INDIANAPOLIS, Oct. 6, 2017 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced that interim results from the
double-blind, placebo-controlled Phase 3 MONARCH 3 study evaluating
VerzenioTM (abemaciclib), a cyclin-dependent kinase
(CDK)4 & 6 inhibitor, in combination with a nonsteroidal
aromatase inhibitor (NSAI) (anastrozole or letrozole) were
published online in the Journal of Clinical Oncology (JCO).
These data, presented at the European Society for Medical
Oncology (ESMO) 2017 Congress in September, demonstrated
that abemaciclib plus an NSAI resulted in a statistically
significant improvement in progression-free survival (PFS) and
objective response rate (ORR) compared to an NSAI alone in women
with hormone-receptor-positive (HR+), human epidermal growth factor
receptor 2-negative (HER2-) advanced breast cancer.
"The significant results seen in MONARCH 3 confirm the clinical
value of combining abemaciclib with an aromatase inhibitor in
patients with endocrine-sensitive advanced breast cancer, and we
look forward to seeing the final PFS data in the coming months,"
said lead author Matthew P. Goetz,
M.D., professor of oncology and pharmacology at Mayo Clinic and
co-lead investigator of the MONARCH 3 study. "These data further
demonstrate that abemaciclib is an effective treatment in the CDK4
& 6 class. This class represents a new standard of care in the
treatment of advanced breast cancer."
MONARCH 3 met a rigorous threshold for demonstrating efficacy at
the time of pre-planned interim analysis with a 46 percent
reduction in the risk of progression or death in patients receiving
initial therapy for metastatic disease. The median PFS for
abemaciclib in combination with an NSAI was not reached (i.e., the
disease had not progressed significantly), compared to 14.7 months
in the placebo arm (HR: 0.54; 95% CI: 0.41-0.72; P=0.000021). These
results are supported by an improvement in response rate, with a
59.2 percent ORR in patients with measurable disease, including
five patients (1.5%) achieving a complete response. Median duration
of response (DoR) was not reached in the abemaciclib-plus-NSAI arm.
Final PFS results are expected at the end of the year and will be
presented at a scientific congress in the first half of 2018.
"At Lilly, we remain deeply committed to delivering
standard-of-care changing medicines that improve the lives of many
cancer patients," said Levi
Garraway, M.D., Ph.D., senior vice president, global
development and medical affairs, Lilly Oncology. "We now have
evidence from two randomized trials showing that the addition of
Verzenio to an endocrine therapy provides clinical benefit to women
with metastatic breast cancer and we look forward to further
advancing our MONARCH clinical program."
In MONARCH 3, abemaciclib in combination with an NSAI was
generally well tolerated. The most frequent adverse events (AEs) of
any grade in the abemaciclib-plus-NSAI arm were diarrhea,
neutropenia, fatigue, infections, and nausea. Of these, the
reported Grade 3/4 AEs in the abemaciclib-plus-NSAI arm versus the
placebo-plus-NSAI arm were diarrhea (Grade 3: 9.5% vs 1.2%; no
Grade 4 observed), neutropenia (Grade 3: 19.6% vs 0.6%; Grade 4:
1.5% vs 0.6%), fatigue (Grade 3: 1.8% vs 0%; no Grade 4 observed),
infections (Grade 3: 4.0% vs 2.5%; Grade 4: 0.9% vs 0.6%), and
nausea (Grade 3: 0.9% vs 1.2%; no Grade 4 observed).
Severity and frequency of diarrhea generally decreased following
28 days (one month), and was managed with over-the-counter
antidiarrheal medication and dose adjustment. The majority (76.3%)
of patients in the abemaciclib-plus-NSAI arm with an AE of diarrhea
did not require treatment modification (dose interruption,
reduction, or discontinuation), and 2.3 percent of patients
discontinued treatment with abemaciclib due to diarrhea.
The MONARCH 3 study also included exploratory subgroup analyses
that underscored consistency of results (when compared to the
overall intention-to-treat [ITT] results) in patients with certain
challenging disease characteristics. Further studies are needed to
explore these findings.
MONARCH 3 was designed to evaluate the efficacy and safety of
abemaciclib in combination with NSAIs as initial endocrine-based
therapy for postmenopausal women with advanced (locoregionally
recurrent or metastatic) breast cancer who have had no prior
systemic treatment for advanced disease. If neoadjuvant/adjuvant
endocrine therapy was administered, a disease-free interval of more
than 12 months since completion of endocrine therapy was required.
