INDIANAPOLIS, Oct. 28, 2021 /PRNewswire/ -- Today, overall
survival (OS) data from Eli Lilly and Company's (NYSE:
LLY) Verzenio® (abemaciclib) Phase 3
monarchE study were published in a Letter to the Editor in the
Annals of Oncology. These OS data, while immature, have been
published to address questions regarding the recent approval by the
U.S. Food and Drug Administration (FDA) in a subgroup of the
population studied in the monarchE trial. Patients participating in
monarchE continue to be followed over time while overall survival
data mature.
Updated data from the Phase 3 monarchE study were recently
disclosed in Annals of Oncology and presented at the
October 14 European Society for
Medical Oncology (ESMO) Virtual Plenary. On October 12, the FDA approved Verzenio in
combination with endocrine therapy (tamoxifen or an aromatase
inhibitor) for the adjuvant treatment of adult patients with
hormone receptor-positive (HR+), human epidermal growth factor
receptor 2-negative (HER2-), node-positive, early breast cancer at
high risk of recurrence and a Ki-67 score of ≥20% as determined by
an FDA-approved test.1 As previously reported, overall
survival was a key secondary outcome measure for the monarchE study
and an important component of the FDA review.
About the monarchE Study
monarchE is a global, randomized, open-label, two cohort,
multicenter Phase 3 study in adult women and men with HR+ HER2-,
node-positive resected EBC with clinical and pathological features
consistent with a high risk of disease recurrence. A total of 5,637
patients were randomized (1:1) to receive two years of Verzenio 150
mg twice daily plus physician's choice of standard endocrine
therapy, or standard endocrine therapy alone. Patients in both
treatment arms were instructed to continue to receive adjuvant
endocrine therapy for up to 5-10 years as recommended by their
clinician. Cohort 1 enrolled patients with ≥4 positive axillary
lymph nodes (ALN), or 1-3 positive ALN and either Grade 3 disease
and/or tumor size ≥5 cm. Cohort 2 enrolled patients with 1-3
positive ALN and centrally determined Ki-67 score of ≥20%. The
primary endpoint was invasive disease-free survival (IDFS) in the
ITT population (Cohorts 1 & 2). Secondary endpoints were IDFS
in patients with high Ki-67 score (in the ITT population and in the
Cohort 1 population), distant relapse-free survival (DRFS), overall
survival, and safety.1,2
About Early Breast Cancer and Risk of Recurrence
It is
estimated that 90 percent of all breast cancers are detected at an
early stage. Although the prognosis for HR+ HER2- EBC is generally
positive, 20 percent of patients will experience recurrence
potentially to incurable metastatic disease.3 Risk
of recurrence is greatest within the initial two to three years
post-diagnosis, particularly in patients with node-positive, high
risk EBC.4 Factors associated with high risk of
recurrence include: positive nodal status, large tumor size (≥5
cm), high tumor grade (Grade 3), and high rate of cellular
proliferation [Ki-67 score (≥20%)].1
Node-positive means that cancer cells from the tumor in the
breast have been found in the lymph nodes in the armpit area.
Although the breast cancer is removed through surgery, the presence
of cancer cells in the lymph nodes signifies that there is a higher
chance of the cancer returning and spreading.
About Breast Cancer
Breast cancer has now surpassed
lung cancer as the most commonly diagnosed cancer worldwide,
according to GLOBOCAN. The estimated 2.3 million new cases indicate
that 1 in every 8 cancers diagnosed in 2020 is breast cancer. With
approximately 685,000 deaths in 2020, breast cancer is the
fifth-leading cause of cancer death worldwide.5 In the
U.S., it is estimated that there will be 281,550 new cases of
breast cancer in 2021.6
Approximately 70 percent of all breast cancers are of the HR+
HER2- subtype.6
About Verzenio® (abemaciclib)
Verzenio® abemaciclib is a targeted treatment known
as a CDK4/6 inhibitor. Verzenio is a non-chemotherapy oral
tablet.
Verzenio works inside the cell to block CDK4/6 activity and help
stop the growth of cancer cells, so they may eventually die (based
on preclinical studies). Cyclin-dependent kinases (CDK)4/6 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.
INDICATIONS FOR VERZENIO
Verzenio® (abemaciclib) in combination with endocrine
therapy (ET) is indicated for the adjuvant treatment of adult
patients with hormone receptor-positive (HR+), human epidermal
growth factor receptor 2-negative (HER2-), node-positive, early
breast cancer (EBC) at high risk of recurrence and a Ki-67 score of
≥20% as determined by an FDA-approved test.
