Coverage of the FDA meeting from The Cancer Letter:
ODAC Votes To Strip Breast Cancer Indication
From Avastin In First Such Action By Committee
By Paul Goldberg
In an FDA “first,” the Oncologic Drugs Advisory Committee voted to strip an indication from a cancer drug that was approved under the accelerated approval mechanism.
At a meeting July 20, the committee voted 12 to 1 to remove locally advanced or metastatic breast cancer from the label of Roche’s widely used agent Avastin (bevacizumab).
The vote represents the first time the FDA staff consulted the oncology advisory committee on revocation of an accelerated approval. If the agency follows the committee’s advice--which it’s expected to do--Avastin would become the second drug to lose an indication received under the accelerated approval mechanism.
• In 2005, the drug Ethyol (amifostine), marketed by MedImmune, lost one of its indications, reducing the cumulative renal toxicity from cisplatin in non-small cell lung cancer. The drug is marketed for its other indications. The indication was withdrawn because of emergence of better treatment options for non-small cell lung cancer.
• Last month, Mylotarg (gemtuzumab ozogamicin) was withdrawn by the sponsor, Pfizer Inc., because three studies failed to demonstrate its efficacy in the approved indication, acute myeloid leukemia. Technically, this is not a revocation of an indication.
• Iressa (gefitinib), sponsored by AstraZeneca, was placed in a restricted access program that barred physicians from prescribing it to new patients. This action was caused by failure of confirmatory trials to demonstrate a survival advantage. These restrictions do not amount to losing an indication.
Avastin is approved for use in combination with paclitaxel, for HER2-negative metastatic breast cancer who have not yet received chemotherapy for advanced disease. The agency deadline for taking action is Sept. 17.
Since the agent is approved for other indications, it will remain available for off-label use in breast cancer. Nonetheless, the loss of the indication could prompt some insurers and, possibly, the government to deny payment.
Getting an accelerated approval used to be equivalent to a full approval. FDA could do little but try to shame sponsors into conducting confirmatory trials to demonstrate that the agents provide tangible benefits.
Now, the agency has stronger authority under the FDA Amendments Act of 2007 to require confirmatory studies for drugs approved based on surrogate endpoints.
Last month, Richard Pazdur, director of the agency’s Office of Oncology Drug Products, said that sponsors would be asked to present detailed plans for conducting confirmatory studies as part of the end of phase II meetings with the agency. Also, the agency is considering using ODAC to conduct annual reviews of outstanding confirmatory study commitments related to accelerated approval drugs (The Cancer Letter. June 25, 2010).
Avastin received an accelerated approval for the breast cancer indication in 2008, but two rigorously designed confirmatory studies conducted by the company failed to reproduce the dramatic improvement in delay of progression seen in the initial trial. The drug was approved based on the E2100 trial conducted by
Eastern Cooperative Oncology Group.
The accelerated approval was controversial. When ODAC considered the indication in December 2007, it voted 5 to 4 against approval. E2100 was never designed as a registration trial, there were problems with collection of data and interpretation of images.
However, the magnitude of effect--a 5.5 month increase in PFS--was sufficient to convince the agency to give the drug an accelerated approval for the indication. Two and a half years and two trials later, the agency found itself looking at two trials that presented very different picture:
• The Avado study (STN 125085\191), a 736-patient trial compared two different doses of Avastin and docetaxel with placebo in metastatic or locally recurring breast cancer. PFS was 7.8 months in the placebo arm and 8.9 months in the high dose Avastin arm. The finding was statistically significant. Overall median survival appeared to be lower on the Avastin arms. Survival was at 31.9 months for placebo, 30.8 months for lower dose Avastin and 30.2 months for higher dose. The findings were not statistically significant.
• The Ribbon 1 study (STN 125085\192) randomized 1,237 patients to chemotherapy with and without Avastin. The randomization was 2:1. In the taxane/anthracycline cohort, median PFS was 8 months for chemotherapy with placebo and 9.2 months for chemo and Avastin. In the capecitabine cohort, PFS was 5.7 months for placebo and 8.6 months for Avastin. The findings were statistically significant. Median survival was 22.8 months for capecitabine and placebo and 25.7 months for capecitabine and Avastin. The finding is not statistically significant. In the taxane and anthracycline cohort, the hazard ratio for median survival favored placebo.
ODAC’s discussion of stripping Avastin’s breast cancer indication is important because it constitutes the first ever public discussion of this sort.
An excerpted transcript follows:
WYNDHAM WILSON (ODAC chair and chief of Lymphoma Therapeutics Section at the NCI Center for Cancer Research): This is a very difficult question, because we are being asked to evaluate whether or not an indication for Avastin should be removed. These confirmatory trials are large, and they have across subset analyses not been able to show a survival advantage. They all show a very small benefit in PFS, and also they show toxicity from Avastin, which can be life-threatening and can lead to death in some patients. So I think the question we need to ask ourselves at this point is how comfortable do we feel allowing this indication to remain?