A total of 493 patients were randomized 2:1 to receive 150 mg of
abemaciclib or placebo orally twice a day, without interruption,
given in combination with either 1 mg of anastrozole or 2.5 mg of
letrozole once daily until disease progression or unacceptable
toxicity. The primary endpoint of the study was PFS, with key
secondary endpoints of ORR, DoR, overall survival and
safety.
Notes to Editor
About Advanced Breast Cancer
Breast cancer is the
most frequently diagnosed cancer in women worldwide with nearly 1.7
million new cases diagnosed in 2012.[1] An estimated 252,710 new
cases of invasive breast cancer are expected to be diagnosed in the
U.S. in women in 2017.[2] Advanced breast cancer includes
metastatic breast cancer, cancer that has spread from the breast
tissue to other parts of the body, and locally or regionally
advanced breast cancer, meaning the cancer has grown outside the
organ where it started but has not yet spread to other parts of the
body.[3] Of all early stage breast cancer cases diagnosed in the
U.S., approximately 30 percent will become metastatic and an
estimated six to 10 percent of all new breast cancer cases are
initially diagnosed as being metastatic.[4] Survival is lower
among women with a more advanced stage at diagnosis: 5-year
relative survival is 99 percent for localized disease, 85 percent
for regional disease, and 26 percent for metastatic disease. Other
factors, such as tumor size, also impact 5-year survival
estimates.[5]
About VerzenioTM
(abemaciclib)
Verzenio (abemaciclib) is an
inhibitor of CDK4 and CDK6, which are activated by binding to
D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell
lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the
retinoblastoma protein (Rb), cell cycle progression, and cell
proliferation.
Verzenio disrupts the cell cycle. Preclinically, Verzenio dosed
daily without interruption as a single agent or in combination with
antiestrogens resulted in reduction of tumor size. In vitro,
continuous exposure to Verzenio inhibited Rb phosphorylation and
blocked progression from G1 to S phase of the cell cycle, resulting
in senescence and apoptosis (cell death). Inhibiting CDK4 & 6
in healthy cells can result in side effects, some of which may be
serious. Clinical evidence also suggests that Verzenio crosses the
blood-brain barrier.[6]
INDICATION
Verzenio is indicated:
- in combination with fulvestrant for women with HR+, HER2-
advanced or metastatic breast cancer with disease progression
following endocrine therapy
- as monotherapy for the treatment of adult patients with HR+,
HER2- advanced or metastatic breast cancer with disease progression
following endocrine therapy and prior chemotherapy in the
metastatic setting
IMPORTANT SAFETY INFORMATION
Diarrhea occurred in 86% of patients receiving Verzenio
plus fulvestrant in MONARCH 2 and 90% of patients receiving
Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 13% of
patients receiving Verzenio plus fulvestrant in MONARCH 2 and in
20% of patients receiving Verzenio alone in MONARCH 1. Episodes of
diarrhea have been associated with dehydration and
infection.
In MONARCH 2, diarrhea incidence was greatest during the first
month of Verzenio dosing. The median time to onset of the first
diarrhea event was 6 days, and the median duration of diarrhea for
Grades 2 and 3 were 9 days and 6 days, respectively. Twenty-two
percent of patients with diarrhea required a dose omission and 22%
required a dose reduction. In the MONARCH 1 study, the time to
onset and resolution for diarrhea were similar to those in MONARCH
2.
Instruct patients that at the first sign of loose stools, they
should start antidiarrheal therapy such as loperamide, increase
oral fluids, and notify their healthcare provider for further
instructions and appropriate follow-up. For Grade 3 or 4 diarrhea,
or diarrhea that requires hospitalization, discontinue Verzenio
until toxicity resolves to ≤Grade 1, and then resume Verzenio at
the next lower dose.
Neutropenia occurred in 46% of patients receiving
Verzenio plus fulvestrant in MONARCH 2 and 37% of patients
receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in
neutrophil count (based on laboratory findings) occurred in 32% of
patients receiving Verzenio plus fulvestrant in MONARCH 2 and in
27% of patients receiving Verzenio in MONARCH 1. In MONARCH 2 and
MONARCH 1, the median time to first episode of Grade >3
neutropenia was 29 days, and the median duration of Grade ≥3
neutropenia was 15 days.
Monitor complete blood counts prior to the start of Verzenio
therapy, every 2 weeks for the first 2 months, monthly for the next
2 months, and as clinically indicated. Dose interruption, dose
reduction, or delay in starting treatment cycles is recommended for
patients who develop Grade 3 or 4 neutropenia.