Verzenio is indicated for the treatment of HR+ HER2- advanced or
metastatic breast cancer:
- in combination with an aromatase inhibitor for postmenopausal
women, and men, as initial endocrine-based therapy
- in combination with fulvestrant for adult patients 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)
Severe diarrhea associated with dehydration and
infection occurred in patients treated with
Verzenio. Across four clinical trials in 3691
patients, diarrhea occurred in 81 to 90% of
patients who received Verzenio. Grade 3 diarrhea occurred in 8 to
20% of patients receiving Verzenio. Most patients experienced
diarrhea during the first month of Verzenio treatment. The
median time to onset of the first diarrhea event ranged from 6 to 8
days; and the median duration of Grade 2 and Grade 3 diarrhea
ranged from 6 to 11 days and 5 to 8 days, respectively. Across
trials, 19 to 26% of patients with diarrhea required a Verzenio
dose interruption and 13 to 23% required a dose reduction.
Instruct patients to start antidiarrheal therapy, such as
loperamide, at the first sign of loose stools, 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, including febrile neutropenia and fatal
neutropenic sepsis, occurred in patients treated with Verzenio.
Across four clinical trials in 3691 patients, neutropenia occurred
in 37 to 46% of patients receiving Verzenio. A Grade ≥3 decrease in
neutrophil count (based on laboratory findings) occurred in 19 to
32% of patients receiving Verzenio. Across trials, the median
time to first episode of Grade ≥3 neutropenia ranged from 29 to 33
days, and the median duration of Grade ≥3 neutropenia ranged from
11 to 16 days. Febrile neutropenia has been reported in <1% of
patients exposed to Verzenio across trials. Two deaths due to
neutropenic sepsis were observed in MONARCH 2. Inform patients to
promptly report any episodes of fever to their healthcare
provider.
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.
Severe, life-threatening, or fatal interstitial lung disease
(ILD) or pneumonitis can occur in patients treated with
Verzenio and other CDK4/6 inhibitors. In Verzenio-treated
patients in EBC (monarchE), 3% of patients experienced ILD or
pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one
fatality (0.1%). In Verzenio-treated patients in MBC (MONARCH 1,
MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD or
pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal
outcomes. Additional cases of ILD or pneumonitis have been observed
in the postmarketing setting, with fatalities reported.
Monitor patients for pulmonary symptoms indicative of ILD or
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 or pneumonitis. Permanently discontinue
Verzenio in all patients with Grade 3 or 4 ILD or pneumonitis.
Grade ≥3 increases in alanine aminotransferase
(ALT) (2 to 6%) and aspartate aminotransferase
(AST) (2 to 3%) were reported in patients receiving
Verzenio. Across three clinical trials in 3559 patients (monarchE,
MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT
increases ranged from 57 to 87 days and the median time to
resolution to Grade <3 was 13 to 14 days. The median time to
onset of Grade ≥3 AST increases ranged from 71 to 185 days and the
median time to resolution to Grade <3 ranged from 11 to 15
days.
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 any Grade 3 or 4 hepatic transaminase
elevation.
Venous thromboembolic events (VTE) were reported in
2 to 5% of patients across three clinical trials in 3559 patients
treated with Verzenio (monarchE, MONARCH 2, MONARCH 3). VTE
included deep vein thrombosis, pulmonary embolism, pelvic
venous thrombosis, cerebral venous sinus thrombosis, subclavian and
axillary vein thrombosis, and inferior vena cava thrombosis. In
clinical trials, deaths due to VTE have been reported in patients
treated with Verzenio.
Verzenio has not been studied in patients with early breast
cancer who had a history of VTE. Monitor patients for signs and
symptoms of venous thrombosis and pulmonary embolism and treat as
medically appropriate. Dose interruption is recommended for EBC
patients with any grade VTE and for MBC patients with a Grade 3 or
4 VTE.
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 3 weeks after the last dose.
Based on findings in animals, Verzenio may impair fertility in
males of reproductive potential. 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.
The most common adverse reactions (all grades,
≥10%) observed in monarchE for Verzenio plus
tamoxifen or an aromatase inhibitor vs tamoxifen or an
aromatase inhibitor, with a difference between arms of
≥2%, were diarrhea (84% vs 9%), infections (51% vs 39%),
neutropenia (46% vs 6%), fatigue (41% vs 18%),
leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs
4%), headache (20% vs 15%), vomiting (18% vs 4.6%),
stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia
(13% vs 2%), decreased appetite (12% vs 2.4%), ALT increased (12%
vs 6%), AST increased (12% vs 5%), dizziness (11% vs 7%), rash (11%
vs 4.5%), and alopecia (11% vs 2.7 %).
The most frequently reported ≥5% Grade 3 or 4
adverse reaction that occurred in the Verzenio arm vs the
tamoxifen or an aromatase inhibitor arm of monarchE were
neutropenia (19.6% vs 1%), leukopenia (11% vs <1%), diarrhea (8%
vs 0.2%), and lymphopenia (5% vs <1%).
