Puma Biotechnology, a development stage biopharmaceutical company, announced the presentation of positive results from the phase II clinical trial of Puma's investigational drug PB272 (neratinib) for the neoadjuvant treatment of breast cancer (I-SPY 2 TRIAL) in an oral presentation at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego, California.

The presentation entitled “Neratinib plus Standard Neoadjuvant Therapy for High-Risk Breast Cancer: Efficacy Results from the I-SPY 2 TRIAL” was presented at the session entitled “Clinical Trials Symposium: Biomarker Driven Clinical Trials.”

The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) is a randomized phase II clinical trial for women with newly diagnosed Stage 2 or higher (tumour size at least 2.5 cm) breast cancer that addresses whether adding investigational drugs to standard chemotherapy in the neoadjuvant setting is better than standard chemotherapy.

The primary endpoint is pathological complete response (pCR) in the breast and the lymph nodes at the time of surgery. The goal of the trial is to match investigational regimens with patient subsets on the basis of molecular characteristics (referred to as biomarker signatures) that benefit from the regimen. The trial enrolled patients who had a high risk of relapse using up-front tumor profiling (including tumor size, hormone receptor status (HR), HER2 status, and the MammaPrint 70-gene signature test).

The I-SPY 2 TRIAL involves an adaptive trial design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard therapy in an equally randomised 300-patient confirmatory trial. Regimens that have a high Bayesian predictive probability of showing superiority in at least one of 10 predefined signatures graduate from the trial. Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. A maximum total of 120 patients can be assigned to each experimental regimen. A regimen can graduate early and at any time after having 60 patients assigned to it.

The neratinib-containing regimen (neratinib plus paclitaxel followed by doxorubicin and cyclophosphamide) graduated from the I-SPY 2 TRIAL based on having a high probability of success in Phase III with a signature of HER2-positive/HR-negative. In this group, treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 55.6 per cent compared to the control arm (standard neoadjuvant chemotherapy: paclitaxel in combination with Herceptin (trastuzumab) followed by doxorubicin and cyclophosphamide) which had an estimated pCR rate of 32.6 per cent.

The Bayesian probability of superiority for the neratinib-containing regimen (compared to standard therapy) is 94.9 per cenrt, which is analogous to a p-value of 0.051. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomised trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab, both followed by doxorubicin/cyclophosphamide, is 79.1 per cent.

There were 115 patients assigned to neratinib in the trial, including 65 patients who were HER2-positive. For the patients in the trial who were HER2-positive (including those who were either hormone receptor-positive or negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 39.4 per cent compared to the control arm, which demonstrated an estimated pCR rate of 22.8 per cent.

The Bayesian probability of superiority for the neratinib-containing regimen is 95.4 per cent, which is analogous to a p-value of 0.046. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab is 72.7 per cent.

Patients in the I-SPY 2 TRIAL were screened using the MammaPrint 70-gene signature test. The median MammaPrint score from the patients in the previous I-SPY 1 TRIAL who fit the eligibility criteria for I-SPY2 was used as a predefined stratification factor for the I-SPY 2 TRIAL. Patients in I-SPY 2 were stratified as either MammaPrint High (below the median from I-SPY 1) or MammaPrint Ultra High (above the median from I-SPY 1). For the 41 neratinib treated patients in the trial who were MammaPrint Ultra High (80.5 per cent of which were HER2 negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 47.5
per cent compared to the control arm, which demonstrated an estimated pCR rate of 29.4 per cent.

The Bayesian probability of superiority for the neratinib-containing regimen is 93.3 per cent, which is analogous to a p-value of 0.067. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel, alone for HER2-negative patients or in combination with trastuzumab for the HER2-positive patients, is 71.8%.

The most frequently observed severe adverse event in the trial was diarrhoea. In the neratinib treated arm of the trial 39 per cent of the patients experienced grade 3/4 diarrhea while 4 per cent of the patients in the control arm experienced grade 3/4 diarrhoea. More specifically, in the first 23 patients in the trial, the rate of grade 3/4 diarrhoea was 43 per cent.

The trial then instituted more aggressive investigator education and therapeutic intervention with antidiarrheal agents and in the next 52 patients the grade 3/4 diarrhea rate dropped to 33 per cent. The trial then instituted the use of low doses of loperamide prophylactically, more specifically, 6 mg on day 1 and then 4 mg for the first two weeks of therapy. In the next 41 patients treated using this low dose prophylaxis the grade 3/4 diarrhoea rate was 34 per cent.

In Puma’s ongoing neratinib trials, the Company is utilising a prophylactic protocol in which a high dose of loperamide, more specifically 16 mg on day 1, then 12 mg for the next two days, then 8 mg for the first two weeks, is given together with neratinib. The ongoing analysis has continued to demonstrate that this high dose loperamide prophylaxis significantly reduces the incidence of grade 3 diarrhea down to less than approximately 5 per cent.

The I-SPY 2 TRIAL is a collaborative effort among academic investigators from approximately 20 major cancer research centers across the country, the US Food and Drug Administration, Quantum Leap Healthcare Collaborative, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium. Major supporters include The Safeway Foundation and the Bill Bowes Foundation.

“We are very pleased with the activity of neratinib in the I-SPY 2 TRIAL and honoured to have been involved with such an innovative trial. This represents the first clinical data on neratinib in the neoadjuvant treatment of breast cancer and suggests that the combination of paclitaxel plus neratinib has potent activity for the treatment of HER2-positive breast cancer and a subset of patients with HER2-negative breast cancer,” said Alan H. Auerbach, chief executive officer and president. “We look forward to advancing PB272 forward for the neoadjuvant treatment of breast cancer and look forward to involvement with the I-SPY 3 TRIAL this year.”