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ORIGINAL ARTICLE
Adjuvant abemaciclib combined with endocrine therapy for high-risk early
breast cancer: updated efficacy and Ki-67 analysis from the monarchE study
N. Harbeck
1*y
, P. Rastogi
2y
, M. Martin
3
, S. M. Tolaney
4
, Z. M. Shao
5
, P. A. Fasching
6
, C. S. Huang
7
, G. G. Jaliffe
8
,
A. Tryakin
9
, M. P. Goetz
10
, H. S. Rugo
11
, E. Senkus
12
, L. Testa
13
, M. Andersson
14
, K. Tamura
15
, L. Del Mastro
16,17
,
G. G. Steger
18
, H. Kreipe
19
, R. Hegg
20
, J. Sohn
21
, V. Guarneri
22,23
, J. Cortés
24,25
, E. Hamilton
26
, V. André
27
, R. Wei
27
,
S. Barriga
27
, S. Sherwood
27
, T. Forrester
27
, M. Munoz
27
, A. Shahir
27
, B. San Antonio
27
, S. C. Nabinger
27
,M.Toi
28
,
S. R. D. Johnston
29z
&J.O’Shaughnessy
30z
1
Breast Center, Department of OB & GYN and CCC Munich, LMU University Hospital, Munich, Germany;
2
University of Pittsburgh/UPMC, NSABP Foundation,
Pittsburgh, USA;
3
Hospital General Universitario Gregorio Marañon, Universidad Complutense, CIBERONC, GEICAM, Madrid, Spain;
4
Dana-Farber Cancer Institute,
Boston, USA;
5
Fudan University Shanghai Cancer Center, Shanghai, China;
6
University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive
Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany;
7
National Taiwan University Hospital and National Taiwan
University College of Medicine, Taipei, Taiwan;
8
Grupo Medico Camino S.C., Mexico City, Mexico;
9
N.N.Blokhin Russian Cancer Research Center, Moscow, Russia;
10
Mayo Clinic, Rochester;
11
Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, USA;
12
Department of Oncology &
Radiotherapy, Medical University of Gda
nsk, Gda
nsk, Poland;
13
Instituto D’Or de Pesquisa e Ensino (IDOR), Sao Paulo, Brazil;
14
Rigshospitalet, Copenhagen, Denmark;
15
National Cancer Center Hospital, Tokyo, Japan;
16
IRCSS Ospedale Policlinico San Martino, UO Breast Unit, Genoa;
17
Università di Genova, Department of Internal
Medicine and Medical Specialties (DIM), Genoa, Italy;
18
Medical University of Vienna, Vienna, Austria;
19
Medizinische Hochschule Hannover, Hannover, Germany;
20
Clin. Pesq. e Centro São Paulo, São Paulo, Brazil;
21
Yonsei Cancer Center, Seoul, Korea;
22
Department of Surgery, Oncology and Gastroenterology, University of
Padova, Padua;
23
Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy;
24
International Breast Cancer Center (IBCC), Madrid & Barcelona, and Vall d’Hebron Institute of
Oncology, Barcelona;
25
Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain;
26
Sarah Cannon Research
Institute/Tennessee Oncology, Nashville;
27
Eli Lilly and Company, Indianapolis, USA;
28
Kyoto University Hospital, Kyoto, Japan;
29
Royal Marsden NHS Foundation Trust,
London, UK;
30
Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, USA
Available online XXX
Background: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically
meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone
receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer
at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary
outcome analysis and an additional follow-up analysis.
Patients and methods: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for 5
years abemaciclib for 2 years. Cohort 1 enrolled patients with 4 positive axillary lymph nodes (ALNs), or 1-3 positive
ALNs and either grade 3 disease or tumor 5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally
determined high Ki-67 index (20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1
and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety.
