PUMA BIOTECHNOLOGY, INC. (NASDAQ:PBYI) Files An 8-K Other Events
Item8.01
| Other Events. |
Expanded Access Program for PB272 (Neratinib) for
U.S. Patients with HER2-Positive Breast Cancer or HER2-Mutated
Cancers
On April2, 2017, Puma Biotechnology, Inc. (the Company) announced
that it has initiated an expanded access program (EAP) in the
United States to provide its investigational therapy, PB272
(neratinib), to patients with HER2-positive breast cancer or
HER2-mutated cancers. The program will provide access to
neratinib for the treatment of early stage HER2-positive breast
cancer (extended adjuvant setting), HER2-positive metastatic
breast cancer and HER2-mutated solid tumors. Patients must not be
able to participate in any ongoing neratinib clinical trial to
qualify for the Companys expanded access program.
The U.S. Food and Drug Administration (FDA) permits expanded
access to investigational drugs for treatment use for patients
with serious or immediately life-threatening diseases or
conditions who do not otherwise qualify for participation in a
clinical trial and lack satisfactory therapeutic alternatives.
Caligor Opco LLC, which administers the managed access program
for neratinib, will also manage the U.S. expanded access program
by providing regulatory and logistical support.
Phase II SUMMIT Trial of PB272 for ERBB2 (HER2)
Mutant, HER2 Non-Amplified, Metastatic Cancer
On April2, 2017, the Company announced that results from an
ongoing Phase II clinical trial of neratinib were presented at
the 2017 American Association for Cancer Research Annual Meeting
(the 2017 AACR Annual Meeting). The presentation entitled,
Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global,
multi-histology, open-label, phase 2 basket study, was presented
as a plenary session by David Hyman, M.D., Director of
Developmental Therapeutics at Memorial Sloan Kettering Cancer
Center (MSK), and principal investigator of the trial.
The Phase II SUMMIT basket trial is an open-label, multicenter,
multinational study to evaluate the safety and efficacy of PB272
administered daily to patients who have solid tumors with
activating HER2 or HER3 mutations. All patients received
loperamide (16 mg per day initially) prophylactically for the
first cycle of treatment in order to reduce the neratinib-related
diarrhea.
Included in the presentation were data on 141 patients enrolled
in the neratinib monotherapy arm of the trial, including 124
patients with HER2 mutations and 17 patients with HER3 mutations.
This included patients with 21 unique tumor types, with the most
common being breast, lung, bladder and colorectal cancer. There
were also 30 distinct HER2 and 12 distinct HER3 mutations
observed among these patients, with the most frequent HER2
variants involving S310, L755, A755_G776insYVMA and V777.
In the HER2-mutant cohort, clinical responses were observed in
tumors with S310, L755, V777, P780_Y781insGSP and
A775_G776insYVMA mutations. When stratified by tumor type,
responses were observed in patients with breast, cervical,
biliary, salivary and non-small-cell lung cancers, which led to
cohort expansions in these tumor types. No activity was observed
in the HER3-mutant cohort. A more detailed presentation of the
data is presented in Table 1 below:
Table 1: SUMMIT Trial Efficacy Summary
| HER2mut | HER2mut | HER2mut | HER2mut | HER2mut | HER2mut | HER3mut | ||||||||
| Breast | Bladder | Lung | Colorectal | Biliarytract | Cervical | NOS | ||||||||
| (n=25) | (n=16) | (n=26) | (n=12) | (n=9) | (n=5) | (n=17) | ||||||||
|
ORR at week 8,n (%) |
8 (32.0) | 0 (0.0) | 1 (3.8) | 0 (0.0) | 2 (22.2) | 1 (20.0) | 0 (0.0) | |||||||
|
(95% CI) |
(14.953.5) | (0.020.6) | (0.119.6) | (0.026.5) | (2.860.0) | (0.571.6) | (0.020.6) | |||||||
|
Clinicalbenefitrate,n(%) |
10 (40.0) | 3 (18.8) | 11 (42.3) | 1 (8.3) | 3 (33.3) | 3 (60.0) | 2 (11.8) | |||||||
|
(95% CI) |
(21.161.3) | (4.045.6) | (23.463.1) | (0.238.5) | (7.570.1) | (14.794.7) | (1.638.3) | |||||||
|
Median PFS,months |
3.5 | 1.8 | 5.5 | 1.8 | 2.8 | 20.1 | 1.7 | |||||||
|
(95% CI) |
(1.94.3) | (1.73.5) | (2.710.9) | (1.41.9) | (0.53.7) | (0.5NA) | (1.42.0) | |||||||
The neratinib safety profile observed in the SUMMIT study is
consistent with that observed previously in metastatic patients
with HER2 amplified tumors. With anti-diarrheal prophylaxis and
management, diarrhea was not a treatment-limiting side effect in
SUMMIT. The interim safety results of the study showed that the
most frequently observed adverse event was diarrhea. For the
141patients enrolled in the neratinib monotherapy arm with safety
data available, 31 patients (22%) reported grade 3 diarrhea. The
median duration of grade 3 diarrhea for those patients was 2
days. 4 patients (2.8%) permanently discontinued neratinib due to
diarrhea and 21patients (14.9%) temporarily discontinued
neratinib due to diarrhea and then restarted after the diarrhea
subsided.
