SAN DIEGO – Puma Biotechnology Inc.says its oral tyrosine kinase inhibitor neratinib will be tested in combination with Roche’s biologic Perjeta in the registrational phase of the I-SPY breast cancer program, which should give neratinib evidence with a partner that is both an emerging standard of care and could have a synergistic effect.

Positive results for neratinib with current standard-of-care treatment, Herceptin and paclitaxel, in HER2-positive, hormone receptor-negative breast cancer in the Phase II I-SPY 2 study were presented at the American Association for Clinical Research meeting on April 7. In an interview at the AACR meeting, I-SPY 2 co-lead investigator Laura Esserman described the data as a “big strong signal” for neratinib. The Phase III design will be finalized in the next two months, she said, and should start by the end of the year. The study will include drugs from multiple sponsors.

In an April 7 investor call, speaking about the “potential” for neratinib to be included in a Phase III I-SPY trial, Puma CEO Alan Auerbach said that the company would like to be ready to start a 300-patient Phase III study by the middle of 2014. According to the current structure, the study will test neratinib with Herceptin (trastuzumab), paclitaxel (Taxol and generics) and Perjeta (pertuzumab)compared with a Perjeta/Herceptin/chemo combination, the exec said.

In the U.S., some might argue that the standard of care now includes Roche’s Perjeta, which became the first drug cleared through FDA’s new neoadjuvant breast cancer accelerated approval pathway in September 2013. Per the label, the drug is indicated for use on top of Herceptin and docetaxel in HER2+ metastatic breast cancer as well as for the early use.

It’s highly likely that there will be a synergistic effect when adding the small molecule neratinib to Perjeta, a monoclonal antibody, and that the mechanisms of action will be complementary, said Esserman, co-director of the breast oncology program at the University of California at San Francisco, a lead I-SPY center.

The brain child of the Foundation of the National Institutes of Health’s public/private Biomarkers Consortium, the I-SPY 2 trial is intended to rapidly test multiple drugs from a variety of sponsors, with the goal of speeding drug development in the early treatment of breast cancer Also see "Biomarkers Consortium Launches Adaptive Trial To Test Targeted Breast Cancer Drugs" - Pink Sheet, 19 March, 2010.. The trial protocol allows investigators to drop or graduate drugs quickly as trial results emerge, and there is a heavy emphasis on biomarkers and targeted treatment. Those that succeed can aim to take advantage of FDA’s new accelerated approval pathway for neoadjuvant breast cancer drugs that demonstrate improvement in pathologic complete response, an emerging endpoint in the field that was used in I-SPY 2 ([A#00120604010]).

As with I-SPY 2, the QuantumLeap Healthcare Collaborative will run the Phase III study. Drug sponsors will pay costs related to their particular candidates.

Graduation Ceremony

Neratinib was tested in 116 high-risk patients and results were analyzed by genetic signatures. The drug showed a high probability of working in patients with the HER2+/hormone receptor-negative signature and had been “graduated” to move on to late-stage testing, researchers said at the AACR meeting. The pCR for this signature was estimated at 55.6% for an arm treated with neratinib, Herceptin and chemotherapy vs. 32.6% for Herceptin/chemo; all patients received follow-up chemo. The trial uses Bayesian statistical analyses, which complicate assessment and are less trusted by investors and FDA, but Puma is confident in the superiority.

For HER2+ cases overall, including patients who were also hormone receptor-positive, the pCR was 39.4% for the neratinib arm vs. 22.8%, a probability of superiority that equates to a p-value of 0.046, according to the company. In this patient population, the probability of success in a Phase III trial is 72.7%, which doesn’t meet I-SPY 2’s requirements for graduation, but which Puma highlighted nonetheless.

Auerbach said that the absolute improvement in pathological complete response for Taxol with neratinib in all HER2+ patients was just slightly less than the absolute benefit in pathologic complete response that was seen when either Perjeta or GlaxoSmithKline PLC’s Tykerb (lapatinib) was added to Herceptin and Taxol in the previously-published NEOSPHERE and NeoALTTO randomized trials.

“Going forward, we would plan to add neratinib to the combination of Taxol plus Herceptin plus Perjeta, which we believe would further increase the pathologic complete response rates,” said Auerbach.

Puma Stock Takes Big Hit

Puma obtained the drug through an October 2011 in-licensing deal from Pfizer Inc., which had itself absorbed the candidate through the acquisition of Wyeth ([A#14111006005]),

Puma stock initially took a big hit after the AACR release. The company stock price declined by $19.47 (18.30%) to $86.94 on April 7.

Investors were confused about the data and some thought that the efficacy looked less impressive for all HER2+ patients, UBS analyst Matthew Roden commented in an April 7 note. Toxicity was also alarming, notably because of diarrhea, which had been a prominent side effect in Wyeth trials ([A#00710350011]).

In the neratinib arm, 39% experienced Grade 3+ diarrhea compared to 4% for control.

Commenting on safety during the investor call, Auerbach said that the company has developed a successful high-dose regimen with loperamide that minimizes the rate of Grade 3+ diarrhea to under 5%. In contrast, in the I-SPY 2 study, investigators used a low-dose regimen of loperamide that Auerbach said is less effective.

Interviews with key opinion leaders suggest that toxicity would have to be watched in combination regimens containing Perjeta, which itself is associated with diarrhea, Leerink Swann analyst Howard Liang said in an April 8 note.

Puma stock was trading down another 7% to $80.86 on April 8. UBS’s Roden advised buying on weakness ahead of the release of other trial data later in 2014.

Life After I-SPY Graduation: Neratinib Likely To Be Tested With Roche’s Perjeta

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