Results: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib þET resulted in a 29%
reduction in the risk of developing an IDFS event [hazard ratio (HR) ¼0.71, 95% confidence interval (CI) 0.58-0.87;
nominal P¼0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients
off treatment, IDFS (HR ¼0.70, 95% CI 0.59-0.82; nominal P<0.0001) and DRFS (HR ¼0.69, 95% CI 0.57-0.83;
nominal P<0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4%
and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67
index. Safety data were consistent with the known abemaciclib risk profile.
Conclusion: Abemaciclib þET significantly improved IDFS in patients with hormone receptor-positive, human epidermal
growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67
index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment
benefit of abemaciclib extended beyond the 2-year treatment period.
Key words: abemaciclib, adjuvant, CDK4/6, early breast cancer, Ki-67
*Correspondence to: Prof Nadia Harbeck, Brustzentrum, LMU Klinikum,
Marchioninistrasse 15, 81377 Munich, Germany. Tel: þ49-89-4400-77581
E-mail: Nadia.Harbeck@med.uni-muenchen.de (N. Harbeck).
y
These authors have contributed equally to this work as first authors.
z
These authors have contributed equally to this work as senior authors.
0923-7534/© 2021 Published by Elsevier Ltd on behalf of European Society
for Medical Oncology.
Volume xxx -Issue xxx -2021 https://doi.org/10.1016/j.annonc.2021.09.015 1
INTRODUCTION
Since the introduction of aromatase inhibition in the early
2000s, there have been limited advancements to the stan-
dard (neo)adjuvant therapies available for patients
with hormone receptor-positive (HRþ), human epidermal
growth factor receptor 2-negative (HER2) early breast
cancer (EBC).
1
While treatment optimizations including
extended endocrine therapy (ET), ovarian suppression in
premenopausal patients,
2
and chemotherapy personaliza-
tion based on clinicopathological and molecular features
have further improved outcomes, unmet need exists for
those at the highest risk of recurrence.
3,4
Novel strategies
are needed to improve outcomes for these patients.
Cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitors
administered in combination with ET have markedly
improved outcomes for patients with HRþ, HER2,
advanced breast cancer.
5-7
While small studies in the pre-
operative setting have also suggested potential activity of
CDK4 and 6 inhibitors in EBC, the benefit of these agents in
the adjuvant setting remained unknown.
8,9
To evaluate this important question, monarchE, an open-
label, global, phase III, randomized trial comparing adjuvant
ET for at least 5 years with or without abemaciclib for 2 years,
was conducted in patients with HRþ, HER2, node-positive,
high-risk EBC. High risk was defined by a compilation of
clinical and pathologic factors including nodal status, tumor
size, grade, and a marker of cellular proliferation (Ki-67). Ki-67
has previously been shown to be prognostic of clinical
outcome in EBC,
3,10
as well as a predictor of response to
neoadjuvant chemotherapy or ET.
11,12
In hormone-sensitive
disease, prospective data demonstrated that suppression of
Ki-67 in the setting of preoperative ET is prognostic for
recurrence-free survival.
12,13
Preoperative abemaciclib has
also been shown to substantially lower Ki-67 expression,
further suggesting CDK4 and 6 inhibition may be effective in
tumors with a high degree of cellular proliferation.
8
There-
fore, in monarchE, Ki-67 expression was used together with
clinicopathological features, to identify patients with a high
risk of recurrence. Ki-67 20% was used to differentiate be-
tween low and high values according to the definition from
the St Gallen International Expert Consensus.
14
At a previous preplanned interim analysis, monarchE met
its primary endpoint when abemaciclib þET demonstrated
a statistically significant improvement in invasive disease-
free survival (IDFS) in the intent-to-treat (ITT) population
compared with ET alone.
15
Here, we present updated re-
sults from two timepoints: (i) the prespecified primary
outcome (PO) analysis and (ii) an additional follow-up
analysis, conducted at regulatory request. Outcomes will
also be reported from prespecified subpopulations based
on Ki-67 levels.