JEAN GREM (oncologist, University of Nebraska Medical Center): Previously, ODAC voted against approval, and in that case FDA did not follow our recommendation and approved it. I don’t want to feel guilty, as if basically, FDA made a mistake, and they did it with good intentions.
PAZDUR: We do not think we made a mistake here. Obviously, accelerated approval is to take a look at the data, and if the data look promising, then to ask for confirmatory trials to clarify this. Believe me, we do not look at this as a mistake, and it’s not a judgment on our past approval of the drug.
GREM: Because right now we are made to feel guilty.
PAZDUR: Let me absolve you of your guilt. We had data in 2008. We have more data here. And that’s what we are looking at. There is a far more comprehensive picture here of the role of Avastin than we did in 2008. And many of you who were on the committee point out that you had different opinions then, based on one trial versus seeing the rest of the data. And that’s why accelerated approval was given. We look at it as a split vote. Five-to-four is not some landslide vote. In internal discussions we felt that going the route of accelerated approval and looking at additional trials was warranted. We have those data now. What’s the entire evaluation of Avastin in 2010, given the complete data package that we have. We are not talking about removing Avastin from the market. We are talking about removing indication. And, yes, they can study the drug further in breast cancer and submit any positive trial that demonstrates clinical benefit. But we don’t look at it as a mistake. We look at this as part of the process of accelerated approval. And drugs will come off accelerated approval because there is a risk here in approving these drugs. And this is management of that risk.
JOANNE MORTIMER (vice chair, Medical Oncology & Therapeutics Research, City of Hope): I voted for [approval] last time we voted. My thought process as someone who takes care of these patients, the more than doubling of response rates and the doubling of PFS is incredibly meaningful. I looked hard at the fact that this was a cooperative group trial, which really does reflect community practice. Also, the pharmaceutical company--it’s really hard to justify continuing this indication.
VIRGINIA MASON (executive director, Inflammatory Breast Cancer Research Foundation): What is the timetable, and is there a time limit for a compound to be moved out of accelerated approval status?
PAZDUR: The sponsors are supposed to do the trials with “due diligence.” That does not have a regulatory definition. My personal definition of due diligence is that the sponsor should conduct these trials with the same enthusiasm and resources as they would with any registration trial. Obviously, we have discussed this at several ODAC meetings, and we plan on having an ODAC meeting in 2011 to look at accelerated approval commitments. We’ve made public statements regarding that with recent withdrawal of the Mylotarg application for accelerated approval. This is not the first time that we have done this. Most of the sponsors after having a discussion will usually voluntarily withdraw an indication. However, if this does not occur, there are other mechanisms outlined in the regulations for removing the indication.
MASON: Is there a way to tease out if there is a population of patients best responds to treatment?
WILSON: I think we have to be careful not to be distracted by trials in different groups that do not inform this indication, or subset analyses. We are at this point addressing whether or not based on the data we have seen so far in two large, well conducted studies in the same patient population in which the accelerated approval indication was made show clinical benefit. I think we should be careful not to get distracted by what-ifs.
BRENT LOGAN (associate professor of biostatistics, Medical College of Wisconsin): In the initial approval the magnitude of PFS was felt to be strong enough to overcome the number of concerns about trial design in terms of being blinded, missing assessments and data collection and those kind of things. Here we have two very well controlled studies. They are blinded, there is good follow-up, and we are seeing much smaller benefit.
WILSON: I think we just have to be very aware that the goal of medicine is first to do no harm. I think that the burden of proof is that a drug is helpful, not that it doesn’t make people worse. And we have definitive evidence that Avastin causes serious and life-threatening side effects; small numbers, but if you are the one, that’s not where you want to be. I think the Good Housekeeping seal of approval is important, and I think it needs to reflect what the data shows.
Mason, the only member of the committee to cast a vote for keeping the indication, said the drug’s current label reflects its costs and benefits. “In the second paragraph of the indications for use it says, ‘There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin,” Mason said. “I can live with the fact that having that on the label would allow patients and physicians to make a decision.”
Pazdur’s opening comments, which reflect the agency’s thinking on Avastin and, by inference, accelerated approval, appear below:
In 2008, Avastin in combination with paclitaxel received accelerated approval for the first-line treatment of metastatic breast cancer based on the results of study E2100. Approval under these regulations required Genentech to conduct adequate and well-controlled studies to further define the degree of clinical benefit to patients.
Genentech identified two trialsthe AVADO trial and the RIBBON 1 trial-- to provide this evidence in the first-line treatment of metastatic breast cancer. The AVADO trial compared the combination of Avastin plus docetaxel to single agent docetaxel. The RIBBON 1 trial examined the benefit of adding Avastin to either anthracycline or taxane- based chemotherapy or capecitabine.