Lab abnormalities (all grades; Grade 3 or 4) for
monarchE in ≥10% for Verzenio plus tamoxifen or an
aromatase inhibitor with a difference between arms
of ≥2% were increased serum creatinine (99% vs
91%; .5% vs <.1%), decreased white blood cells (89% vs 28%;
19.1% vs 1.1%), decreased neutrophil count (84% vs 23%; 18.7% vs
1.9%), anemia (68% vs 17%; 1% vs .1%), decreased lymphocyte count
(59% vs 24%; 13.2 % vs 2.5%), decreased platelet count (37% vs 10%;
.9% vs .2%), increased ALT (37% vs 24%; 2.6% vs 1.2%), increased
AST (31% vs 18%; 1.6% vs .9%), and hypokalemia (11% vs 3.8%; 1.3%
vs 0.2%).
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 3 for Verzenio plus anastrozole
or letrozole vs anastrozole or letrozole, with a difference
between arms of ≥2%, were diarrhea (81% vs 30%), fatigue
(40% vs 32%), neutropenia (41% vs 2%), 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 3.1%), influenza-like illness (10% vs
8%), and thrombocytopenia (10% vs 2%).
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 1%), diarrhea (9% vs 1.2%), leukopenia (7% vs
<1%)), increased ALT (6% vs 2%), and anemia (6% vs 1%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 3 in ≥10% for Verzenio plus anastrozole or
letrozole with a difference between arms of
≥2% were increased serum creatinine (98% vs
84%; 2.2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs
0.6%), anemia (82% vs 28%; 1.6% vs 0%), decreased neutrophil count
(80% vs 21%; 21.9% vs 2.6%), decreased lymphocyte count (53% vs
26%; 7.6% vs 1.9%), decreased platelet count (36% vs 12%; 1.9% vs
0.6%), increased ALT (48% vs 25%; 6.6% vs 1.9%), and increased AST
(37% vs 23%; 3.8% vs 0.6%).
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 2 for Verzenio plus
fulvestrant vs fulvestrant, with a difference between arms
of ≥2%, 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 2.7%),
thrombocytopenia (16% vs 3%), alopecia (16% vs 1.8%), 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 4.5%), pyrexia (11% vs 6%), and weight
decreased (10% vs 2.2%).
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 (25% vs 1%), diarrhea (13% vs 0.4%), leukopenia (9% vs
0%), anemia (7% vs 1%), and infections (5.7% vs
3.5%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 2 in ≥10% for Verzenio plus fulvestrant with a
difference between arms of ≥2% were increased serum
creatinine (98% vs 74%; 1.2% vs 0%), decreased white blood cells
(90% vs 33%; 23.7% vs .9%), decreased neutrophil count (87% vs 30%;
32.5% vs 4.2%), anemia (84% vs 34%; 2.6% vs .5%), decreased
lymphocyte count (63% vs 32%; 12.2% vs 1.8%), decreased platelet
count (53% vs 15%; 2.1% vs 0%), increased ALT (41% vs 32%; 4.6% vs
1.4%), and increased AST (37% vs 25%; 3.9% vs 4.2%).
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%), constipation
(17%), leukopenia (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 from MONARCH 1 with Verzenio were
diarrhea (20%), neutropenia (24%), fatigue (13%), and leukopenia
(5%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 1 with Verzenio were increased serum creatinine
(99%; .8%), decreased white blood cells (91%; 28%), decreased
neutrophil count (88%; 26.6%), anemia (69%; 0%), decreased
lymphocyte count (42%; 13.8%), decreased platelet count (41%;
2.3%), increased ALT (31%; 3.1%), and increased AST (30%;
3.8%).
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 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 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 12OCT2021
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 2021. 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 early breast cancer and reflects Lilly's current
beliefs and expectations. 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 planned or ongoing studies will be
completed as planned, 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.
1 Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company.
2 Johnston SRD, Harbeck N, Hegg R, et al; monarchE
Committee Members and Investigators. Abemaciclib combined with
endocrine therapy for the adjuvant treatment of HR+, HER2-,
node-positive, high-risk, early breast cancer (monarchE) [published
online ahead of print, September 20,
2020]. J Clin Oncol. doi:10.1200/JCO.20.02514.
3 Early Breast Cancer Trialists' Collaborative Group
(EBCTCG). Effects of chemotherapy and hormonal therapy for early
breast cancer on recurrence and 15-year survival: an overview of
the randomised trials. Lancet. 2005;365(9472):1687-1717.
doi:10.1016/S0140-6736(05)66544-0.
4 Cheng L, Swartz MD, Zhao H, et al. Hazard of
recurrence among women after primary breast cancer treatment--a
10-year follow-up using data from SEER-Medicare. Cancer
Epidemiol Biomarkers Prev. 2012;21:800-809.
5 Sung H, Ferlay J, Siegel RL, et al. Global cancer
statistics 2020: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA Cancer J Clin.
2021;71(3):209-249
6 National Cancer Institute, SEER. Cancer Stat Facts:
Female Breast Cancer.
https://seer.cancer.gov/statfacts/html/breast.html. Accessed
September 14, 2021.
Refer to:
|
Tracy Henrikson;
tracy.henrikson@lilly.com; 609-454-7116 (Lilly): media
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (Lilly): investors
|
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