METHODS
Study design and participants
monarchE (Clinicaltrials.gov registration: NCT03155997)
included women and men, with HRþ, HER2, EBC at high
risk of recurrence according to clinicopathological fea-
tures.
15
Patients were assigned to one of two cohorts.
Cohort 1 enrolled patients with either 4 positive axillary
lymph nodes (ALNs), or 1-3 positive ALNs and at least one of
the following: tumor size 5 cm or histologic grade 3.
Cohort 2 started enrolling 1 year after cohort 1 and included
patients with 1-3 positive ALNs, tumor size <5 cm, grade
<3, and a centrally determined high Ki-67 index (20%). Ki-
67 index was also determined centrally in cohort 1 patients
with a suitable breast tumor tissue sample, but Ki-67
determination was not required for enrollment. All pa-
tients were required to have radiographic staging between
diagnosis and randomization.
The inclusion criteria for selecting the patient population
at high risk of recurrence were based on efficacy outcome
data from the West German Group (WSG) Plan B trial
3
and
the NSABP B-28 trial.
16
Among a subset of the Plan B pa-
tient population who satisfied the monarchE criteria for
high risk disease, the estimated 5-year IDFS rate was 82.5%
[95% confidence interval (CI) 77.8% to 87.2%], reflecting
that approximately 17.5% of those patients who were at
high risk of recurrence would develop recurrence events
within the first 5 years.
This study, including all amendments, was approved by
Institutional Review Boards and was conducted in accordance
with consensus ethic principles derived from international
ethic guidelines, including the Declaration of Helsinki and
Council for International Organizations of Medical Sciences
(CIOMS) and the International Conference on Harmonisation-
Good Clinical Practice (ICH-GCP) Guidelines.
Treatment
Patients were randomized (1 : 1) to receive adjuvant abe-
maciclib plus ET or ET alone for 2 years (treatment period),
with ET prescribed for at least 5 years. Patients were
stratified by prior chemotherapy, menopausal status at the
time of breast cancer diagnosis, and region. Abemaciclib
was administered orally at 150 mg twice daily. ET was
administered per physician’s choice including antiestrogen
agents (e.g. tamoxifen) or aromatase inhibitors, with or
without a gonadotropin-releasing hormone agonist per
standard practice. Further details about the randomization,
stratification, and other study procedures have been pre-
viously described.
15
Ki-67 central assay
Ki-67 index was determined centrally in all suitable un-
treated breast primary tumor samples using an investiga-
tional Ki-67 immunohistochemistry assay developed by
Agilent Technologies (formerly Dako; Santa Clara, CA).
17
The
assay was carried out in formalin-fixed paraffin-embedded
tissue using the anti-Ki-67 antibody, MIB-1, and Negative
Control Reagent in an automated platform. Results were
interpreted using a light microscope by a certified pathol-
ogist using a standardized scoring algorithm involving the
evaluation of the entire tissue slide. A cut-off of 20% was
used to define high Ki-67 index.
Annals of Oncology N. Harbeck et al.
2https://doi.org/10.1016/j.annonc.2021.09.015 Volume xxx -Issue xxx -2021
Outcomes
The primary endpoint was IDFS per the Standardized Defi-
nitions for Efficacy End Points in Adjuvant Breast Cancer
Trials (STEEP) criteria in the ITT population (cohorts 1 þ2).
18
Key secondary endpoints included distant relapse-free
survival (DRFS), overall survival (OS), IDFS in the Ki-67 high
population (both ITT and cohort 1), and safety. All patients
who received at least one dose of study treatment were
included in the safety analysis. Adverse events (AEs) were
graded according to the Common Terminology Criteria for
Adverse Events version 4.0.
Statistical analyses
The primary objective of IDFS in the ITT population was met
at the second efficacy interim analysis.
15
A secondary
objective was to test the superiority of abemaciclib þET
versus ET alone in patients whose tumors had high Ki-67
index in both the ITT population as well as those enrolled
in cohort 1. The overall type I error was controlled with
gate-keeping strategy for IDFS in the ITT and Ki-67 high
populations.
