Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical
company, will present updated interim results from a Phase II
clinical trial of Puma’s drug neratinib at the 2019 San Antonio
Breast Cancer Symposium (SABCS) that is currently taking place in
San Antonio, Texas. The presentation entitled, “Effect of
prophylaxis or neratinib dose escalation on neratinib-associated
diarrhea and tolerability in patients with HER2-positive
early-stage breast cancer: Phase II CONTROL trial,” will be
displayed at a poster session on December 13 at 5:00 p.m. CST. A
full copy of the poster is available on the Puma Biotechnology
website.
This press release features multimedia. View
the full release here:
https://www.businesswire.com/news/home/20191213005405/en/
CONTROL Trial Poster at SABCS 2019
(Graphic: Business Wire)
Neratinib was approved by the U.S. Food and Drug Administration
(FDA) in July 2017 for the extended adjuvant treatment of adult
patients with early stage HER2-positive breast cancer following
adjuvant trastuzumab-based therapy and is marketed in the United
States as NERLYNX® (neratinib) tablets.
The main adverse event seen to date in clinical trials of
neratinib is diarrhea and, more specifically, grade 3 diarrhea. In
the Phase III ExteNET trial of neratinib as extended adjuvant
treatment of HER2-positive early stage breast cancer that has
previously been treated with adjuvant Herceptin, prophylactic use
of anti-diarrheal medications was not mandatory. In the trial,
95.4% of the patients experienced all grade diarrhea and 39.8% of
the patients experienced grade 3 or higher diarrhea (there was one
event of grade 4 diarrhea). The median cumulative duration of grade
3 diarrhea in the ExteNET trial was 5 days and 16.8% of patients
who received neratinib in the ExteNET trial discontinued the drug
due to diarrhea.
The CONTROL trial is an international, open-label, Phase II
study investigating the use of antidiarrheal prophylaxis or dose
escalation in the reduction of neratinib-associated diarrhea that
has a primary endpoint of the incidence of grade 3 diarrhea.
In the CONTROL trial, patients with HER2-positive early stage
breast cancer who had completed trastuzumab-based adjuvant therapy
received neratinib daily for a period of one year. The trial
initially tested high dose loperamide prophylaxis given for the
first 2 cycles (56 days) of treatment (12 mg on days 1-14, 8 mg on
days 15-56 and as needed thereafter). The CONTROL trial was then
expanded to include four additional cohorts. One cohort received
the combination of loperamide and budesonide, the second cohort
received the combination of loperamide plus colestipol, the third
cohort received colestipol plus loperamide as needed and the fourth
cohort did not use any antidiarrheal drugs as mandatory prophylaxis
but instead used a dose escalation during the first month of
neratinib treatment. Budesonide is a locally acting corticosteroid
that Puma believes targets the inflammation identified in a
preclinical model of neratinib-induced diarrhea and colestipol is a
bile acid sequestrant that Puma believes targets potential bile
acid malabsorption that could result from such inflammation. The
dose escalation involved treating with neratinib at 120 mg per day
for the first week, 160 mg per week for the second week and 240 mg
per week starting at week 3 and until the end of treatment.
The interim analysis of the CONTROL trial presented in the
poster included a total of 137 patients who received neratinib plus
loperamide prophylaxis, 64 patients who received neratinib plus
loperamide prophylaxis for 2 cycles and budesonide for 1 cycle, 136
patients who received neratinib plus loperamide prophylaxis for 1
cycle and colestipol for 1 cycle, 104 patients who received
colestipol for 1 cycle and loperamide as needed and 60 patients who
received the dose escalation regimen of neratinib.
The results of the trial showed that the incidence of grade 3
diarrhea for the 137 patients who received the loperamide
prophylaxis was 31% and that for the 137 patients in this cohort,
20% discontinued neratinib due to diarrhea. The median cumulative
duration of grade 3 diarrhea was 3 days.
