Genentech's advance summary of evidence and arguments for FDA's upcoming hearing on the agency's proposed withdrawal of the metastatic breast cancer approval for Avastin shows that the company is trying to keep the focus on the additional confirmatory trial it proposes to conduct.

The document, released May 13, provides an overview of the case Genentech will make to support maintaining the accelerated approval of bevacizumab, in combination with paclitaxel, for first-line MBC at the June 28-29 hearing, as requested by the presiding officer, Center for Biologics Evaluation and Research Director Karen Midthun (Also see "ODAC Will Have Bigger Role At Avastin Hearing Than Previously Described" - Pink Sheet, 10 May, 2011.).

Midthun recently released the agenda for the hearing and the issues that are to be discussed. These include whether the AVADO and RIBBON1 trials failed to verify Avastin's clinical benefit in MBC as seen in the pivotal E2100 study, whether the available evidence shows it is safe and effective, and whether FDA should withdraw the approval (Also see "An Avastin Loophole: Hamburg Could Decide To Retain Approval During Confirmatory Trial" - Pink Sheet, 9 May, 2011.).

In its pre-hearing summary of evidence, Genentech notes it has recognized the view of the Center for Drug Evaluation and Research and the Oncologic Drugs Advisory Committee that the AVADO and RIBBON1 trials failed to confirm the benefit and has responded by tailoring its proposal to maintaining accelerated approval for use with paclitaxel "subject to" an additional confirmatory trial.

Thus, the company does not plan to focus on AVADO and RIBBON1, the summary explains. "Instead, Genentech intends to focus on the question of whether accelerated approval should be maintained for Avastin and paclitaxel subject to a further confirmatory study of this combination, even in light of the views of CDER and the ODAC on AVADO and RIBBON1."

"The only open question is whether the magnitude of benefit observed in the E2100 study is reasonably likely to be confirmed in a second study of Avastin with paclitaxel," the company argues.

"Given the meaningful probability that the chemotherapy partner has an impact on the magnitude of benefit, and given that an additional study can resolve this question, accelerated approval should be maintained pending completion of Genentech's further study."

The company also says that continuing the approval while gaining further evidence fits with the overall goals of the accelerated approval program and that the accelerated approval regime allows FDA that regulatory flexibility.

The New Confirmatory Trial

Genentech first proposed conducting a new confirmatory trial in August 2010 after FDA's Oncologic Drugs Advisory Committee voted against continued approval in MBC, and that proposal was a pivotal point in its request for a hearing on FDA's proposed withdrawal.

The company intends to conduct a new trial using a biomarker to select for patients more likely to derive a greater benefit from treatment - an option alluded to in CDER's memo on the proposed withdrawal - a double-blind, randomized, multicenter Phase III trial of Avastin in combination with weekly paclitaxel.

"Based on the company's extensive research, including a new assay sensitive to specific isoforms, plasma concentration of VEGF-A (Avastin's target) has been identified as a potential predictive biomarker in breast, gastric and pancreatic cancers," the summary of evidence states.

An analysis of the AVADO trial, presented as an abstract at the San Antonio Breast Cancer Symposium in December, showed that patients with high levels of VEGF-A had a hazard ratio for progression-free survival analysis of 0.49, compared to 0.87 for patients with low levels of VEGF-A. "The data suggest that patients with high VEGF-A levels may be more likely to derive a substantial benefit from Avastin, and it is important and appropriate to validate this predictive biomarker in a prospective Phase III trial," Genentech argues.

The company met with the agency to discuss the trial on Feb. 22, the preparatory documents for the hearing reveal, the day before the hearing was granted. At that meeting, Genentech reports, CDER stated that "PFS results confirming the magnitude of treatment effect observed in E2100 without a detriment to OS, coupled with the E2100 data, would support Avastin's full approval with paclitaxel."

The company has proceeded with study planning and intends to submit the protocol under a Special Protocol Assessment, the summary states.

Nothing Wrong With E2100

Genentech presents an overview of the E2100 findings that emphasize their statistical rigor and clinical significance, an essential point of agreement to support continuing the accelerated approval based upon those findings while another confirmatory trial is conducted.

In the context of Midthun's posed question on whether Avastin's benefit-risk ratio remains favorable in MBC, the company notes that withdrawal would "necessarily rest on a determination that the findings from the E2100 study are no longer reliable and that Avastin presents unique toxicity concerns in the MBC setting."

"Respectfully, that determination would be contrary to the most reasonable interpretation of the scientific data."

In addition to defending E2100, the summarys show that Genentech will focus on FDA's application of the accelerated approval standard, the external support for Avastin's use in MBC (including that of other regulatory bodies), and the agency's potential regulatory flexibility.

In the end, it's that flexibility that Genentech is really appealing to. "Regulatory flexibility is intended for cases like this," the summary concludes, "where a formulaic application of the withdrawal standard would deprive patients and physicians of the choice intended by the accelerated approval program - and do so in the face of continued findings of benefit, a well-understood safety profile, and a viable option for providing a clearer answer to the remaining scientific questions."

-Mary Jo Laffler (m.laffler@elsevier.com)

Genentech Appeals To FDA's "Regulatory Flexibility"

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