Interim Results of Phase Ib/II FB-10 Trial of PB272
in Combination with Trastuzumab Emtansine (T-DM1) in HER2-Positive
Metastatic Breast Cancer
On April2, 2017,
the Company announced that interim results from the Phase Ib/II
FB-10 clinical trial of neratinib given in combination with the
antibody drug conjugate T-DM1 (Kadcyla, ado-trastuzumab
emtansine) were presented at the 2017 AACR Annual Meeting. The
presentation entitled, NSABP FB-10: Phase Ib dose-escalation
study evaluating trastuzumab emtansine (T-DM1) with neratinib in
women with metastatic HER2-positive breast cancer was selected
for an oral presentation.
The trial enrolled
patients with HER2-positive metastatic breast cancer who had
previously been treated with chemotherapy and the combination of
trastuzumab (Herceptin) and pertuzumab (Perjeta). Study treatment
consisted of the standard dose of T-DM1 at 3.6mg/kg administered
intravenously every 3 weeks and neratinib administered orally at
escalating doses of 120, 160, 200 and 240mg per day continuously.
Primary diarrhea prophylaxis with high dose loperamide was
administered.
For the 16
patients who were evaluable for efficacy, the objective response
(CR/PR) rate was 56%. More specifically, the efficacy results
from the trial demonstrated that 3 patients had a complete
response (CR) lasting 17.1 months, 11.9 months and 12 months;
6patients had a partial response (PR); 3 patients had stable
disease (SD); and 4 patients had progressive disease (PD). The
number and types of response per dose cohort are summarized in
the table below:
|
NeratinibDose (mg/day) |
No. of Objective Responses (CR/PR) / No. of Evaluable (CR/PR/SD/PD) |
|
| 5/5 (CR 2, PR 3) | ||
| 2/4 (CR 1, PR 1, PD 2) | ||
| 1/5 (PR 1, SD 2, PD 2) | ||
| 1/2 (PR 1, SD 1) |
The waterfall plot
for the trial, % Change in Size of Target Lesions, is shown in
Figure 1 below:
The safety results
of the study showed that the most frequently observed grade 3
adverse events were diarrhea, nausea, thrombocytopenia and
hypertension. More specifically, for the 21 patients with
available safety assessments, grade 3 diarrhea was reported in 4
patients (19%), grade 3 nausea was reported in 3 patients (14%),
grade 3 thrombocytopenia was reported in 3 patients (14%), and
grade 3 hypertension was reported in 2 patients (10%). There was
1 dose limiting toxicity (DLT) at the 120 mg dose (1 of 6
patients), 3 DLTs at the 200 mg dose (3 of 8) and 2 DLTs at the
240 mg dose (2 of 3). Additional patients are currently being
accrued at the 160 mg dose in order to define the recommended
Phase II dose.
Interim Results of
Phase II CONTROL Trial of PB272 in Extended Adjuvant Treatment of
HER2-Positive Early Stage Breast Cancer
On April4, 2017,
the Company announced that interim results from a Phase II
clinical trial of neratinib were presented at the 2017 AACR
Annual Meeting. The presentation entitled, Effects of adding
budesonide or colestipol to loperamide prophylaxis on
neratinib-associated diarrhea in patients with HER2-positive
early stage breast cancer: the CONTROL trial, was presented as a
poster presentation.