For the 64 patients who received the combination of loperamide
plus budesonide, the results of the trial showed that the incidence
of grade 3 diarrhea was 28% and that for the 64 patients in this
cohort, 11% discontinued neratinib due to diarrhea. The median
cumulative duration of grade 3 diarrhea was 2.5 days.
For the 136 patients who received the combination of loperamide
plus colestipol, the results of the trial showed that the incidence
of grade 3 diarrhea was 21% and that for the 136 patients in this
cohort, 4% discontinued neratinib due to diarrhea. The median
cumulative duration of grade 3 diarrhea was 3.5 days.
For the 104 patients who received colestipol and loperamide as
needed, the results of the trial showed that the incidence of grade
3 diarrhea was 34% and that for the 104 patients in this cohort, 8%
discontinued neratinib due to diarrhea. The median cumulative
duration of grade 3 diarrhea was 3 days.
For the 60 patients who received no antidiarrheal drugs as
mandatory prophylaxis and dose escalation of neratinib in the first
month, the results of the trial showed that the incidence of grade
3 diarrhea was 15% and that for the 60 patients in this cohort, 3%
discontinued neratinib due to diarrhea. The median cumulative
duration of grade 3 diarrhea was 2 days.
Further information is provided in Table 1 below:
Table 1: Incidence of
Treatment-Emergent Diarrhea
Neratinib dose
Budesonide +
Colestipol +
Colestipol +
escalation +
Loperamide
loperamide
loperamide
loperamide prn
loperamide prn
(n=137)
(n=64)
(n=136)
(n=104)
(n=60)
Treatment-emergent diarrhea
incidence, n (%)
No diarrhea
28 (20)
9 (14)
23 (17)
5 (5)
2 (3)
Grade 1
33 (24)
16 (25)
38 (28)
33 (32)
24 (40)
Grade 2
34 (25)
21 (33)
47 (35)
31 (30)
25 (42)
Grade 3
42 (31)
18 (28)
28 (21)
35 (34)
9 (15)
Grade 4
0
0
0
0
0
Diarrhea leading to discontinuation
28 (20.4)
7 (10.9)
5 (3.7)
8 (7.7)
2 (3.3)
Hospitalization (due to diarrhea)
2 (1.5)
0
0
0
0
Discontinuation of study (any cause)
61 (44.5)
13 (20.3)
39 (28.7)
29 (27.9)
12 (20.0)
Note:
Each patient was counted only
once in the highest grade category.
No Grade 4 events reported in the
CONTROL study.
Carlos H. Barcenas, MD, MS, Associate Professor in the
Department of Breast Medical Oncology of The University of Texas MD
Anderson Cancer Center, said, “We are pleased to see the maturation
of the data supporting observations of a reduction in incidence,
severity and duration of neratinib-associated diarrhea with
loperamide prophylaxis, loperamide plus budesonide prophylaxis or
the loperamide plus colestipol prophylaxis. Along with the
continued reduction in the incidence and severity of grade 3
diarrhea with neratinib, diarrhea appears to be early onset, acute,
self-limiting and manageable. Not only does the addition of
budesonide or colestipol to loperamide prophylaxis appear to
greatly improve the tolerability of neratinib, the dose escalation
regimen appears as another promising option since there is no
mandatory prophylaxis.”
Alan H. Auerbach, Chief Executive Officer and President of Puma
Biotechnology, said, “We are pleased to note that the
dose-escalation cohort of our CONTROL trial continues to show a
marked improvement in the incidence of grade 3 diarrhea and related
discontinuation of therapy. We remain committed to improving the
tolerability of neratinib in early stage breast cancer
patients.”
About HER2-Positive Breast Cancer
Approximately 20% to 25% of breast cancer tumors over-express
the HER2 protein. HER2-positive breast cancer is often more
aggressive than other types of breast cancer, increasing the risk
of disease progression and death. Although research has shown that
trastuzumab can reduce the risk of early stage HER2-positive breast
cancer returning after surgery, up to 25% of patients treated with
trastuzumab experience recurrence.
