INDIANAPOLIS, Sept. 20, 2020 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced Verzenio®
(abemaciclib) in combination with standard adjuvant endocrine
therapy (ET) significantly decreased the risk of breast cancer
recurrence by 25 percent compared to standard adjuvant ET alone for
people with hormone receptor-positive (HR+), human epidermal growth
factor receptor 2-negative (HER2-) high risk early breast cancer
(HR: 0.747; 95% CI: 0.598, 0.932; p = 0.0096). This statistically
significant benefit was consistent across all pre-specified
subgroups and corresponds to a 3.5 percent difference between arms
(92.2 percent in the Verzenio arm and 88.7 percent in the control
arm) at two years. These results are from a preplanned interim
analysis with 323 IDFS events observed in the intent-to-treat
population across both arms, including 136 in the Verzenio arm and
187 in the control arm. The data were presented today in the
Presidential Symposium at the European Society for Medical Oncology
(ESMO) 2020 Virtual Congress and simultaneously published in the
Journal of Clinical Oncology.
Safety data from monarchE were consistent with the known safety
profile of Verzenio and no new safety signals were observed. At the
time of analysis, approximately 70 percent of patients in each arm
were still on the two-year treatment period. The median follow up
was approximately 15.5 months in both arms. The median duration on
Verzenio was 14 months.
"This is a major milestone for people living with high risk HR+,
HER2- early breast cancer – potentially one of the most notable
treatment advances in the last two decades for this population of
breast cancer patients," said Stephen
Johnston, M.D., Ph.D., Professor of Breast Cancer Medicine
and Consultant Medical Oncologist at The Royal Marsden NHS
Foundation Trust (London, U.K.)
and lead investigator for the monarchE trial. "Abemaciclib added to
adjuvant endocrine therapy significantly improved invasive
disease-free survival in women and men with HR+, HER2- early breast
cancer at high risk of early recurrence, and if approved could
represent a new standard of care for this population."
monarchE randomized 5,637 patients with HR+, HER2- high risk
early breast cancer from more than 600 sites in 38 countries. High
risk was defined by cancer that spread to the lymph nodes, a large
tumor size, or high cellular proliferation (as determined by tumor
grade or Ki-67 index). Patients were treated for two years
(treatment period) or until meeting criteria for discontinuation.
After the treatment period, all patients will continue ET for five
to 10 years, as clinically indicated.
"We are excited that Verzenio has demonstrated a clinically
meaningful reduction in the risk of recurrence for people with HR+,
HER2- high risk early breast cancer, and Lilly would like to thank
the patients and investigators around the world who made this trial
possible," said Maura Dickler, M.D.,
vice president, late phase development, Lilly Oncology. "The
results on invasive disease-free survival are significant and
provide hope for people with high risk early breast cancer living
with concerns of recurrence. Lilly will submit these results to
regulatory bodies around the world as soon as possible and we look
forward to being able to offer Verzenio as a new treatment option
for these patients. We are proud of the way monarchE builds on the
vast body of clinical evidence established for Verzenio."
The addition of Verzenio to endocrine therapy also resulted
in an improvement in distant relapse-free survival, or the
time to developing cancer that has spread to other parts of the
body. The combination reduced the risk of developing metastatic
disease by 28 percent (HR: 0.717; 95% CI: 0.559, 0.920), with the
largest reductions occurring in rates of metastases to the liver
and bone. This treatment benefit was consistent across all
prespecified subgroups. Two-year distant relapse-free survival
rates were 93.6 percent in the Verzenio arm and 90.3 percent in the
control arm.
"The results of monarchE are welcome news for our community,"
said Jean Sachs, MSS, MLSP, CEO of
Living Beyond Breast Cancer. "Up to 30 percent of people with
hormone receptor-positive early breast cancer may have a
recurrence, so this finding is an exciting development for those
with high risk hormone receptor-positive, HER2- early breast
cancer, especially because the trial included women of any
menopausal status as well as men."
Overall survival results were immature and monarchE will
continue through the completion date, estimated for June 2027. At the time of the interim analysis,
the IDFS results are considered definitive. All patients on
monarchE will be followed until primary analysis and beyond to
assess overall survival and other endpoints. Lilly will submit the
monarchE data to regulatory authorities before the end of 2020.