The PO analysis was preplanned at w390 IDFS events,
which was reached on 8 July 2020. At PO, IDFS in the ITT Ki-
67 high and cohort 1 Ki-67 high populations was tested
sequentially, with two-sided Pvalue boundaries of 0.0424
and 0.0426, respectively, calculated using the method of
Slud and Wei.
19
In addition, exploratory analyses evaluated
IDFS in cohort 1 patients whose tumors had Ki-67 <20%
(cohort 1 Ki-67 low), IDFS in cohort 2 patients, as well as
DRFS in the Ki-67 subpopulations.
An additional analysis was conducted in response to
regulators, with a data cut-off date on 1 April 2021 (addi-
tional follow-up 1 [AFU1]) at which point the majority of
patients had discontinued or completed the study treat-
ment period.
For efficacy endpoints, a stratified Cox proportional haz-
ard model was used to estimate the treatment effect hazard
ratio (HR). Unless otherwise specified, all Pvalues were
reported using a two-sided alpha level and all CIs used a
95% level. Additionally, an exploratory analysis was carried
out to estimate the piecewise yearly HR for IDFS and DRFS
at AFU1. This analysis breaks the observation period into
yearly time intervals and assesses treatment effect within
each interval using a Bayesian piecewise exponential model.
The reported 95% credible intervals (Crls) were calculated
by equal tails in the posterior samples of the Bayesian
exponential model.
RESULTS
A total of 5637 patients were randomized to receive
abemaciclib þET (n¼2808) or ET alone (n¼2829)
(Supplementary Figure S1, available at https://doi.org/10.
1016/j.annonc.2021.09.015); of those, 5120 were enrolled
in cohort 1. Some 44.3% of all randomized patients and
39.1% of patients in cohort 1 had tumors with high Ki-67
index. Within cohort 1, 37.4% of patients had tumors with
low Ki-67 index and 23.5% of patients had unavailable Ki-67
index (Supplementary Figure S2, available at https://doi.
org/10.1016/j.annonc.2021.09.015).
Baseline demographics and disease characteristics were
balanced between the treatment arms in the ITT and ITT Ki-
67-high populations (Table 1). In cohort 1, the frequency of
grade 3 tumors was higher in patients with Ki-67-high tu-
mors, while the proportion of patients with 4 positive
lymph nodes was higher in the Ki-67-low population
(Supplementary Table S1, available at https://doi.org/10.
1016/j.annonc.2021.09.015). Supplementary Figure S3,
available at https://doi.org/10.1016/j.annonc.2021.09.015,
demonstrates the percentages of patients in cohort 1 with
Ki-67-high and -low tumors within each clinicopathological
feature.
From the preplanned PO analysis (data cut-off: 8 July
2020) to AFU1 (data cut-off: 1 April 2021), the median
follow-up increased from 19 to 27 months. The percentage
of patients who were off the study treatment period
increased from 40.9% at PO to 89.6% at AFU1, including
4071 (72.2%) who completed the 2-year treatment
period and 982 (17.4%) who discontinued prematurely
(Supplementary Figure S1, available at https://doi.org/10.
1016/j.annonc.2021.09.015). Efficacy data from both PO
and AFU1 are presented to show the evolution of the
treatment effect over time (Table 2).
Efficacy
Efficacy in the ITT population (PO, median follow-up 19
months). After reaching statistical significance at the
interim analysis, abemaciclib þET continued to demon-
strate clinically meaningful benefit in IDFS with a greater
magnitude of effect size at PO (Table 2;HR¼0.71, 95% CI
0.58-0.87; nominal P<0.001). There was also an absolute
improvement of 3.0% in the 2-year IDFS rates
(abemaciclib þET: 92.3% versus ET alone: 89.3%). Similarly,
abemaciclib þET continued to demonstrate clinically
meaningful benefit in DRFS (Table 2;HR¼0.69, 95% CI
0.55-0.86; nominal P<0.001), corresponding to an abso-
lute difference of 3.0% at 2 years (abemaciclib þET: 93.8%
versus ET alone: 90.8%).