Febrile neutropenia has been reported in 1% of patients exposed
to Verzenio in MONARCH 2 and MONARCH 1. Two deaths due to
neutropenic sepsis were observed in MONARCH 2. Inform patients to
promptly report any episodes of fever to their healthcare
provider.
Grade ≥3 increases in alanine aminotransferase (ALT) (4%
versus 2%) and aspartate aminotransferase (AST) (2% versus
3%) were reported in the Verzenio and placebo arms respectively, in
MONARCH 2.
In MONARCH 2, for patients receiving Verzenio plus fulvestrant
with Grade ≥3 ALT increased, median time to onset was 57 days, and
median time to resolution to Grade <3 was 14 days. For patients
with Grade ≥3 AST increased, median time to onset was 185 days, and
median time to resolution was 13 days.
For assessment of potential hepatotoxicity, monitor liver
function tests (LFTs) prior to the start of Verzenio therapy, every
2 weeks for the first 2 months, monthly for the next 2 months, and
as clinically indicated. Dose interruption, dose reduction, dose
discontinuation, or delay in starting treatment cycles is
recommended for patients who develop persistent or recurrent Grade
2, or Grade 3 or 4, hepatic transaminase elevation.
Venous thromboembolic events were reported in 5% of
patients treated with Verzenio plus fulvestrant in MONARCH 2 as
compared to 0.9% of patients treated with fulvestrant plus placebo.
Venous thromboembolic events included deep vein thrombosis,
pulmonary embolism, cerebral venous sinus thrombosis, subclavian
and axillary vein thrombosis, and inferior vena cava thrombosis.
Across the clinical development program, deaths due to venous
thromboembolism have been reported. Monitor patients for signs and
symptoms of venous thrombosis and pulmonary embolism and treat as
medically appropriate.
Verzenio can cause fetal harm when administered to a
pregnant woman based on findings from animal studies and the
mechanism of action. In animal reproduction studies, administration
of abemaciclib to pregnant rats during the period of organogenesis
caused teratogenicity and decreased fetal weight at maternal
exposures that were similar to the human clinical exposure based on
area under the curve (AUC) at the maximum recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception
during treatment with Verzenio and for at least 3 weeks after the
last dose. There are no data on the presence of Verzenio in
human milk or its effects on the breastfed child or on milk
production. Advise lactating women not to breastfeed during
Verzenio treatment and for at least 3 weeks after the last dose
because of the potential for serious adverse reactions in breastfed
infants. Based on findings in animals, Verzenio may impair
fertility in males of reproductive potential.
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 2 for Verzenio plus
fulvestrant and ≥2% higher than placebo plus
fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs
4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs
25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia
(28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs
10%), headache (20% vs 15%), dysgeusia (18% vs 3%),
thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15%
vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough
(13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%),
peripheral edema (12% vs 7%), creatinine increased (12% vs <1%),
rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs
2%).
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 1 with Verzenio were
diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite
(45%), abdominal pain (39%), neutropenia (37%), vomiting (35%),
infections (31%), anemia (25%), thrombocytopenia (20%), headache
(20%), cough (19%), leukopenia (17%), constipation (17%),
arthralgia (15%), dry mouth (14%), weight decreased (14%),
stomatitis (14%), creatinine increased (13%), alopecia (12%),
dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration
(10%).
The most frequently reported ≥5% Grade 3 or
4 adverse reactions that occurred in the Verzenio arm of
MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs
<1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections
(6% vs 3%).
The most frequently reported ≥5% Grade 3
or 4 adverse reactions from MONARCH 1 with Verzenio were
neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%),
leukopenia (6%), anemia (5%), and nausea (5%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher
than placebo plus fulvestrant were increased serum creatinine
(98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%;
23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%),
anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63%
vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs
0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37%
vs 25%; 4% vs 4%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 1 with Verzenio were increased serum creatinine (98%;
<1%), decreased white blood cells (91%; 28%), decreased
neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte
count (42%; 14%), decreased platelet count (41%; 2%), increased ALT
(31%; 3%), and increased AST (30%; 4%).
