|[April 06, 2014]
Pfizer's Novel CDK 4/6 Inhibitor Palbociclib plus Letrozole Significantly Prolonged Progression-Free Survival in Patients with Advanced Breast Cancer
NEW YORK --(Business Wire)--
Pfizer Inc. today announced detailed results from the PALOMA-1 study, a
randomized Phase 2 study of palbociclib (PD-0332991) in combination with
letrozole. PALOMA-1 achieved its primary endpoint by significantly
prolonging progression-free survival (PFS) compared with letrozole alone
in post-menopausal women with estrogen receptor positive (ER+), human
epidermal growth factor receptor 2 negative (HER2-) locally advanced or
metastatic breast cancer. For women treated with the combination of
palbociclib plus letrozole, the median PFS was 20.2 months, a
statistically significant improvement compared to the 10.2 months of PFS
in women who received letrozole alone (HR=0.488 [95% CI: 0.319, 0.748];
p=0.0004). These data will be presented today by Dr. Richard S. Finn,
associate professor of medicine at University of California, Los Angeles
(UCLA) at the American Association of Cancer Research (AACR) Annual
Meeting 2014 in San Diego (Abstract #CT101).
"These data demonstrate the potential of palbociclib to be a major
advance in the treatment of women with this type of advanced breast
cancer," said Dr. Mace Rothenberg, senior vice president of Clinical
Development and Medical Affairs and chief medical officer for Pfizer
Oncology. "We are proud to be at the forefront of research and
development with respect to this promising new class of investigational
anticancer agents and have initiated a broad clinical development
program for palbociclib that includes breast and non-breast cancers."
Final results for the secondary efficacy endpoints of duration of
treatment and clinical benefit rate demonstrated superiority in the
palbociclib plus letrozole arm compared to the letrozole-only arm. Per
the PALOMA-1 trial protocol, an initial assessment of overall survival
(OS), a secondary endpoint, was also performed. Based on the events at
the time of the assessment, a median OS of 37.5 months was observed in
the combination arm versus 33.3 months for those who received letrozole
alone, a difference of 4.2 months (HR = 0.813, 95% CI: 0.492, 1.345).
This OS observation at the time of final PFS analysis was not
statistically significant. A follow-up OS analysis will be conducted
following the accrual of additional events.
The combination of palbociclib and letrozole was generally
well-tolerated and the safety profile of the combination was consistent
with previously reported data. The most common adverse events in the
palbociclib plus letrozole arm were neutropenia (a decrease of the
neutrophil count), leukopenia (a decrease in the total white blood cell
count), fatigue and anemia. The neutropenia observed with the
combination in this study was non-cumulative and clinically manageable.
No cases of febrile neutropenia were reported in either arm of the
study. Neutropenia is an on-target, anti-proliferative side effect of
palbociclib and signifies inhibition of CDK4 and its effect on bone
Palbociclib received Breakthrough Therapy designation from the United
States Food and Drug Administration (FDA) in April 2013, for the initial
treatment of women with advanced or metastatic ER+, HER2- breast cancer.
This designation was based on interim data from the PALOMA-1 trial.
Pfizer continues to work with the FDA and other regulatory authorities
to define the appropriate regulatory path forward for palbociclib.
Pfizer invites investors and the general public to view and listen to a
webcast of a presentation by Pfizer's Oncology leadership today at 1:30
p.m. Pacific Daylight Time, in connection with the presentation of the
final results of PALOMA-1. To view and listen to the webcast, visit our
website at www.pfizer.com
and click on the "Review of Palbociclib Phase 2 PALOMA-1 Results
at AACR Annual Meeting 2014" webcast link in the For Investors section
located on the lower right-hand corner of that page.
PALOMA-1 (also known as Study 1003 and TRIO-18) is a Phase 2 trial
designed to assess PFS in post-menopausal women with ER+, HER2- advanced
breast cancer receiving palbociclib (125 mg once daily for three out of
four weeks in repeated cycles) in combination with letrozole versus
letrozole alone (2.5 mg once daly on a continuous regimen). This trial
consisted of two parts. Part 1 enrolled 66 patients with ER+, HER2-
advanced breast cancer. Part 2 enrolled 99 additional patients whose
tumors were selected for presence of biomarkers: cyclin D1 amplification
and/or p16 loss. Final results from PALOMA-1 showed that statistically
significant improvement in PFS was achieved for the study arm
(palbociclib + letrozole) in both Parts 1 and 2. PFS is comprised of
time from randomization to time of disease progression or death from any
PALOMA-1 is conducted in collaboration with the Jonsson Cancer Center's
Revlon/UCLA Women's Cancer Research Program, led by Dr. Dennis Slamon.
PALOMA-1 is a multi-center trial with 101 global sites participating.
Palbociclib Development Program in ER+, HER2- Breast Cancer
Pfizer has worked closely with investigators and international breast
cancer experts to establish a robust development program for palbociclib
in ER+, HER2- breast cancer across stages and treatment settings.
Pfizer has initiated two Phase 3 studies of palbociclib in
advanced/metastatic breast cancer. PALOMA-2 (also known as Study 1008)
is a randomized (2:1), multi-center, double blind Phase 3 study that
evaluates palbociclib in combination with letrozole versus letrozole
plus placebo as a first-line treatment for post-menopausal patients with
ER+, HER2- advanced breast cancer. PALOMA-3 (also known as Study 1023)
is a randomized (2:1), multi-center, double blind Phase 3 study that
evaluates palbociclib in combination with fulvestrant versus fulvestrant
plus placebo in women with hormone receptor-positive (HR+), HER2-
metastatic breast cancer whose disease has progressed after prior
Additional, investigator-led studies of palbociclib in
advanced/metastatic breast cancer and in early breast cancer are open
and enrolling patients, including the PEARL and PENELOPE-B studies.