These trials could support additional new first-line breast cancer indications for Avastin combinations. In addition, these studies could convert the 2008 accelerated approval of Avastin to regular approval.
As previously noted, Avastin in combination with paclitaxel received accelerated approval for first-line treatment of patients with metastatic breast cancer based on the results of the E2100 study.
This trial was a randomized, multicenter, open-labeled trial of Avastin with paclitaxel or paclitaxel alone that enrolled patients with HER-2 neu negative breast cancer who received no previous chemotherapy for metastatic disease.
The addition of Avastin to paclitaxel resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS. There was no significant difference in overall survival between the two treatment arms. The tumor response rate was higher with Avastin plus paclitaxel as compared to paclitaxel alone (48.9% versus 22.2%).
This application was discussed at an ODAC meeting in December 2007. A split vote (5 to 4) was recorded in response to the question of whether a favorable risk/benefit analysis for the use of Avastin plus paclitaxel was provided by E2100.
FDA subsequently granted accelerated approval to this indication with the provision that additional data be provided to further define the degree of clinical benefit. Progression-free survival has been used as a clinical benefit endpoint in a variety of diseases.
The magnitude of benefit attributed to the addition of Avastin to paclitaxel (median PFS difference of 5.5 months, HR 0.48) was considered to be clinically meaningful in light of Avastin’s toxicity by several of the ODAC discussants. In addition, this supplemental BLA was supported by two prior approvals of Avastin in the first-line treatment of non-small cell lung cancer and colorectal cancer. Both the colorectal and non-small cell lung cancer indications that combined Avastin with chemotherapy regimens were supported by improvements in overall survival.
In the E2100 trial supporting the 2008 approval of Avastin the hazard ratio for overall survival was 0.87 (95% CI 0.72, 1.05) indicating that a detrimental effect on OS was unlikely with the addition of Avastin to paclitaxel.
As a condition of the accelerated approval, Genentech was required to submit data from two ongoing, placebo-controlled trials (AVADO and RIBBON1) to confirm the magnitude of the treatment effect on PFS and to provide additional information on the effects on overall survival. In a pre-BLA meeting on February 2009, Genentech was asked to provide mature survival data with evidence that the addition of Avastin did not have a detrimental effect on overall survival.
This ODAC meeting is called to re-evaluate the role of Avastin in breast cancer. At the present time we have the results of four trials allowing us to have a more comprehensive view of the role of Avastin in breast cancer. Three trialsE2100, AVADO, and RIBBON 1were conducted in the first line setting have been submitted to FDA. An additional trial AVF 2119g, a trial comparing the Avastin plus capecitabine to single-agent capecitabinewas conducted in the second and third-line setting of breast cancer. This trial failed to demonstrate statistical significant effects on either PFS or OS. To date no trial examining the role of Avastin in breast cancer has demonstrated an improvement in overall survival.
Although an improvement in overall survival remains the gold standard for approval, progression-free survival and disease-free survival in the adjuvant setting, have been advocated as approval endpoints. Proponents of using PFS note that OS analysis may be confounded by cross-over and/or subsequent therapies and that PFS, measured prior to the introduction of other post-progression therapies, may more accurately depict a treatments therapeutic effect.
FDA believes that in accepting PFS as a regulatory endpoint a close examination of the magnitude of improvement in PFS must be closely evaluated in a risk-benefit analysis. Because treatment with Avastin is associated with considerable toxicity, the magnitude of PFS improvement--especially if not supported by an improvement in overall survival--should be substantial, clinically meaningful and be able to be replicated in additional trials. Also, the addition of Avastin to chemotherapy, should not result in a deleterious effect on survival. Hence, we ask you to evaluate the findings of the risk/benefit analysis of the E2100 trial in relation to the AVADO and RIBBON 1 trial.
AVADO was a double-blind, placebo-controlled, three-arm trial of docetaxel plus placebo, docetaxel plus Avastin 7.5mg/kg, and docetaxel plus Avastin 15 mg/kg. A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled.
The addition of Avastin 7.5 mg/kg to docetaxel resulted in 30% increase in progression-free survival [HR 0.70 (95% CI 0.55, 0.90)] with less than a month difference in median PFS while the addition of Avastin 15 gm/kg to docetaxel resulted in 39% increase in progression-free survival [HR 0.62 (95% CI 0.48, 0.79)] again with less than a month difference in median PFS.
Objective responses were observed in 44% of patients in the placebo arm, 55% in the Avastin 7.5 mg/kg arm (p-value 0.0295) and 63% in the Avastin 15 mg/kg arm (p -value 0.0001).
