INDIANAPOLIS, Oct. 10, 2017 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced that its Phase 3 JUNIPER study
evaluating Verzenio™ (abemaciclib), a cyclin-dependent kinase
(CDK)4 and CDK6 inhibitor, as monotherapy in KRAS-mutated, advanced
non-small lung cancer (NSCLC) did not meet its primary endpoint of
overall survival (OS). However, an analysis of the secondary study
endpoints of both progression-free survival (PFS) and overall
response rate (ORR) showed evidence of monotherapy activity in the
abemaciclib arm. In addition, the control arm showed a higher
overall survival rate than expected based on historical data in
this setting. Lilly will submit the data for presentation at a
medical meeting in 2018.
"While the outcome is unfortunate for patients with
KRAS-mutated, advanced lung cancer, we remain encouraged by the
antitumor activity observed with abemaciclib in this form of lung
cancer where few clinical advances have been achieved," said
Levi Garraway, M.D., Ph.D., senior
vice president, global development and medical affairs, Lilly
Oncology.
Dr. Garraway added, "As we analyze secondary endpoints and
explore specific patient subgroups in order to better evaluate the
prospects for abemaciclib in NSCLC, we will continue to work with
the oncology community to inform potential future treatment avenues
for patients with KRAS-mutated advanced lung cancer. Moreover, we
have several studies ongoing of rational combinations that include
abemaciclib in non-small cell lung cancer and other malignancies.
We look forward to seeing the results of these studies."
JUNIPER, a global Phase 3, interventional, open-label study was
designed to evaluate the efficacy and safety of abemaciclib versus
erlotinib in patients with stage IV NSCLC with a detectable KRAS
mutation, who have progressed after platinum-based chemotherapy and
who may have received one additional systemic therapy. A total of
453 patients were randomized to receive 200 mg of abemaciclib
orally twice a day on a continuous dosing schedule, every 12 hours
or 150 mg of erlotinib administered at its approved dose and
schedule until disease progression, death or unacceptable toxicity.
The primary endpoint of the study was OS, with key secondary
endpoints of safety, ORR, and PFS. The adverse events were
generally consistent with previous studies of abemaciclib, with the
most common adverse events being diarrhea, fatigue, decreased
appetite, and nausea.
Notes to Editor
About Verzenio™
(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.1
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 www.lilly.com/newsroom/social-channels.
(P-LLY)
Verzenio ™ is a trademark owned by or
licensed to Eli Lilly and Company, its subsidiaries, or
affiliates.
© Lilly USA, LLC 2017. ALL
RIGHTS RESERVED.
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 the potential of abemaciclib as a treatment for
patients with advanced non-small cell lung 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 future study results will be
consistent with the study findings to date or that abemaciclib will
be commercially successful. For further discussion of these and
other risks and uncertainties that could cause actual results to
differ from Lilly's expectations, please see the company's latest
Forms 10-K and 10-Q filed with the U.S. Securities and Exchange
Commission. Except as required by law, Lilly undertakes no duty to
update forward-looking statements.
1 Verzenio [package insert].
Indianapolis, IN: Eli Lilly and
Company; 2017.
Refer to:
Erin Graves;
graves_erin_elissa@lilly.com; 908-541-2857 (media)
Phil Johnson;
johnson_philip_l@lilly.com; 317-655-6874 (investors)
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