Neratinib Graduates from I-SPY 2 TRIAL
LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NYSE: PBYI), a development stage
biopharmaceutical company, today 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 today 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 (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 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 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 39% of the patients
experienced grade 3/4 diarrhea while 4% of the patients in the control
arm experienced grade 3/4 diarrhea. More specifically, in the first 23
patients in the trial, the rate of grade 3/4 diarrhea was 43%. 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%. 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
diarrhea rate was 34%. In Puma’s ongoing neratinib trials, the Company
is utilizing 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%.
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.
“We are very pleased with the activity of neratinib in the I-SPY 2 TRIAL
and honored 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.”
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, stated, “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.”
Conference Call and Webcast
The Company will host a conference call to discuss the positive results
of the I-SPY 2 TRIAL at 2:00 p.m. PDT (5:00 p.m. EDT) on April 7, 2014.
The conference call may be accessed by dialing 1-877-709-8150 for
domestic callers and 1-201-689-8354 for international callers. Please
specify to the operator that you would like to join the “Puma
Biotechnology I-SPY 2 Update Call.” The conference call will also be
webcast live and accessible through the Investor Relations section of
Puma’s website at http://www.pumabiotechnology.com/ir_events.html
and will be archived there for 30 days following the call. Please visit
Puma’s website several minutes prior to the start of the broadcast to
ensure adequate time for any software download that may be necessary.
About Puma Biotechnology
Puma Biotechnology, Inc. is a development stage biopharmaceutical
company that acquires and develops innovative products for the treatment
of various forms of cancer. The Company focuses on in-licensing drug
candidates that are undergoing or have already completed initial
clinical testing for the treatment of cancer and then seeks to further
develop those drug candidates for commercial use. The Company is
initially focused on the development of PB272 (oral neratinib), a potent
irreversible tyrosine kinase inhibitor, for the treatment of patients
with HER2-positive metastatic breast cancer and patients with non-small
cell lung cancer, breast cancer and other solid tumors that have a HER2
mutation.
Further information about Puma Biotechnology can be found at www.pumabiotechnology.com.
Forward-Looking Statements:
This press release contains forward-looking statements, including
statements regarding anticipated timing for the commencement and
completion of various clinical trials and the announcement of data
relative to these trials. All forward-looking statements included in
this press release involve risks and uncertainties that could cause the
Company's actual results to differ materially from the anticipated
results and expectations expressed in these forward-looking statements.
These statements are based on current expectations, forecasts and
assumptions, and actual outcomes and results could differ materially
from these statements due to a number of factors, which include, but are
not limited to, the fact that the Company has no product revenue and no
products approved for marketing, the Company’s dependence on PB272,
which is still under development and may never receive regulatory
approval, the challenges associated with conducting and enrolling
clinical trials, the risk that the results of clinical trials may not
support the Company’s drug candidate claims, even if approved, the risk
that physicians and patients may not accept or use the Company’s
products, the Company’s reliance on third parties to conduct its
clinical trials and to formulate and manufacture its drug candidates,
the Company’s dependence on licensed intellectual property, and the
other risk factors disclosed in the periodic reports filed by the
Company with the Securities and Exchange Commission from time to time,
including the Company’s Annual Report on Form 10-K for the year
ended December 31, 2013. Readers are cautioned not to place undue
reliance on these forward-looking statements, which speak only as of the
date hereof. The Company assumes no obligation to update these
forward-looking statements, except as required by law.

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