PEARL, sponsored by Grupo Español de Investigación en Cáncer de Mama
(GEICAM, Spanish Breast Cancer Research Group), with participation from
the Central European Cooperative Oncology Group (CECOG), is a randomized
(1:1), multi-center, open-label Phase 3 study evaluating palbociclib in
combination with exemestane versus capecitabine in post-menopausal women
with ER+, HER2- metastatic breast cancer whose disease was refractory to
previous non-steroidal aromatase inhibitors (letrozole or anastrozole).
PENELOPE-B is a randomized (1:1), double blind, placebo-controlled Phase
3 study comparing palbociclib plus standard endocrine therapy to placebo
plus standard endocrine therapy in patients with HR+, HER2-normal (also
known as HER2-) early-stage breast cancer with certain features that
suggest an increased risk for recurrence after completing pre-operative
chemotherapy followed by surgery. This international study is sponsored
by the German Breast Group (GBG).
For more information on these and other ongoing clinical trials of
palbociclib in breast cancer and other tumor types, please visit www.clinicaltrials.gov.
Palbociclib is an investigational oral targeted agent that selectively
inhibits cyclin-dependent kinases (CDKs) 4 and 6 to regain cell cycle
control and block tumor cell proliferation.1
Loss of cell cycle control is a hallmark of cancer and CDK 4/6 are
overactivated in numerous cancers, leading to loss of proliferative
control.2,3 CDK 4/6 are key regulators of the cell cycle that
trigger cellular progression from growth phase (G1) into phases
associated with DNA replication (S).4,5 CDK 4/6, whose
increased activity is frequent in estrogen receptor-positive (ER+)
breast cancer (BC), are key downstream targets of ER signaling in ER+ BC.6,7
Preclinical data suggest that dual inhibition of CDK 4/6 and ER
signaling is synergistic and has been shown to stop growth of ER+ BC
cell lines in the G1 phase.
Palbociclib is not approved for any indication in any markets.
About Pfizer Oncology
Pfizer Oncology is committed to the discovery, investigation and
development of innovative treatment options to improve the outlook for
cancer patients worldwide. Our strong pipeline of biologics and small
molecules, one of the most robust in the industry, is studied with
precise focus on identifying and translating the best scientific
breakthroughs into clinical application for patients across a wide range
of cancers. By working collaboratively with academic institutions,
individual researchers, cooperative research groups, governments, and
licensing partners, Pfizer Oncology strives to cure or control cancer
with breakthrough medicines, to deliver the right drug for each patient
at the right time. For more information, please visit www.Pfizer.com.
DISCLOSURE NOTICE: The information contained in this release is as of
April 6, 2014. Pfizer assumes no obligation to update forward-looking
statements contained in this release as the result of new information or
future events or developments.
This release contains forward-looking information that involves
substantial risks and uncertainties about palbociclib, an
investigational therapy, including with regard to potential indications.
Such risks and uncertainties include, among other things, the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical trial commencement and completion
dates and regulatory submission dates as well as the possibility
unfavorable clinical trial results, including unfavorable new clinical
data and additional analyses of existing clinical data; whether
PALOMA-2 will demonstrate a statistically significant improvement in
progression-free survival; whether regulatory authorities will be
satisfied with the design of and results from our clinical studies;
whether and when drug applications may be filed in any jurisdictions for
any potential indications for palbociclib; whether and when any such
applications may be approved by regulatory authorities, as well as their
decisions regarding labeling and other matters that could affect the
availability or commercial potential of any such indications; and
A further description of risks and uncertainties can be found in
Pfizer's Annual Report on Form 10-K for the fiscal year ended December
31, 2013 and in its subsequent reports on Form 10-Q and Form 8-K.
Clinicaltrials.gov. Study of Letrozole with or without PD 0332991 for
the first-line treatment of hormone-receptor positive advanced breast
cancer. Available here: http://www.clinicaltrials.gov/ct2/show/NCT00721409?term=PD+0332991&rank=10.
Accessed April 6, 2014.
2 Shapiro GI. Cyclin-dependent
kinase pathways as targets for cancer treatment. J Clin Oncol.
3 Weinberg RA. The Biology of
Cancer. New York, NY. Garland Science; 2013.
4 Hirama T
and H. Phillip Koeffler. Role of the Cyclin-Dependent Kinase Inhibitors
in the Development of Cancer. Blood. 1995; 86: 841-854.
Fry D et al. Specific Inhibition of cyclin-dependent kinase 4/6 by PD
0332991 and associated antitumor activity in human tumor xenografts. Molecular
Cancer Therapeutics. 2004; 3: 1427-1437.
6 Finn RS
et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor,
preferentially inhibits proliferation of luminal estrogen
receptor-positive human breast cancer cell lines in vitro. Breast
Cancer Res. 2009;11(5):R77.
7 Lamb R, Lehn S,
Rogerson L, Clarke RB, Landberg G. Cell cycle regulators cyclin D1 and
CDK4/6 have estrogen receptor-dependent divergent functions in breast
cancer migration and stem cell-like activity. Cell Cycle.
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