IMPORTANT SAFETY INFORMATION
NERLYNX® (neratinib) tablets, for oral use
INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor
indicated for the extended adjuvant treatment of adult patients
with early-stage HER2 overexpressed/amplified breast cancer, to
follow adjuvant trastuzumab-based therapy.
CONTRAINDICATIONS: None
WARNINGS AND PRECAUTIONS:
- Diarrhea: Aggressively manage diarrhea occurring despite
recommended prophylaxis with additional antidiarrheals, fluids, and
electrolytes as clinically indicated. Withhold NERLYNX in patients
experiencing severe and/or persistent diarrhea. Permanently
discontinue NERLYNX in patients experiencing Grade 4 diarrhea or
Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
- Hepatotoxicity: Monitor liver function tests monthly for
the first 3 months of treatment, then every 3 months while on
treatment and as clinically indicated. Withhold NERLYNX in patients
experiencing Grade 3 liver abnormalities and permanently
discontinue NERLYNX in patients experiencing Grade 4 liver
abnormalities.
- Embryo-Fetal Toxicity: NERLYNX can cause fetal harm.
Advise patients of potential risk to a fetus and to use effective
contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥
5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash,
stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or
ALT increase, nail disorder, dry skin, abdominal distention, weight
decreased and urinary tract infection.
To report SUSPECTED ADVERSE REACTIONS, contact Puma
Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and
www.NERLYNX.com or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
DRUG INTERACTIONS:
- Gastric acid reducing agents: Avoid concomitant use with proton
pump inhibitors. When patients require gastric acid reducing
agents, use an H2-receptor antagonist or antacid. Separate NERLYNX
by at least 3 hours with antacids. Separate NERLYNX by at least 2
hours before or 10 hours after H2-receptor antagonists.
- Strong or moderate CYP3A4 inhibitors: Avoid concomitant
use.
- Strong or moderate CYP3A4 inducers: Avoid concomitant use.
- P-glycoprotein (P-gp) substrates: Monitor for adverse reactions
of narrow therapeutic agents that are P-gp substrates when used
concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:
- Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety
information.
The recommended dose of NERLYNX is 240 mg (six 40 mg tablets)
given orally once daily with food, continuously for one year.
Antidiarrheal prophylaxis should be initiated with the first dose
of NERLYNX and continued during the first 2 months (56 days) of
treatment and as needed thereafter.
To help ensure patients have access to NERLYNX, Puma has
implemented the Puma Patient Lynx support program to assist
patients and healthcare providers with reimbursement support and
referrals to resources that can help with financial assistance.
More information on the Puma Patient Lynx program can be found at
www.NERLYNX.com or 1-855-816-5421.
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. Puma in-licenses the global
development and commercialization rights to PB272 (neratinib,
oral), PB272 (neratinib, intravenous) and PB357. Neratinib, oral
was approved by the U.S. Food and Drug Administration in July 2017
for the extended adjuvant treatment of adult patients with early
stage HER2-overexpressed/amplified breast cancer, following
adjuvant trastuzumab-based therapy, and is marketed in the United
States as NERLYNX® (neratinib) tablets. NERLYNX was granted
marketing authorization by the European Commission in August 2018
for the extended adjuvant treatment of adult patients with early
stage hormone receptor-positive HER2-overexpressed/amplified breast
cancer and who are less than one year from completion of prior
adjuvant trastuzumab-based therapy. NERLYNX is a registered
trademark of Puma Biotechnology, Inc.
Further information about Puma Biotechnology can be found at
www.pumabiotechnology.com.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20191213005405/en/
Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc.,
+1 424 248 6500 info@pumabiotechnology.com
ir@pumabiotechnology.com
David Schull or Maggie Beller, Russo Partners, +1-212-845-4200
david.schull@russopartnersllc.com
maggie.beller@russopartnersllc.com
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