About the monarchE Study
monarchE is a Phase 3, multicenter, randomized, open-label trial
that enrolled 5,637 patients with HR+, HER2- node-positive, high
risk early breast cancer. Patients were randomized 1:1 to
Verzenio (150 mg twice daily) plus standard adjuvant endocrine
therapy or standard adjuvant endocrine therapy alone. Patients were
treated for two years (treatment period) or until meeting criteria
for discontinuation. After the treatment period, all patients
will continue on endocrine therapy for five to 10 years, as
clinically indicated. The primary objective is invasive
disease-free survival (IDFS) defined according to the Standard
Definitions for Efficacy Endpoints (STEEP) criteria. In adjuvant
breast cancer trials, this includes the length of time
before any cancer comes back, a new cancer develops or death.
Secondary objectives include distant relapse-free survival, overall
survival, safety, pharmacokinetics and health outcomes.
High risk was specifically defined as women (any menopausal
status) and men with resected HR+, HER2- invasive early breast
cancer with either ≥4 pathologically positive axillary lymph nodes
(ALNs) or 1 to 3 positive ALNs and at least one of the following
high-risk features: primary invasive tumor size ≥5 cm, histological
grade 3 tumor, or central Ki-67 index ≥20%. If applicable, patients
must have also completed adjuvant chemotherapy and radiotherapy
prior to enrolling and have recovered from all acute side
effects.
About Early Breast Cancer
Breast cancer is the most common cancer among women
worldwide.1 An estimated 90 percent of all breast cancer
is diagnosed at an early stage.2 Approximately 70
percent of all breast cancers are HR+, HER2-, the most common
subtype.3 Even within this subtype, HR+, HER2- breast
cancer is a complex disease, and many factors – such as if the
cancer has spread to the lymph nodes and the biology of the tumor –
can impact the risk of recurrence. Approximately 30 percent of
people diagnosed with HR+ early breast cancer are at risk of their
cancer returning, potentially to incurable metastatic
disease.4
About Verzenio® (abemaciclib)
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases
(CDK)4 & 6, 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.
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).
Preclinically, Verzenio dosed daily without interruption resulted
in reduction of tumor size. 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. In patients with advanced cancer, including
breast cancer, concentrations of Verzenio and its active
metabolites (M2 and M20) in cerebrospinal fluid are comparable to
unbound plasma concentrations.
Verzenio is Lilly's first solid oral dosage form to be made
using a faster, more efficient process known as continuous
manufacturing. Continuous manufacturing is a new and advanced type
of manufacturing within the pharmaceutical industry, and Lilly is
one of the first companies to use this technology.
INDICATION
Verzenio is indicated for the treatment of HR+, HER2- advanced or
metastatic breast cancer:
- in combination with an aromatase inhibitor for postmenopausal
women as initial endocrine-based therapy
- in combination with fulvestrant for women with disease
progression following endocrine therapy
- as a single agent for adult patients with disease progression
following endocrine therapy and prior chemotherapy in the
metastatic setting
IMPORTANT SAFETY INFORMATION FOR VERZENIO
(abemaciclib)
Diarrhea occurred in 81% of patients receiving Verzenio
plus an aromatase inhibitor in MONARCH 3, 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
9% of patients receiving Verzenio plus an aromatase inhibitor in
MONARCH 3, 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.
Diarrhea incidence was greatest during the first month of
Verzenio dosing. In MONARCH 3, the median time to onset of the
first diarrhea event was 8 days, and the median duration of
diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In
MONARCH 2, 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. In MONARCH 3, 19% of patients with
diarrhea required a dose omission and 13% required a dose
reduction. In MONARCH 2, 22% of patients with diarrhea required a
dose omission and 22% required a dose reduction. The time to onset
and resolution for diarrhea were similar across MONARCH 3, MONARCH
2, and MONARCH 1.
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 41% of patients receiving
Verzenio plus an aromatase inhibitor in MONARCH 3, 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 22%
of patients receiving Verzenio plus an aromatase inhibitor in
MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in
MONARCH 2 and in 27% of patients receiving Verzenio alone in
MONARCH 1. In MONARCH 3, the median time to first episode of Grade
≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29
days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11
days, and for MONARCH 2 and MONARCH 1 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 the MONARCH studies. Two deaths due to
neutropenic sepsis were observed in MONARCH 2. Inform patients to
promptly report any episodes of fever to their healthcare
provider.
Severe, life-threatening, or fatal interstitial lung disease
(ILD) and/or pneumonitis can occur in patients treated with
Verzenio and other CDK4/6 inhibitors. Across clinical trials
(MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated
patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4,
and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis
have been observed in the post-marketing setting, with fatalities
reported.
