“Not Another Avastin,” FDA Panel Warns Genentech At Perjeta Review

Under questioning from FDA’s Richard Pazdur, VP Sandra Horning says company would be willing to withdraw pertuzumab’s neoadjuvant indication if results from ongoing adjuvant study are “clearly negative”; advisory committee members say they expect sponsor to bow out more gracefully than it did in the fight over bevacizumab’s breast cancer claim.

Genentech Inc.’s hard-fought but unsuccessful battle to retain Avastin’s metastatic breast cancer claim came back to haunt it at the Oncologic Drugs Advisory Committee’s Sept. 12 review of a neoadjuvant indication for Perjeta (pertuzumab).

The company was put on the defensive by FDA Office of Hematology and Oncology Products Director Richard Pazdur, who sought Genentech’s commitment that it would not fight removal of a neoadjuvant breast cancer claim granted under accelerated approval if data from the ongoing APHINITY study in the adjuvant setting failed to confirm pertuzumab’s clinical benefit.

The Perjeta meeting marked the first time that Genentech had come before ODAC with a new drug or new indication since the June 2011 Avastin hearing.

Genentech also received some stern warnings from advisory committee members, who made it clear they did not wish to see a repeat of the fight the sponsor waged in 2011 over Avastin’s (bevacizumab) breast cancer claim after FDA determined that post-approval trials failed to confirm the VEGF-inhibitor’s clinical benefit.

Chairman Mikkael Sekeres, Cleveland Clinic, was among the 13 members of the panel who voted for pertuzumab’s accelerated approval in the novel neoadjuvant indication (see related story, (Also see "Genentech’s Perjeta Passes Neoadjuvant Pathway Test, FDA Panel Says" - Pink Sheet, 16 Sep, 2013.)). However, he had some “words of advice” for Genentech.

“All eyes will be on the confirmatory APHINITY trial and on you to verify this initial signal of efficacy and to confirm the bandwidth of safety we’ve seen so far,” Sekeres said. “If these are not confirmed, we urge you to avoid a repeat performance of Avastin and voluntarily remove this drug from the market.”

Remembering The Saga

The Avastin saga was still fresh in the minds of FDA staff and ODAC members as they discussed whether pertuzumab should be given accelerated approval for neoadjuvant use on the basis of pathological complete response (pCR), an unvalidated surrogate endpoint.

FDA granted bevacizumab accelerated approval for metastatic breast cancer in February 2008 on the basis of a 5.5-month median progression-free survival benefit in the E2100 trial. However, in December 2010 the Center for Drug Evaluation and Research proposed withdrawal of the claim because two confirmatory studies – AVADO and RIBBON1 – failed to verify the magnitude of PFS benefit seen in the E2100 study. CDER’s decision to rescind was in line with a July 2010 ODAC recommendation.

Genentech fought the withdrawal and requested a hearing under FDA’s accelerated approval regulations. At the two-day, first-of-its-kind hearing in June 2011, ODAC played the figurative role of “jury” and voted 6-0 to remove the claim (Also see "Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?" - Pink Sheet, 4 Jul, 2011.).

Three of the six committee members who sat on the Avastin hearing panel also participated in the Perjeta review.

In November 2011, Commissioner Margaret Hamburg issued a memo revoking the claim’s accelerated approval, a decision that Genentech did not contest further (Also see "Avastin Loses Its Breast Cancer Claim; FDA’s Hamburg Opts For Withdrawal Over Restrictions" - Pink Sheet, 21 Nov, 2011.).

Had Hamburg’s decision gone the other way and the breast cancer claim remained on Avastin’s label, it was widely believed the agency’s review divisions would become more reluctant to grant accelerated approval.

Neither Genentech nor the agency came out of the nearly year-long Avastin fight looking very good. The dispute revealed rifts within FDA’s oncology review division about the original 2008 decision to grant accelerated approval in breast cancer (Also see "Avastin Breast Cancer Approval Memo Comes Back To Haunt FDA’s Pazdur" - Pink Sheet, 18 Jul, 2011.). Genentech received a public scolding from ODAC members such as Sekeres, who said the company should have known the AVADO and RIBBON1 results were not enough to confirm the benefit seen in E2100 (Also see "Avastin Debate Could Provide Clarity On Use Of Progression-Free Survival Endpoints" - Pink Sheet, 11 Jul, 2011.).

In addition, the entire proceeding was a resource-draining experience that FDA officials have been eager to avoid repeating (Also see "FDA “Regulatory Flexibility” On Accelerated Approval Must Result In Some Withdrawals" - Pink Sheet, 15 Apr, 2013.). Toward this aim, the oncology review division occasionally asks sponsors to affirm in writing that they will waive their right to a hearing when evaluating whether accelerated approval would be appropriate (Also see "Lessons From Avastin: Accelerated Approval Needs “Easy On, Easy Off” Mechanism, Pazdur Says" - Pink Sheet, 26 Nov, 2012.).