Efficacy in the ITT population (AFU1, median follow-up 27
months). With 8 months of additional median follow-up,
the benefit of abemaciclib þET was maintained for IDFS
(Table 2;HR¼0.70, 95% CI 0.59-0.82; nominal P<0.0001)
and DRFS (Table 2;HR¼0.69, 95% CI 0.57-0.83; nominal
P<0.0001). The KaplaneMeier (KM) curves (Figure 1A,
Supplementary Figure S4A, available at https://doi.org/10.
1016/j.annonc.2021.09.015) continued to show the
benefit of abemaciclib, even beyond the 2-year study
treatment period. With more patients at risk for recurrence
at 3 years, the data demonstrated an absolute improvement
of 5.4% for 3-year IDFS rates (abemaciclib þET: 88.8%
versus ET alone: 83.4%) and 4.2% for 3-year DRFS rates
(abemaciclib þET: 90.3% versus ET alone: 86.1%). Treat-
ment benefit in IDFS and DRFS was generally consistent
across prespecified subgroups (Figure 1B, Supplementary
Figure S4B, available at https://doi.org/10.1016/j.annonc.
N. Harbeck et al. Annals of Oncology
Volume xxx -Issue xxx -2021 https://doi.org/10.1016/j.annonc.2021.09.015 3
2021.09.015). Bone and liver were the most common sites
of distant recurrence with fewer recurrences in the abe-
maciclib arm (Supplementary Table S2, available at https://
doi.org/10.1016/j.annonc.2021.09.015). OS data remained
immature as the required number of events was not
reached at the time of this analysis.
The piecewise HR estimates within each year for IDFS
demonstrated increasing magnitude of effect size over time:
from the first year (0-1 year HR ¼0.80, 95% CrI 0.59-1.03)
to the second year (1-2 year HR ¼0.68, 95% CrI 0.52-0.87),
and strengthened beyond the 2-year study treatment
period (2þyear HR ¼0.60, 95% CrI 0.40-0.86). Similarly,
there was also an evolution of the piecewise DRFS HR es-
timates from the first year (0-1 year HR ¼0.73, 95% CrI
0.52-0.99) to the second year (1-2 year HR ¼0.68, 95% CrI
0.51-0.88), which further persisted beyond the 2-year study
treatment period (2þyear HR ¼0.69, 95% CrI 0.45-1.03).
Efficacy in the ITT Ki-67-high population. At PO,
abemaciclib þET significantly reduced the risk of devel-
oping an IDFS event by 31% (HR ¼0.69, 95% CI 0.52-0.92,
two-sided P¼0.0111) for the prespecified, alpha-
controlled, ITT Ki-67-high population. Two-year IDFS rates
were 91.6% in the abemaciclib arm and 87.1% in the control
Table 1. Baseline characteristics
Category ITT population
d
ITT Ki-67-high population (‡20%)
Abemaciclib þET
N¼2808, n(%)
a
ET alone
N¼2829, n(%)
a
Abemaciclib þET
N¼1262, n(%)
a
ET alone
N¼1236, n(%)
a
Age, median (range) 51 (23-89) 51 (22-86) 51 (23-88) 51 (24-86)
<65 2371 (84.4%) 2416 (85.4%) 1095 (86.8%) 1070 (86.6%)
65 437 (15.6%) 413 (14.6%) 167 (13.2%) 166 (13.4%)
