Jefferson: Despite advances in managing and curing some forms of breast cancer, women whose disease becomes metastatic have fewer effective options. A new phase 3 study in some of the most difficult-to-treat patients, women with endocrine-resistant disease, showed that the newly approved drug, palbociclib, more than doubled the time to cancer recurrence for women with hormone-receptor (HR+) positive metastatic breast cancer. The results will be presented at the 2015 annual American Society of Clinical Oncology (ASCO, abstract LBA-502) and published in the New England Journal of Medicine.
“These are women with advanced metastatic cancer whose disease was
kept in check without the use of toxic and life-disrupting
chemotherapy,” says Dr. Massimo Cristofanilli, M.D., Director of the
Breast Care Center at Thomas Jefferson University
and senior author of the study. “This is a major advance for this
population of women for which we had very few active options and are
often treated with chemotherapy alone.”
The study, called the PALOMA-3, enrolled 521 pre-/peri- and
postmenopausal patients with hormone receptor positive and human
epidermal growth factor receptor-negative (HR+/HER2-) advanced disease.
These women had typically already relapsed on hormone therapy and were
not candidates for the HER2-blocking therapy herceptin. The patients
were randomized to treatment and control arms at a 2:1 ratio (with 345
treated and 172 receiving placebo). The treatment arm received
palbociclib together with standard of care for this population,
fulvestrant, a drug that blocks the hormone receptor via a different
mechanism than first-line therapies. The placebo arm received
fulvestrant plus placebo.
The study experienced very rapid enrollment and at the preplanned
independent data and safety monitoring review panel, the study was
stopped early only 10 months after the study commenced because it met
the primary endpoint of improving progression-free survival (time to
cancer relapse). Patients taking palbociclib plus fulvestrant showed a
median progression-free survival of 9.2 months compared to 3.8 months on
fulvestrant plus placebo. Progression or recurrence of cancer occurred
in only 25 percent of palbociclib plus fulvestrant treated patients
versus 50 percent of patients treated with fulvestrant alone.
Palbociclib was approved by the Food and Drug Administration (FDA) on
February 3rd, 2015, based on data from the PALOMA-1, an earlier phase 2
clinical trial in postmenopausal women with newly-diagnosed estrogen
receptor (ER+)/HER2- breast cancer that had not received any treatment
for their advanced disease. PALOMA-1 showed that palbociclib in
combination with the estrogen-production blocker, letrozole, doubled the
time it took for metastatic cancer to recur from a median of 10 months
with letrozole plus placebo, to 20 months for palbociclib plus
letrozole. The drug was approved by the FDA as a combination first-line
therapy for postmenopausal women with ER+/HER2- breast cancer, as
initial endocrine-based treatment for their metastatic disease.
The current PALOMA-3 study demonstrates benefit in a population of
women with a later stage of metastatic breast cancer. For example, women
whose cancer was no longer controlled by letrozole or other aromatase
inhibitors, those who had already begun to receive chemotherapy, and
premenopausal patients with metastatic disease.
“Part of what was exciting about the design of this clinical trial is
that we decided early on to accept women from a younger and generally
sicker population than is typically enrolled in clinical trials,” says
Dr. Cristofanilli, who is also a researcher at the Sidney Kimmel Cancer
Center at Thomas Jefferson University. “The PALOMA-3 study showed that
palbociclib extends the time to progression of disease while maintaining
very good quality of life.”
The most commonly reported side effects were a decrease in certain
populations of immune cells, conditions called neutropenia and
leukopenia, an expected effect that indicates the drug is working. The
rates of nausea and fatigue were low and overall slightly elevated over
placebo group, but the increase was not statistically significant. The
drug was better tolerated than other biological therapies used in this
setting. Furthermore, there was a significant difference in quality of
life as measured by the rate of clinical deterioration of symptomatic
disease in patients treated with the investigational combination.
Typically the first-line therapy for ER+ positive patients is to
administer hormone therapy, which blocks cellular growth and
reproduction signals that are triggered by the hormone estrogen and the
estrogen receptor. However, many ER+ breast cancers begin to take
advantage of alternative growth pathways. Palbociclib blocks a major
alternate route, called the CDK4/6 growth signal, by inhibiting cancer
cell proliferation and cellular division.
“Although palbociclib has yet to be approved for this population of
women, this study is likely to be practice changing,” says Dr.
Cristofanilli, a practicing oncologist. “I don’t envision a situation
where single-agent endocrine therapy would be appropriate any longer for
ER+/Her2- metastatic breast cancer patients.”
“Pfizer extends our deepest thanks to the investigators of the
PALOMA-3 study for their efforts in leading a successful trial, and most
importantly, the more than 500 women for their participation,” said Dr.
Mace Rothenberg, senior vice president of Clinical Development and
Medical Affairs and chief medical officer for Pfizer Oncology. “Patients
with HR+, HER2- metastatic breast cancer whose disease have progressed
after endocrine therapy have significant unmet needs, and we’re pleased
with the results of this study that demonstrate the potential for
palbociclib as an important treatment option for this patient
The study was sponsored by Pfizer. Dr. Cristofanilli did not receive
any honoraria or individual research support from Pfizer. The authors
have no other conflicts to report.