Mature survival data showed a HR of 1.103 (95% CI 0.84, 1.45) favoring the placebo arm over the 7.5mg/kg Avastin arm. The HR for OS was 1.003 (95% CI 0.76, 1.32) for the 15mg/kg Avastin arm compared to the placebo arm.
Safety data showed an increase of grade 3-5 adverse events, serious adverse events and study drug interruption and dose reduction with the addition of Avastin to docetaxel. More patients in the Avastin -containing arms required interruption/dose reduction of docetaxel due to an adverse event.
The second trial that we will discuss today is the RIBBON 1 trial. RIBBON 1 was a double-blind, randomized, parallel group study conducted in women with metastatic or locally recurrent HER 2- neu negative adenocarcinoma of the breast, who had not received prior chemotherapy for advanced or metastatic cancer.
A total of 1237 patients were randomized (2:1) to receive anthracycline- or taxane-based chemotherapy (n=622) or capecitabine (n=615) in combination with Avastin or placebo. The taxane/anthracycline cohort and capecitabine cohort were analyzed separately with the alpha split equally (1-sided a0.025) for comparisons of PFS within each subgroup.
The addition of Avastin to taxane/anthracycline-based chemotherapy resulted in 36% increase in PFS [HR 0.64 (95% CI 0.52, 0.80)], with an observed 1.2-month difference in median PFS. Objective response rate was higher in the Avastin-containing arm, with an absolute increase of 13.5 % (95% CI 4.6, 22.3%) with the addition of Avastin to anthracycline/taxane-based chemotherapy.
Mature survival analysis of the anthracycle/taxane arm yielded a HR of 1.11 (95% CI 0.86, 1.43) again favoring the placebo arm. Pre-specified subgroup analysis of patients treated in the taxane cohort showed a hazard ratio of 1.25 again favoring the placebo arm. This analysis was performed because of the relevance of the taxane-treated patients to the 2008 approved indication of Avastin plus paclitaxel in the first-line treatment of breast cancer.
The addition of Avastin to capecitabine resulted in 31% increase in PFS [HR 0.69 (95% CI 0.56, 0.84)], with an observed difference of 2.9 months in median PFS. Objective response rate was higher in the Avastin-containing arm, with an absolute increase of 11.8 % (95% CI 3.4, 20.2 %) observed with the addition of Avastin to capecitabine.
A comparison of the mature survival data for the capecitabine cohort showed a HR of 0.88 (95% CI 0.69, 1.13) favoring the Avastin-containing arm.
Overall, the incidence of grade 3-5 AEs and serious AEs were almost twice as high in the Avastin arms compared to placebo arms in both cohorts. In the taxane subgroup, there were more deaths in the Avastin- containing arm than placebo arm (49.8 % versus 43.1 %). The majority of the deaths were attributed to breast cancer.
Adverse events known to be attributed to Avastin were, as expected, increased in the Avastin-containing arms in both cohorts. The most common AEs associated with Avastin were hypertension, bleeding/hemorrhage and febrile neutropenia. The incidence of AEs is not significantly different than currently described in the package insert.
Both the AVADO and RIBBON 1 are well conducted, double-blinded trials. They demonstrated statistically significant improvements in PFS. However, as we have discussed at previous ODAC meetings, there is a difference in the demonstration of statistical significance and the determination of a clinically meaningful finding that must weigh the risks and benefits of the drug.
FDA questions whether the magnitude of the PFS improvement observed in the AVADO and RIBBON 1 confirms the magnitude of PFS improvement and the initial enthusiasm of the findings observed in the E2100 trial. This initial enthusiasm resulted from a 52% increase in progression-free survival (HR 0.48, 95% CI0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS observed when Avastin was added to paclitaxel.
The magnitude of treatment effect is clinically important providing a measure of delaying symptoms from tumor progression and must be weighed against drug toxicity.
In 2010, we now have a more comprehensive understanding of the Avastin’s role in the initial treatment of metastatic breast cancer compared to 2008 when accelerated approval was granted. We will be asking the committee to re-evaluate Avastin’s risk and benefits in this clinical setting.
Genentech submitted two sBLAs requesting labeling expansion for Avastin for the initial treatment of MBC based on the results of the AVADO and RIBBON 1 trials. During your discussion and deliberations, we ask you to focus on the following:
First, consider the results of each trial individually, to determine if the requested new indications for Avastin in first-line metastatic breast cancer should be granted.
Second, based on the totality of findings, discuss if the results of the AVADO and RIBBON 1 trials support the conversion of Avastin in combination with paclitaxel r from accelerated approval to regular approval
Third, if you do not recommend that results of AVADO and RIBBON1 support the conversion of Avastin from accelerated approval to regular approval, should the indication of using Avastin with paclitaxel for the first-line treatment of metastatic breast cancer be removed from the Avastin label?
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