Female 2787 (99.3%) 2814 (99.5%) 1250 (99.0%) 1227(99.3%)
Male 21 (0.7%) 15 (0.5%) 12 (1.0%) 9 (0.7%)
Hormone receptor status
Estrogen receptor-positive 2786 (99.2%) 2810 (99.3%) 1251 (99.1%) 1224 (99.0%)
Estrogen receptor-negative 16 (0.6%) 17 (0.6%) 8 (0.6%) 11 (0.9%)
Progesterone receptor-positive 2426 (86.4%) 2456 (86.8%) 1062 (84.2%) 1043 (84.4%)
Progesterone receptor-negative 298 (10.6%) 295 (10.4%) 165 (13.1%) 152 (12.3%)
Menopausal status
b,c
Premenopausal 1221 (43.5%) 1232 (43.5%) 575 (45.6%) 564 (45.6%)
Postmenopausal 1587 (56.5%) 1597 (56.5%) 687 (54.4%) 672 (54.4%)
Prior chemotherapy
b
Neoadjuvant chemotherapy 1039 (37.0%) 1048 (37.0%) 457 (36.2%) 472 (38.2%)
Adjuvant chemotherapy 1642 (58.5%) 1647 (58.2%) 749 (59.4%) 704 (57.0%)
No chemotherapy 127 (4.5%) 134 (4.7%) 56 (4.4%) 60 (4.9%)
Region
b
North American/Europe 1470 (52.4%) 1479 (52.3%) 692 (54.8%) 674 (54.5%)
Asia 574 (20.4%) 582 (20.6%) 272 (21.6%) 280 (22.7%)
Other 764 (27.2%) 768 (27.1%) 298 (23.6%) 282 (22.8%)
Positive axillary lymph nodes
0 7 (0.2%) 7 (0.2%) 2 (0.2%) 2 (0.2%)
1-3 1118 (39.8%) 1142 (40.4%) 672 (53.2%) 668 (54.0%)
4 1682 (59.9%) 1680 (59.4%) 588 (46.8%) 566 (45.8%)
Histopathological grade at diagnosis
Grade 1 209 (7.4%) 216 (7.6%) 60 (4.8%) 53 (4.3%)
Grade 2 1377 (49.0%) 1395 (49.3%) 546 (43.3%) 531 (43.0%)
Grade 3 1086 (38.7%) 1064 (37.6%) 605 (47.9%) 590 (47.7%)
Grade cannot be assessed 126 (4.5%) 141 (5.0%) 49 (3.9%) 56 (4.5%)
Pathologic tumor size
<2 cm 781 (27.8%) 767 (27.1%) 384 (30.4%) 371 (30.0%)
2-5 cm 1372 (48.9%) 1419 (50.2%) 664 (52.6%) 663 (53.6%)
5 cm 607 (21.6%) 610 (21.6%) 199 (15.8%) 185 (15.0%)
Ki-67 index
<20% 953 (33.9%) 974 (34.4%)
20% 1262 (44.9%) 1233 (43.6%) 1262 (100.0%) 1236 (100.0%)
TNM stage (derived
e
)
IA 2 (0.1%) 1 (0.0%) 2 (0.2%) 0 (0.0%)
IIA 324 (11.5%) 353 (12.5%) 225 (17.8%) 235 (19.0%)
IIB 392 (14.0%) 387 (13.7%) 258 (20.4%) 252 (20.4%)
IIIA 1029 (36.6%) 1026 (36.3%) 356 (28.2%) 340 (27.5%)
IIIB 99 (3.5%) 88 (3.1%) 37 (2.9%) 34 (2.8%)
IIIC 950 (33.8%) 963 (34.0%) 379 (30.0%) 367 (29.7%)
ET, endocrine therapy; ITT, intent-to-treat; n, number of patients; N, number of patients in population; TNM, tumor, node, metastasis.
a
Where values do not add up to 100%, remaining data are missing, unavailable, or could not be assessed.
b
Per interactive web response system.
c
Menopausal status is at the time of diagnosis and all males are considered postmenopausal.
d
Thirty-eight patients were found not to meet the high risk criteria and hence were considered ineligible but were included in the ITT population.
e
Derived TNM stage based on the pathological tumor size and number of positive lymph nodes.
Annals of Oncology N. Harbeck et al.