Pinning Down Genentech

The Perjeta meeting marked the first time that Genentech had come before ODAC with a new drug or new indication since the June 2011 Avastin hearing.

Pazdur used the public forum to extract a pledge that the company would not fight to retain Perjeta’s neoadjuvant indication if APHINITY, which would serve as the confirmatory trial under accelerated approval, were negative. The 4,800-patient trial is fully enrolled, and final data are expected in 2016.

Unlike the Phase II NEOSPHERE study in the neoadjuvant population that used pCR as a primary endpoint, APHINITY’s primary endpoint is invasive disease-free survival, with overall survival among the key secondary endpoints. The study’s statistical analysis plan was discussed and agreed upon by FDA and Genentech.

Sandra Horning, senior vice-president and global head of clinical hematology/oncology, said Genentech would be willing to withdraw the indication if the APHINITY results were “clearly negative,” although she left some room for how that could be interpreted (see box).

If APHINITY is negative, “let’s not have a drop-down, dog-rolling-over type of fight as with Avastin,” ODAC’s Steensma said.

Like Sekeres, other ODAC members went on record with their expectations for how Genentech should respond in the event APHINITY fails to confirm clinical benefit.

“I just want to second Dr. Sekeres’ comment that I look forward to the day several years from now that this has improved survival,” committee member Louis Diehl, Duke University, said. “But if we don’t see that day, then I think we all have the courage to stand up and say that it didn’t work, that we did the very best we could today but it didn’t work, and to not have a fight over withdrawing it.”

“If the APHINITY trial comes and looks like a strongly positive signal, I think we’ll all feel good about what we did today,” committee member David Steensma, Harvard University, said. “If it’s negative, I share all the comments, the sentiments that have been made. Perhaps my quote is not quite as newspaper-ready as Mikkael’s, but let’s not have a drop-down, dog-rolling-over type of fight as with Avastin.”

As for Pazdur and Horning, who did battle over Avastin, they had a collegial, lighthearted moment after the Perjeta meeting ended.

“I said it,” Horning was overheard telling Pazdur. “We wanted to hear it,” he replied.

FDA’s Pazdur Vs. Genentech’s Horning

At the Perjeta advisory committee meeting, FDA Office of Hematology and Oncology Products Director Richard Pazdur pressed Sandra Horning, Genentech’s senior vice-president and global head of clinical hematology/oncology, on the company’s plans for the neoadjuvant indication if the Phase III APHINITY study in the adjuvant population were negative. Here is their exchange:

Richard Pazdur: “I think a much more cogent question to ask Genentech at this time, and perhaps Dr. Horning would like to answer it, is if that trial is negative. We only have one adjuvant trial that’s ongoing here. It would take years to launch another adjuvant trial. Are there other adjuvant trials, and what is the corporate philosophy of Genentech if this trial is negative in removing that indication? Dr. Horning?

.

Sandra Horning: Give me all the easy ones. The APHINITY trial, as you have heard, is fully enrolled and that is our main study that we propose as a conversion plan for this application. With regard to other large, ongoing studies, at this time we are not sponsoring other large adjuvant studies. With this application for Perjeta and for future applications, we would of course be speaking with the agency and working in a very collaborative manner all across the spectrum from the standpoint of the original conception of the study, the endpoints, and following right through to the endpoints. So I think it would be a discussion for the future as to the outcome of the APHINITY study.

.

As you can imagine with this FDA draft guidance, we and others have looked at this as an innovation from the FDA and we do applaud the efforts to try to bring promising new agents to patients with high-risk, early breast cancer at an earlier point in time. And we do think that this particular application not only contains strong data, but it is somewhat unique in that we have the mechanism of action that has been shown in multiple studies of dual HER2 blockade, we have the overall survival benefit from the CLEOPATRA study, and we have what we believe is a favorable benefit/risk in our neoadjuvant study.

.

Pazdur: Well, you didn’t answer the question. The question is, and you can just answer it yes or no, if the adjuvant trial is negative and does not demonstrate any difference between the two arms with the addition of pertuzumab to the Herceptin-containing combination, would Genentech voluntarily withdraw this application or this indication?

.

Horning: If the APHINITY study is negative … and of course we’re hopeful that that isn’t going to be the case, and we don’t expect it to be the case …

.

Pazdur: We all are, we all are.

.

Horning: … then we would certainly speak to the agency about withdrawing the neoadjuvant.

.

Pazdur: So you are unwilling to make a commitment then?

.

Horning: I think that when you’re speaking to the result of a trial, quite honestly, negative or positive might be a very simplistic way to look at the overall outcome. I do think that if the trial is clearly negative, that we would be willing to withdraw the indication. I do think that we should leave some room for evaluating the context of the trial, and we know that context is always important and can be very rich in these very large trials, but to answer your question specifically, yes we would be willing to withdraw this if the APHINITY study were negative.”