Strong CYP3A inhibitors increased the exposure of
abemaciclib plus its active metabolites to a clinically meaningful
extent and may lead to increased toxicity. Avoid concomitant use of
ketoconazole. Ketoconazole is predicted to increase the AUC of
abemaciclib by up to 16-fold. In patients with recommended starting
doses of 200 mg twice daily or 150 mg twice daily, reduce the
Verzenio dose to 100 mg twice daily with concomitant use of other
strong CYP3A inhibitors. In patients who have had a dose reduction
to 100 mg twice daily due to adverse reactions, further reduce the
Verzenio dose to 50 mg twice daily with concomitant use of other
strong CYP3A inhibitors. If a patient taking Verzenio discontinues
a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5
half-lives of the inhibitor) to the dose that was used before
starting the strong inhibitor. Patients should avoid grapefruit
products.
Avoid concomitant use of strong CYP3A inducers and consider
alternative agents. Coadministration of Verzenio with rifampin,
a strong CYP3A inducer, decreased the plasma concentrations of
abemaciclib plus its active metabolites and may lead to reduced
activity.
With severe hepatic impairment (Child-Pugh Class C),
reduce the Verzenio dosing frequency to once daily. The
pharmacokinetics of Verzenio in patients with severe renal
impairment (CLcr <30 mL/min), end stage renal disease, or in
patients on dialysis is unknown. No dosage adjustments are
necessary in patients with mild or moderate hepatic (Child-Pugh A
or B) and/or renal impairment (CLcr ≥30-89 mL/min).
Please see full Prescribing Information for
Verzenio.
AL HCP ISI 02OCT2017
About Lilly Oncology
For more than 50 years, Lilly
has been dedicated to delivering life-changing medicines and
support to people living with cancer and those who care for them.
Lilly is determined to build on this heritage and continue making
life better for all those affected by cancer around the world. To
learn more about Lilly's commitment to people with cancer, please
visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global
healthcare leader that unites caring with discovery to make life
better for people around the world. We were founded more than a
century ago by a man committed to creating high-quality medicines
that meet real needs, and today we remain true to that mission in
all our work. Across the globe, Lilly employees work to discover
and bring life-changing medicines to those who need them, improve
the understanding and management of disease, and give back to
communities through philanthropy and volunteerism. To learn more
about Lilly, please visit us at www.lilly.com and
newsroom.lilly.com/social-channels. (P-LLY)
© Lilly USA, LLC 2017. ALL
RIGHTS RESERVED.
Verzenio™ is a trademark owned by or licensed to
Eli Lilly and Company, its subsidiaries, or affiliates.
Lilly Forward-Looking Statement
This press release contains forward-looking statements (as
that term is defined in the Private Securities Litigation Reform
Act of 1995) about abemaciclib as a potential treatment for
patients with breast cancer and reflects Lilly's current beliefs.
However, as with any pharmaceutical product, there are substantial
risks and uncertainties in the process of development and
commercialization. Among other things, there can be no guarantee
that abemaciclib will receive additional regulatory approvals or be
commercially successful. For further discussion of these and other
risks and uncertainties, see Lilly's most recent Form 10-K and Form
10-Q filings with the United States Securities and Exchange
Commission. Except as required by law, Lilly undertakes no duty to
update forward-looking statements to reflect events after the date
of this release.
___________________________________
[1] World Cancer Research Fund International. Breast
Cancer Statistics.
http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breast-cancer-statistics.
Accessed: September 26, 2017.
[2] American Cancer Society. Cancer Facts & Figures
2017.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf.
Accessed: September 26, 2017.
[3] American Cancer Society. Understanding Advanced
Cancer, Metastatic Cancer and Bone Metastases.
https://www.cancer.org/treatment/understanding-your-diagnosis/advanced-cancer/what-is.html.
Accessed: September 26, 2017.
[4] Metastatic Breast Cancer Network. 13 Facts about
Metastatic Breast Cancer.
http://www.mbcn.org/13-facts-about-metastatic-breast-cancer/.
Accessed: September 26, 2017.
[5] American Cancer Society. Breast Cancer Facts &
Figures 2015-2016.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2015-2016.pdf.
Accessed: September 26, 2017.
[6] Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company;
2017.
Refer
to:
|
Erin Graves;
graves_erin_elissa@lilly.com; 908-202-6354 (media)
|
|
Phil Johnson;
johnson_philip_l@lilly.com; 317-655-6874 (investors)
|
View original
content:http://www.prnewswire.com/news-releases/lilly-monarch-3-study-published-in-journal-of-clinical-oncology-demonstrates-benefit-of-verzenio-abemaciclib-plus-nsai-in-advanced-breast-cancer-300532294.html
SOURCE Eli Lilly and Company