The main adverse
event that has been 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, 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 CONTROL trial is an international,
open-label, Phase II study investigating the use of loperamide
prophylaxis with or without other agents 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. High dose loperamide
prophylaxis was given for the first 2 cycles (56 days) of
treatment. Initially, the loperamide dosing used was 16 mg on day
1, then 12 mg on days 2 and 3 and then 6-8 mg on days 4-56
(original dosing). The protocol was later amended to simplify the
regimen such that patients took 12 mg on days 1-14 and 8 mg on
days 15-56 (modified dosing). The CONTROL trial was also expanded
to include two additional cohorts. One cohort received the
combination of loperamide and budesonide and the other cohort
received the combination of loperamide plus colestipol.
Budesonide is a locally acting corticosteroid that the Company
believes targets the inflammation identified in a preclinical
model of neratinib-induced diarrhea and colestipol is a bile acid
sequestrant that the Company believes targets the bile acid
malabsorption also seen in preclinical models of
neratinib-induced diarrhea.
The interim
analysis of the trial presented in the poster included a total of
137 patients who received neratinib plus loperamide prophylaxis
(28 patients taking the original dosing and 109 patients taking
the modified dosing), 64 patients who received neratinib plus
loperamide prophylaxis for 2 cycles and budesonide for 1 cycle,
and 26 patients who received neratinib plus loperamide
prophylaxis for 1 cycle and colestipol for 1 cycle.
The results of the
trial showed that the incidence of grade 3 diarrhea for the 137
patients who received the loperamide prophylaxis was 30.7%. For
the 137 patients who received the loperamide prophylaxis, the
median number of grade 3 diarrhea episodes per patient was 1 and
the median cumulative duration of grade 3 diarrhea was 3 days.
For the 137 patients who received loperamide prophylaxis, 20.4%
discontinued neratinib due to diarrhea.
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 23.4%. The median number of grade 3 diarrhea
episodes per patient was 1 and the median cumulative duration of
grade 3 diarrhea was 2 days. For the 64 patients who received
loperamide plus budesonide prophylaxis, 9.4% discontinued
neratinib due to diarrhea.
For the 26
patients who received the combination of loperamide plus
colestipol, the results of the trial showed that the incidence of
grade 3 diarrhea was 11.5%. The median number of grade 3 diarrhea
episodes per patient was 2 and the median cumulative duration of
grade 3 diarrhea was 2 days. For the 26 patients who received
loperamide plus colestipol prophylaxis, no patient (0%)
discontinued neratinib due to diarrhea. Further information is
provided in Table 1 below:
Table 1:
Characteristics of Treatment-Emergent Diarrhea
| Study | CONTROL | ExteNET | ||||||||||||||
| Loperamide | Budesonide | Colestipol | ||||||||||||||
|
Antidiarrheal prophylaxis |
(original modified) | loperamide | loperamide | Loperamide prn | ||||||||||||
|
N (at data cut-off) |
||||||||||||||||
|
Diarrhea, % |
||||||||||||||||
|
Any grade |
77.4 | 79.7 | 57.7 | 95.4 | ||||||||||||
|
Grade 1 |
24.1 | 26.6 | 30.8 | 22.9 | ||||||||||||
|
Grade 2 |
22.6 | 29.7 | 15.4 | 32.5 | ||||||||||||
|
Grade 3 |
30.7 | 23.4 | 11.5 | 39.8 | ||||||||||||
|
Grade 4 |
0.1 | |||||||||||||||
|
Median cumulative duration of diarrhea, days |
||||||||||||||||
|
Any grade |
12.0 | 10.0 | 8.0 | 59.0 | ||||||||||||
|
Grade 2 |
4.0 | 3.0 | 2.0 | 10.0 | ||||||||||||
|
Grade 3a |
3.0 | 2.0 | 2.0 | 5.0 | ||||||||||||
|
Median episodes of diarrhea per patient, n |
||||||||||||||||
|
Any grade |
2.0 | 4.0 | 3.0 | 8.0 | ||||||||||||
|
Grade 2 |
2.0 | 2.0 | 2.0 | 3.0 | ||||||||||||
|
Grade 3a |
1.0 | 1.0 | 2.0 | 2.0 | ||||||||||||
|
Median duration of neratinib treatment, months |
||||||||||||||||
|
Median |
10.6 | 5.1 | 1.7 | 11.6 | ||||||||||||
|
Tolerability related to neratinib diarrhea |
||||||||||||||||
|
Neratinib dose hold due to diarrhea, % |
14.6 | 14.1 | 7.7 | 33.9 | ||||||||||||
