The decision on whether Avastin’s metastatic breast cancer indication should be retained may come down to three words – “magnitude of benefit.”

FDA Commissioner Margaret Hamburg’s interpretation of this phrase as it relates to Avastin’s (bevacizumab) efficacy could prove crucial in her ultimate verdict on the indication’s fate. Differences in the expectations that Genentech and the Center for Drug Evaluation and Research had for confirming efficacy under the accelerated approval program also could factor into Hamburg’s evaluation.

CDER asserts Genentech needed to confirm the magnitude of the progression-free survival benefit seen in the E2100 study, upon which accelerated approval for first-line MBC in combination use with paclitaxel was based. The failure of the AVADO and RIBBON1 studies to confirm the 5.5-month median PFS benefit in the E2100 study warrants withdrawal of the MBC indication, in CDER’s view.

On the other hand, Genentech argues that CDER never established the magnitude of PFS benefit that the two confirmatory studies needed to achieve. Rather than serving as justification for withdrawing the MBC indication, the AVADO and RIBBON1 studies met their PFS endpoints and showed no adverse impact on survival, thus satisfying the standard for full approval, the company contends.

A Failure To Confirm

The magnitude of benefit issue comes up frequently in CDER and Genentech’s respective written summaries of evidence that they intend to present at the June 28-29 hearing on CDER’s proposal to withdraw the MBC indication. The summaries filed on May 13 highlight the importance of the Avastin proceedings to the integrity of the accelerated approval regime (Also see "Accelerated Approval Program’s Future Is On The Line At Avastin Hearing" - Pink Sheet, 23 May, 2011.).

In its argument summary, CDER says Avastin was the first approval of a non-hormonal agent in MBC “in which evidence of a treatment effect on PFS alone was viewed not as a surrogate endpoint, but rather as a clinical benefit because of the magnitude of improvement in PFS.”

E2100 studied Avastin in combination with paclitaxel. The AVADO and RIBBON1 trials studied Avastin in combination with other chemotherapy partners. Improvement in median PFS was 0.9 months in AVADO and 1.2-2.9 months in RIBBON1.

“The required post-approval trials, which were proposed by Genentech and agreed to by CDER, have failed to confirm the magnitude of effect on PFS that was seen in the trial supporting approval,” CDER says.

PFS effect in the confirmatory studies needed to be “of the same or similar magnitude” as the E2100 study, CDER said.

Because the data on Avastin show no improvement in overall survival or quality of life, CDER says, the regulator requires that the PFS effect “must be substantial – of the same or similar magnitude as the 5.5-month improvement shown in the E2100 trial – to constitute the ‘clinical benefit’ required under the accelerated approval regulations.”

CDER’s evidence summary references 35 appendices which include various review documents, regulatory action letters and minutes of meetings between the regulator and Genentech.

Although CDER premised Avastin’s accelerated approval on the significant magnitude of benefit seen in E2100, this phrase does not appear in the regulator’s Feb. 22, 2008, approval letter outlining the post-marketing study requirements that accompanied accelerated approval

The approval letter required Genentech to conduct “adequate and well-controlled studies to further define the degree of clinical benefit to patients.”

The letter was signed by Office of Oncology Drug Products Director Richard Pazdur. Division of Biologic Oncology Products Director Patrician Keegan was not the signatory authority because she did not believe approval was warranted (see related story, Also see "Avastin’s Breast Cancer Approval Followed CDER Rift On Efficacy" - Pink Sheet, 30 May, 2011.).

Subsequent meetings between CDER and Genentech on the AVADO and RIBBON1 studies also do not appear not to have included specific reference to the magnitude of benefit requirement, according to meeting minutes.

The minutes from a March 6, 2009, meeting between Pazdur, Keegan and Genentech representatives reflect clarifying comments by Pazdur following a Type B meeting on Feb. 26, 2009. “FDA confirmed that the basis for conversion to full approval will be demonstrated improvement in progression-free survival and evidence that survival is not impaired,” the minutes state.

No Bright-line Standard On Level Of Benefit

Genentech seizes upon this statement in its written summary to support its argument that CDER did not establish a specific magnitude of PFS benefit that AVADO and RIBBON1 needed to achieve.

“At the time it granted accelerated approval, CDER knew the magnitude of PFS improvement observed in the AVADO study based on a summary of the AVADO data. This summary included the PFS data for the standard Avastin dose of 15 mg/kg, which showed an improvement in median PFS of 0.8 months with an HR of 0.64 (95% CI 0.50, 0.82) (p=0.0003). CDER accepted AVADO as a confirmatory trial for E2100 aware of this result,” Genentech says.

AVADO and RIBBON1 showed statistically significant PFS improvements, thereby confirming Avastin’s activity in first-line MBC with multiple chemotherapy partners, Genentech said. However, the lesser magnitude of benefit seen in the two confirmatory trials suggests that Avastin’s benefit may vary by chemotherapy regimen.

Genentech seeks to maintain Avastin’s accelerated approval while it conducts a new confirmatory trial in combination use with paclitaxel for first-line MBC. The proposed study includes a biomarker component to identify patients most likely to respond.

Genentech noted that CDER has not provided general guidance to industry on the level of benefit that must be established in confirmatory trials. “CDER also has not articulated a clear rationale for its view that a 5.5-month improvement in median PFS is clinically meaningful but lesser improvements are not.”

CDER said it consistently told Genentech that whether a PFS improvement represents a direct clinical benefit depends upon the magnitude of effect and the drug’s risk-benefit profile compared to other therapies.

“CDER does not and cannot commit to a specific magnitude of effect in advance of a clinical trial’s completion because outcomes will vary based on factors such as the toxicity profile of the drug being investigated,” the regulator says.

Disputing Genentech’s assertion that it has shifted its approval standards, CDER said it has not changed its views on the usefulness of PFS as a clinical endpoint for oncology drug approvals.

“CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable.”

By Sue Sutter

Avastin Breast Cancer Dispute Centers On “Magnitude Of Benefit” Questions

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