I-SPY a controversy over Puma's positive PhII test of neratinib

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When Puma Biotechnology ($PBYI) set out last summer to assess neratinib for metastatic HER2-positive breast cancer in a closely watched, Phase III study that would go head-to-head with Tykerb, investigators said they would stick with the traditional goal posts for experimental cancer drugs: establishing progression-free and overall survival rates, with a plan to rush any positive PFS data to regulators in search of an accelerated approval. And on Wednesday evening the company issued a press release outlining top-line results from an adaptive Phase II trial, asserting that investigators were able to nail down clear evidence of its chances of success in Phase III, sending shares soaring.

Only this study was anything but traditional.

At a point where most investigators would be looking for evidence of PFS over a relatively short time frame to prove that their drug was active and having an impact on cancer that could be further explored in a larger and longer Phase III, Puma switched to a Bayesian statistical model in its I-SPY 2 study to predict the likelihood of late-stage success. And the subsequent brouhaha on Twitter indicates that this approach could make the industry pause before the Bayesian predictive formula is widely adopted in the biotech world.

Here's what Puma reported: Looking for a pathological complete response in the breast and lymph nodes of 116 advanced, very sick patients (65 of whom were HER2 positive), the investigators said they found the positive data they were looking for (full data is reserved for an upcoming conference, which is standard in the field). Comparing a cocktail of cancer drugs with neratinib versus the same cocktail with Herceptin, the investigators concluded that there was a 78.1% chance of establishing superiority over Herceptin in a Phase III study involving 300 patients who were HER2-positive/HR-negative. Just looking at the HER2-positive patients, the odds were 72.5%.

So neratinib vs. Herceptin was cleared for the I-SPY 3 study. Dr. Laura Esserman at UC San Francisco is the principal investigator for the I-SPY adaptive studies, which are designed to assess a drug's potential using shorter, more efficient studies that require fewer patients. And in this case Puma is using I-SPY to establish which subsets of cancer patients, defined by specific biomarkers, are likely to respond most positively to their drug.

One of the reasons why Puma is closely watched is that its executive crew has been here before. Puma CEO Alan Auerbach sold his other biotech cat--Cougar Biotechnology, which developed Zytiga--to Johnson & Johnson ($JNJ) in a billion-dollar deal. And he's back in the same development zone he was in when he did the highly successful Cougar deal. That has investors watching every twist and turn the company makes--whether they understand it or not.

The conversation among analysts and investors on Twitter has been raucous at times, featuring a full array of critiques and compliments about the numbers of patients involved and the general accuracy of Bayesian analysis--a new topic for longtime observers. But the company counts it as a clear success. And at last two prominent analysts endorsed the outcome, helping to spur Puma shares up by 25% this morning.

Win or lose, Puma's pioneering experience in I-SPY will go a long way to either establishing a new model for development--or not.

"We are very pleased to have neratinib graduate from the I-SPY 2 trial and honored to have been involved with such an innovative trial," said Auerbach. "This represents the first clinical data on neratinib in the neoadjuvant treatment of HER2-positive breast cancer and suggests that the combination of paclitaxel plus neratinib has potent activity for the treatment of HER2-positive breast cancer. We look forward to advancing PB272 forward for the neoadjuvant treatment of HER2-positive breast cancer and look forward to potential future involvement with the I-SPY 3 trial."

- here's the release

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