|
Neratinib dose reductions due to diarrhea, % |
7. 3 | 1.6 | 3.8 | 26.4 | ||||||||||||
|
Neratinib discontinuations due to diarrhea, % |
20.4 | 9.4 | 16.8 | |||||||||||||
|
Hospitalization due to diarrhea, % |
1. 5 | 1.4 | ||||||||||||||
| a |
No grade 4 events in the CONTROL study; one grade 4 event in the ExteNET study. |
In the ExteNET
trial, higher grade (grade 2 and grade 3) diarrhea occurred early
and persisted throughout the duration of the 12-month treatment
period. In the CONTROL trial, in the loperamide prophylaxis,
loperamide plus budesonide prophylaxis and loperamide plus
colestipol prophylaxis arms, the results showed that higher grade
diarrhea (grades 2 and 3) occurred early but did not typically
recur. This is shown in more detail in Figure 1: Treatment
Emergent Diarrhea below:
During the course
of the CONTROL trial there has been an increase in the proportion
of patients previously treated with pertuzumab (mainly in the
neoadjuvant setting). For the 55 patients in the loperamide
prophylaxis cohort who received prior pertuzumab, the grade 3
diarrhea rate was 38.2% (Table 2). For the 82 patients who did
not receive prior pertuzumab, the grade 3 diarrhea rate was
25.6%. For the 39 patients in the budesonide cohort who received
prior pertuzumab, the grade 3 diarrhea rate was 10.3%. For the 25
patients in the budesonide cohort who did not receive prior
pertuzumab, the grade 3 diarrhea rate was 36.0%. This analysis
suggests that prior pertuzumab exposure may have led to a higher
rate of grade 3 diarrhea in the CONTROL trial that was not
effectively managed by loperamide prophylaxis alone but was more
effectively managed by loperamide plus budesonide.
Table 2:
Incidence ofGrade 3 Diarrhea in CONTROL by Prior
Pertuzumab Treatment
| LoperamideCohort | BudesonideCohort | |||||||
| Yes | No | Yes | No | |||||
| (n=55) | (n=82) | (n=39) | (n=25) | |||||
|
Grade 3 Diarrhea |
38.2% | 25.6% | 10.3% | 36.0% |
Forward-Looking
Statements
This Current
Report on Form 8-K contains forward-looking statements, including
statements regarding the Companys the expanded access program for
PB272 (neratinib) for the treatment of early stage HER2-positive
breast cancer (extended adjuvant setting), HER2-positive
metastatic breast cancer and HER2-mutated solid tumors and the
development of the Companys drug candidates. All forward-looking
statements included in this Current Report on Form 8-K involve
risks and uncertainties that could
cause the Companys
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 Companys 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 Companys drug candidate claims, even if approved, the
risk that physicians and patients may not accept or use the
Companys products, the Companys reliance on third parties to
conduct its clinical trials and to formulate and manufacture its
drug candidates, the Companys 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 Companys Annual
Report on Form 10-K for the year ended December31, 2016. 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.
About PUMA BIOTECHNOLOGY, INC. (NASDAQ:PBYI)
Puma Biotechnology, Inc. is a biopharmaceutical company that focuses on the development and commercialization of products for the treatment of cancer. The Company focuses on in-licensing the global development and commercialization rights to over three drug candidates, including PB272 (neratinib (oral)), which the Company is developing for the treatment of patients with human epidermal growth factor receptor type 2 (HER2), positive breast cancer, and patients with non-small cell lung cancer, breast cancer and other solid tumors that have a HER2 mutation; PB272 (neratinib (intravenous)), which the Company is developing for the treatment of patients with advanced cancer, and PB357, which is an orally administered agent. Neratinib is a potent irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the epidermal growth factor receptors (EGFRs), HER1, HER2 and HER4. PUMA BIOTECHNOLOGY, INC. (NASDAQ:PBYI) Recent Trading Information
PUMA BIOTECHNOLOGY, INC. (NASDAQ:PBYI) closed its last trading session up +0.65 at 34.75 with 713,063 shares trading hands.