Puma Biotechnology Announces I-SPY 2 Phase II Study of Neratinib Published in The New England Journal of Medicine

LOS ANGELES–(BUSINESS WIRE)–Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company,
announced that the positive results from the I-SPY 2 Phase II clinical
trial of neratinib for the neoadjuvant treatment of breast cancer were
published in the July 7 issue of The New England Journal of
Medicine.
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 (tumor 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 neoadjuvant therapy in an equally randomized
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%
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%. The Bayesian probability of superiority for the
neratinib-containing regimen (compared to standard therapy) is 94.9%,
which is analogous to a one-sided p-value of 0.051. 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, both followed by
doxorubicin/cyclophosphamide, is 79.1%.
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% compared to the control arm, which
demonstrated an estimated pCR rate of 22.8%. The Bayesian probability of
superiority for the neratinib-containing regimen is 95.4%, 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%.
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% of which were HER2 negative), treatment
with the neratinib-containing regimen resulted in an estimated pCR rate
of 47.5% compared to the control arm, which demonstrated an estimated
pCR rate of 29.4%. The Bayesian probability of superiority for the
neratinib-containing regimen is 93.3%, 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
diarrhea. In the neratinib treated arm of the trial 38% of the patients
experienced grade 3/4 diarrhea while 4% of the patients in the control
arm experienced grade 3/4 diarrhea. In several clinical trials
subsequent to I-SPY 2, high dose loperamide significantly reduced the
incidence of grade 3/4 diarrhea.
The I-SPY 2 TRIAL is a collaborative effort among academic investigators
from approximately 20 major cancer research centers across the country,
the U.S. 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.
“I-SPY 2 is an innovative adaptive clinical trial that enabled the
investigators to evaluate several agents in the neoadjuvant setting,”
said Alan H. Auerbach, Chief Executive Officer and President. “We were
very pleased with the activity of neratinib in I-SPY 2 as it 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.”
I-SPY 2 Principal Investigators Dr. Laura Esserman, Director of the
Carol Franc Buck Breast Care Center and Co-Leader of the Breast Oncology
Program at the University of California, San Francisco Helen Diller
Family Comprehensive Cancer Center, and Dr. Donald Berry, Professor of
the Department of Biostatistics at the University of Texas MD Anderson
Cancer Center, both expressed their enthusiasm for moving successful
agents into confirmatory Phase 3 trials. “We are excited for the
opportunity to confirm these promising results in I-SPY 3 in our quest
to get better treatments to those women who stand to benefit most. I SPY
3 represents a much needed approach to the conduct of Phase 3 trials,”
said Laura Esserman.
About Puma Biotechnology
Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on
the development and commercialization of innovative products to enhance
cancer care. The Company in-licenses the global development and
commercialization rights to three drug candidates—PB272 (neratinib
(oral)), PB272 (neratinib (intravenous)) and PB357. Neratinib is a
potent irreversible tyrosine kinase inhibitor that blocks signal
transduction through the epidermal growth factor receptors, HER1, HER2
and HER4. Currently, the Company is primarily focused on the development
of the oral version of neratinib, and its most advanced drug candidates
are directed at the treatment of HER2-positive breast cancer. The
Company believes that neratinib has clinical application in the
treatment of several other cancers as well, including non-small cell
lung cancer and other tumor types that over-express or have a mutation
in HER2.
Further information about Puma Biotechnology can be found at www.pumabiotechnology.com.