4https://doi.org/10.1016/j.annonc.2021.09.015 Volume xxx -Issue xxx -2021
arm; with an absolute improvement of 4.5%. At AFU1, the
clinically meaningful benefit in IDFS was of greater magni-
tude (Figure 2A; HR ¼0.66, 95% CI 0.52-0.84; nominal P¼
0.0006), with an absolute improvement of 6.0% in 3-year
IDFS rates. Consistently, there was a 36% reduction in the
risk of developing a DRFS event (Supplementary Table S3,
available at https://doi.org/10.1016/j.annonc.2021.09.015;
HR ¼0.64, 95% CI 0.49-0.83; nominal P¼0.0006) with an
absolute improvement of 4.0% in the 3-year DRFS rates.
Efficacy in the cohort 1 Ki-67-high and -low populations. At
PO, abemaciclib þET significantly reduced the risk of
developing an IDFS event in the prespecified, alpha-
controlled, cohort 1 Ki-67-high population by 36% (HR ¼
0.64, 95% CI 0.48-0.87; two-sided P¼0.0042). The 2-year
IDFS rates were 91.3% in abemaciclib þET and 86.1% in
ET alone, with an absolute improvement of 5.2% at PO.
Similarly, abemaciclib benefit was observed in the cohort 1
Ki-67-low population, with 31% reduction in the risk of
developing an IDFS event (HR ¼0.69, 95% CI 0.46-1.02;
nominal P¼0.059) and an absolute difference in 2-year
IDFS rate of 2.8% (94.8% in abemaciclib þET and 92.0%
in ET alone).
At AFU1, analyses of Ki-67 subpopulations in cohort 1
showed consistent results with PO. The clinically meaningful
benefit in IDFS and DRFS in the cohort 1 Ki-67-high popu-
lation was maintained (Figure 2B; IDFS HR ¼0.63, 95% CI
0.49-0.80; nominal P¼0.0002 and Supplementary Table S3,
available at https://doi.org/10.1016/j.annonc.2021.09.015;
DRFS HR ¼0.60, 95% CI 0.46-0.79; nominal P¼0.0002),
with an absolute improvement of 7.1% and 5.2% in 3-year
IDFS and DRFS rates, respectively. Numerical benefit was
also observed in the cohort 1 Ki-67-low population (IDFS
HR ¼0.70, 95% CI 0.51-0.98; nominal P¼0.036), sug-
gesting that abemaciclib þET resulted in an IDFS benefit
regardless of the Ki-67 index in cohort 1 (Figure 3). In
addition, the 3-year IDFS rates in the control arm suggested
that patients with Ki-67-high tumors had a higher risk of
developing an IDFS event than those with Ki-67-low tumors
(79.0% versus 87.2%, respectively), thus indicating the
prognostic value of Ki-67 in this patient population. The
data for IDFS in cohort 2 remained immature.
Safety
At AFU1, the median duration of abemaciclib and ET in both
arms was 24 months. A higher incidence of grade 3 AEs
and serious AEs was observed with abemaciclib þET versus
ET alone (50% versus 16% and 15% versus 9%, respectively).
The most frequent AEs were diarrhea, neutropenia, and
fatigue in the abemaciclib arm, and arthralgia, hot flush,
and fatigue in the control arm (Supplementary Table S4,
available at https://doi.org/10.1016/j.annonc.2021.09.015).
In total, 181 patients (6.5%) in the abemaciclib þET arm
and 30 patients (1.1%) in the control arm discontinued from
the 2-year study treatment period due to AEs.
DISCUSSION
At the prespecified PO analysis of monarchE, with a median
follow-up of 19 months and 41% of patients off study
treatment,abemaciclib þET reduced the risk of developing
an IDFS event by 29%. At the AFU1, with a longer median
follow-up of 27 months and 90% of patients having
completed or discontinued from the study treatment
period, the benefit of abemaciclib þET was confirmed in
terms of IDFS (30% risk reduction) and DRFS (31% risk
reduction). The separation of the KM curves, in addition to
the increasing magnitude of yearly piecewise HR estimates,
demonstrates the continued treatment benefit over time
that extended beyond the 2-year treatment period of
abemaciclib.