Monitor patients for pulmonary symptoms indicative of
ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or
interstitial infiltrates on radiologic exams. Infectious,
neoplastic, and other causes for such symptoms should be excluded
by means of appropriate investigations.
Dose interruption or dose reduction is recommended in patients
who develop persistent or recurrent Grade 2 ILD/pneumonitis.
Permanently discontinue Verzenio in all patients with grade 3 or 4
ILD/pneumonitis.
Grade ≥3 increases in alanine aminotransferase (ALT) (6%
versus 2%) and aspartate aminotransferase (AST) (3% versus
1%) were reported in the Verzenio and placebo arms, respectively,
in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2%
versus 3%) were reported in the Verzenio and placebo arms
respectively, in MONARCH 2.
In MONARCH 3, for patients receiving Verzenio plus an aromatase
inhibitor with Grade ≥3 increases in ALT or AST, median time to
onset was 61 and 71 days, respectively, and median time to
resolution to Grade <3 was 14 and 15 days, respectively. In
MONARCH 2, for patients receiving Verzenio plus fulvestrant with
Grade ≥3 increases in ALT or AST, median time to onset was 57 and
185 days, respectively, and median time to resolution to Grade
<3 was 14 and 13 days, respectively.
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 an aromatase inhibitor as
compared to 0.6% of patients treated with an aromatase inhibitor
plus placebo in MONARCH 3. 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, pelvic venous thrombosis,
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 3 for Verzenio plus anastrozole or
letrozole and ≥2% higher than placebo plus anastrozole or
letrozole vs placebo plus anastrozole or letrozole were
diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs
32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain
(29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia
(27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs
2%), creatinine increased (19% vs 4%), constipation (16% vs 12%),
ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs
5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%),
dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like
illness (10% vs 8%), and thrombocytopenia (10% vs 2%).
The most common adverse reactions (all grades, ≥10%)
observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2%
higher than placebo plus fulvestrant vs 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 vs the placebo arm
of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs
1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and
anemia (6% vs 1%).
The most frequently reported ≥5% Grade 3 or 4 adverse
reactions that occurred in the Verzenio arm vs the placebo 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 3 in ≥10% for Verzenio plus anastrozole or letrozole and
≥2% higher than placebo plus anastrozole or letrozole vs placebo
plus anastrozole or letrozole were increased serum creatinine
(98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%;
13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil
count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs
26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs
<1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST
(37% vs 23%; 4% vs <1%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher
than placebo plus fulvestrant vs 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 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 and moderate 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 the strong CYP3A inhibitor 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 strong CYP3A inhibitors
other than ketoconazole. 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 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 inhibitor. With concomitant use of moderate CYP3A
inhibitors, monitor for adverse reactions and consider reducing the
Verzenio dose in 50 mg decrements. Patients should avoid grapefruit
products.
Avoid concomitant use of strong or moderate CYP3A inducers
and consider alternative agents. Coadministration of strong or
moderate CYP3A inducers 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).
AL HCP ISI 17SEP2019
Please see full Prescribing Information for
Verzenio.
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 health
care leader that unites caring with discovery to create medicines
that 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 lilly.com and
lilly.com/newsroom. P-LLY
© Lilly USA, LLC 2020. ALL
RIGHTS RESERVED.
Verzenio® is a trademark owned by or licensed to Eli Lilly and
Company, its subsidiaries, or affiliates.
This press release contains forward-looking statements (as that
term is defined in the Private Securities Litigation Reform Act of
1995) about Verzenio (abemaciclib) as a 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 future study
results will be consistent with the results to date or that
Verzenio 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.
Refer to:
|
Courtney Kasinger;
ckasinger@lilly.com; 317-501-7056 (media)
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (investors)
|
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1 World Health Organization. Breast
cancer: prevention and control.
https://www.who.int/cancer/detection/breastcancer/en/index1.html.
Accessed: September 8, 2020.
|
2 Howlader N, et al. SEER Cancer
Statistics Review, 1975-2013.
http://seer.cancer.gov/csr/1975_2013/. Accessed: September 8,
2020.
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3 Howlader N, Altekruse S, Li C. US
incidence of breast cancer subtypes defined by joint hormone
receptor and HER2 status. J Natl Cancer Inst.
2014;106(5).
|
4 Reinert T and Barrios CH. Optimal
Management of Hormone Receptor Positive Metastatic Breast Cancer in
2016. Ther Adv Med Oncol. 2015;7(6):304-20.
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