investigate the effect of this improvement on quality of life — especially if there is no overall improvement in survival," she told Medscape Oncology.
"This appears to be a new direction for the FDA, because in the past they have required that registration trials for first-line metastatic (and even refractory) breast cancer use an FDA-approved regimen, and that overall survival be the primary reason for approval (at least in the first-line setting)," Dr. Perez commented. "I wonder the impact this decision (i.e., approval based on a commonly used but not approved [therapy], such as weekly paclitaxel, and a primary end point of PFS) will have on future phase 3 study designs and approvals of other agents for breast cancer.
Dr. Perez noted that few details of the results from the AVADO trial have been made available. "It will be interesting to determine whether the lower dose of bevacizumab used in AVADO will have an impact on any subsequent decision by the FDA. The press release sent last week from Roche appeared to indicate that both the 7.5 mg/kg and 15 mg/kg doses every 3 weeks were better than no bevacizumab — but details of the data" have not been made available.
Another breast cancer expert, Gabriel N. Hortobagyi, MD, FACP, from the University of Texas MD Anderson Cancer Center in Houston, told Medscape Oncology: "I believe the FDA did the only appropriate thing with bevacizumab in breast cancer — approve it."
"It is going to be increasingly rare to find significant survival differences with new drugs in the metastatic setting unless we are willing to do increasingly larger clinical trials, which would limit our ability to evaluate new drugs," he said. Dr. Hortobagyi also suggested that metastatic breast cancer should be viewed as "a relatively chronic condition. It is treated with all available drugs in sequence. Therefore, a single patient might receive 8 to 10 different treatments during her life with metastatic disease. When you introduce a new drug, it will become part of 1 of those 8 to 10 treatments, so if the new drug doubles the duration of control of the disease, it will affect 1/10th of the survival for that patient. To detect that statistically, you need thousands of patients. In addition, overall survival duration will be affected by the other 7 to 9 drugs the patient will receive during the rest of her life."
"PFS, on the other hand, is a direct measure of the effect of the drug under evaluation," Dr. Hortobagyi commented. In addition, there are other factors that should be taken into consideration, he continued. "For instance, suppose that a new drug is as effective as an old drug but is better tolerated, less toxic. Or suppose that the new drug costs less or is easier and more convenient to administer. It would be foolish to discard such new drugs just because they do not provide prolongation in survival."
George Sledge, MD, BallÃ©-Lantero Professor of Oncology at Indiana University, in Indianapolis, who chaired the committee that ran the E2100 study, told Medscape Oncology, "I am strongly in favor of the approval based on PFS. In breast cancer, we use disease-free survival as a basis for approval in the adjuvant setting, and PFS or time-to-progression as a basis for approval in second-/third-line metastatic breast cancer."
"I do not see why front-line therapy should represent an exception to the other settings," Dr. Sledge continued. "I cannot see the logic that says PFS is a more valuable end point in more refractory disease. For example, we approved trastuzumab (Herceptin, Genentech/Roche) in the adjuvant setting prior to demonstration of an overall survival advantage, as well as lapatinib (Tykerb, GlaxoSmithKline) and ixabepilone (Ixempra, Bristol-Myers Squibb), this last year, based on a PFS end point."
"Clearly, we want drugs that improve overall survival — who would not? But E2100 suggests why this may be difficult," Dr. Sledge commented. "Patients in E2100 spent the majority of their lives off front-line therapy, and routinely received second-, third-, or fourth-line therapy with existing (FDA-approved) agents. These all have the potential to muddy the waters for any survival analysis. E2100 had an 80% power to show a 7-month improvement in overall survival with a P < .05, which is to say it was weakly powered. Patients in the experimental (bevacizumab) arm on average lived 6 weeks longer than patients in the control arm, and an appropriately powered trial in the front-line setting would have required 2 to 3 times as many patients to show this 6-week advantage with statistical significance. I do not consider this a good use of clinical resources."
Mark Pegram, MD, from the University of Miami Cancer Center, in Florida, who was not involved in the E2100 trial, agrees with the approval being based on a PFS end point. He also noted that a PFS end point has been used for several drugs in the breast cancer setting, including in the approval for adjuvant anastrozole (Arimidex, AstraZeneca). "So there is a historical precedent here, and a statistical improvement in overall survival is not mandated for approval," he told Medscape Oncology. He said such a result cannot be expected from the E2100 trial — "that survival data are now mature" — because of the number of patients involved and because of confounding from the use of other therapies. It is also unlikely to come out of the AVADO trial, which involved a similar number of patients (705). It might, however, come out of the RIBBON I trial, which is larger (1200 patients) and which involves 1 of several chemotherapy agents (including docetaxel, Abraxane, capcitebine, and anthracyclines) used in combination with bevacizumab.
Dr. Pegram also emphasized that, in the clinical setting of metastatic breast cancer, the overall goal of therapy is palliation of disease-related symptoms, and the combination of bevacizumab with 1 chemotherapeutic agent is "clearly less toxic" than the alternative of several chemotherapeutic agents. This translates into a significant improvement in quality of life, which was demonstrated in the published results from E2100, he noted. This approval for bevacizumab is "good news for patients," he said, because it adds another therapeutic option and widens patients' choices of therapy.
"There is no cure for metastatic breast cancer, so it is important to control the disease as early and for as long as possible," said Kathy Miller MD, associate professor of medical oncology at Indiana University, and lead investigator on the E2100 trial. "Now, with bevacizumab plus paclitaxel, we can increase the time a woman's cancer is kept under control, and offer a biological option to women who previously were limited to chemotherapies alone," Dr. Miller said in a press statement.
"The FDA's approval of Avastin will give many women an additional option in the treatment of a serious disease," commented Otis Brawley, MD, chief medical officer of the American Cancer Society, when the approval was announced. "The FDA has almost always required that drugs be shown toextend life in order to be approved, which makes them much more likely to be covered by insurers. The FDA's approval process for Avastin tells us that regulators are now making quality-of-life issues an important part of their decision-making," he said.
Medscape Medical News © 2008 Medscape
Cite this: Zosia Chustecka . Experts Welcome Accelerated Approval of Bevacizumab for Breast Cancer - Medscape - Feb 25, 2008.