Revised pCR Guidance Likely To Include Failed ALTTO Trial, FDA Says

Oncology office director Pazdur says whole data package supporting accelerated approval in neoadjuvant breast cancer of Roche’s Perjeta was far stronger than the data for GSK’s Tykerb, which just failed in ALTTO. FDA is standing by use of pCR as a surrogate endpoint but says only a select group of drugs will qualify.

Revised guidance on the accelerated approval pathway for neoadjuvant breast cancer likely will include an assessment of the failed ALTTO study of GlaxoSmithKline PLC’s Tykerb, but FDA does not plan to alter its course on speeding clearance of new drugs that show a robust effect early in high-risk women.

Described as the “largest-ever” trial in HER2+ breast cancer in the adjuvant (post-operative) setting, the study of more than 8,000 patients found that dual HER2 blockade with Roche’s Herceptin (trastuzumab) and Tykerb (lapatinib) did not improve disease-free survival at four years compared to Herceptin alone (Also see "Failed ALTTO Breast Cancer Trial Casts Doubt On pCR Marker" - Pink Sheet, 2 Jun, 2014.). The result was a surprise because the combination had doubled pathological complete response (pCR) in the 455-patient NeoALTTO neoadjuvant (preoperative) study.

“This pathway has all along been intended for the minority of applications,” FDA medical officer Prowell said.

Presentation of ALTTO data during a plenary session at the American Society of Clinical Oncology annual meeting June 1 cast doubt on the validity of pCR, an emerging surrogate marker that has the potential to dramatically reduce trial size, expense and development time.

Perjeta Tested The Waters

In 2012, FDA created an accelerated approval pathway for neoadjuvant (preoperative) breast cancer that uses pCR, allowing drugs to be cleared early based partly on data from a small neoadjuvant study (Also see "FDA Lays Out Path For Neoadjuvant Approvals In Breast Cancer" - Pink Sheet, 4 Jun, 2012.). Roche inaugurated this pathway in September 2013 with the supplemental approval of its HER2/neu receptor antagonist Perjeta (pertuzumab) in neoadjuvant breast cancer (Also see "Roche’s Master Plan: Perjeta Gains Early Breast Cancer Approval, Late-Stage Kadcyla Data" - Pink Sheet, 7 Oct, 2013.).

The ASCO release prompted discussion at the plenary session and a press briefing about whether Perjeta or any drug should be approved based on early evidence showing a pCR benefit, and the need for FDA to re-evaluate its regulatory policy on neoadjuvant breast cancer drug approvals (see related story, (Also see "After ALTTO: I-SPY Will Hold More Clues About pCR Surrogate Endpoint" - Pink Sheet, 9 Jun, 2014.)).

FDA Office of Hematology and Oncology Products Director Richard Pazdur said the neoadjuvant approval for Perjeta was based on the totality of data in the filing, not just pCR evidence (Also see "Neoadjuvant Surrogate Endpoint Is Tough Sell, But FDA Panel Says Perjeta Worth A Chance" - Pink Sheet, 23 Sep, 2013.). The application included evidence of an “unprecedented effect on overall survival” in metastatic disease, Pazdur said in an interview with “The Pink Sheet.”

The agency will be looking for a similarly impressive data package in other applications requesting neoadjuvant approval, including data showing an impact on pCR bolstered by strong efficacy and safety in another line of therapy, Pazdur said. The agency realizes there is uncertainty with this endpoint, but it is willing to take the risk for certain drugs that appear to be very effective to provide earlier access for high-risk women (Also see "FDA’s Neoadjuvant Breast Cancer Accelerated Approval Pathway Starts To Take Shape" - Pink Sheet, 15 Apr, 2013.).

“The path CR rate is not for all drugs in breast cancer … but really in drugs that really have demonstrated a transformative effect in breast cancer therapy. That’s why we are asking for a package of studies,” Pazdur said.

Only a very select group of drugs will qualify, according to the agency.

“This pathway has all along been intended for the minority of applications,” said Tatiana Prowell, a Johns Hopkins oncologist and medical officer in FDA’s breast cancer group who co-authored the pCR guidance.

Updated FDA guidance on pCR likely will include an analysis contrasting studies of Perjeta and Tykerb.

Guidance on pCR had already been revised prior to the ASCO meeting and an updated version is expected to be released soon. The latest version likely will likely be further revised to include an analysis of data for Tykerb in contrast with Perjeta. Unlike Perjeta, Tykerb has not demonstrated an impressive effect in the metastatic disease setting, Pazdur said.

“These two drugs are dissimilar,” he said.

The new guidance also will include results from an FDA-led meta-analysis of breast cancer trials involving more than 12,000 women, which was published in the Lancet in February. That analysis found a correlation between pCR and outcomes overall, but could not show on the trial level that improving pCR with treatment resulted in better disease-free or overall survival.

Two Models For Gaining Approval

The ALTTO data underscore the uncertainties. However, there were a number of limitations in the trial so the jury is still out on pCR, according to Laura Esserman, co-lead investigator of the public/privately run I-SPY trials, which are using the surrogate marker to predict success in Phase III. This will be the “true test” of pCR, Esserman said.

According to FDA guidance on neoadjuvant trials, it’s possible to get accelerated approval by doing a small trial in the neoadjuvant setting with pCR as a marker and then a different, confirmatory adjuvant trial using an event-free survival endpoint. In the case of the Tykerb trials, the patient populations were significantly different – in line with treatment patterns in neoadjuvant and adjuvant care at the time the trials were started, NeoALTTO tested a higher-risk patient population than ALTTO. However, I-SPY’s plan is to run one neoadjuvant Phase III study assessing pCR and event-free survival in the same patients.

FDA’s updated guidance will discuss both models – one large neoadjuvant study evaluating both pCR and long-term outcomes, or a small neoadjuvant study followed by a confirmatory adjuvant study.

The agency’s preference is a single, large neoadjuvant trial, Prowell said. Among other advantages, this ensures that the confirmatory trial will be completed. Also, this provides more information within a single trial about pCR and long-term outcomes, as opposed to extrapolating the connection from different trials.

“That would definitely be our preference and our advice for most sponsors and most drugs. There may be some circumstances where a two-trial model would still be appropriate, but they are going to be limited,” Prowell said.

Updated guidance also includes detailed standard operating procedures for evaluating pCR, she said.