The observed improvement in IDFS to date reflects
abemaciclib was efficacious in preventing early recurrence
in patients with primary resistance to ET as defined by
Table 2. Evolution of IDFS and DRFS data in the intent-to-treat population at PO and AFU1
Primary outcome Additional follow-up 1
Data cut-off date 8 July 2020 1 April 2021
Patients off study treatment period 41.0% 89.6%
Completed 2-year study treatment period 25.5% 72.2%
Efficacy results Abemaciclib þET ET alone Abemaciclib þET ET alone
Median follow-up, months 19.1 27.1
IDFS
Events, n163 232 232 333
IDFS rates, % (95% CI)
2-year 92.3 (90.9-93.5) 89.3 (87.7-90.7) 92.7 (91.6-93.6) 90.0 (88.8-91.1)
3-year Not estimable Not estimable 88.8 (87.0-90.3) 83.4 (81.3-85.3)
HR (95% CI) 0.71 (0.58-0.87) 0.70 (0.59-0.82)
Pvalue
a
Nominal Pvalue ¼0.0009
a
Nominal Pvalue <0.0001
DRFS
Events, n131 193 191 278
DRFS rates, % (95% CI)
2-year 93.8 (92.6-94.9) 90.8 (89.3-92.1) 94.1 (93.2-95.0) 91.6 (90.5-92.6)
3-year Not estimable Not estimable 90.3 (88.6-91.8) 86.1 (84.2-87.9)
HR (95% CI) 0.69 (0.55-0.86) 0.69 (0.57-0.83)
AFU1, additional follow up 1; DRFS, distant relapse-free survival; HR, hazard ratio; IDFS, invasive disease-free survival; PO, primary outcome.
a
The primary efficacy endpoint was statistically significant at interim analysis 2.
N. Harbeck et al. Annals of Oncology
Volume xxx -Issue xxx -2021 https://doi.org/10.1016/j.annonc.2021.09.015 5
ESO-ESMO criteria (recurrence within 2 years of beginning
adjuvant ET).
20
Early recurrences represent the rapid
outgrowth of endocrine-resistant subclinical disease that
persist despite optimal systemic adjuvant treatment. The
high rate of invasive recurrence in the ET alone arm of
monarchE (16.6% after 3 years) demonstrates that the
trial enrolled a high-risk population, that could be placed
in perspective by considering the outcomes from the
patient population in Plan B that would have met
enrollment criteria for monarchE (17.5% risk at 5 years).
Overall
Region
North America/Europe
Asia
Other
Menopausal status
Premenopausal
Postm enopausal
Prior chemotherapy
Neoadjuvant
Adjuvant
Age
<65 years
≥
65 years
Race
White
Asian
All others
Baseline ECOG PS
0
1
Primary tumor size
<2 cm
2-5 cm
≥5 cm
Number of pos. lymph nodes
1-3
4-9
10 or more
Histologic grade
Grade 1
Grade 2
Grade 3
Progesterone receptor
Negative
Positive
Tumor stage
Stage IIA
Stage IIB
Stage IIIA
Stage IIIC
2808
1470
574
764
1221
1587
1039
1642
2371
437
1947
675
146
2405
401
781
1371
607
1118
1107
575
209
1377
1086
298
2426
324
392
1029
950
232
111
41
80
85
147
119
101
192
40
166
47
17
193
39
40
125
62
75
75
80
11
101
112
42
185
15
31
73
100
2829
1479
582
768
1232
1597
1048
1647
2416
413
1978
669
140
2369
455
767
1419
610
1142
1126
554
216
1395
1064
295
2456
353
387
1026
963
333
156
60
117
142
191
184
135
285
48
237
75
16
280
52
86
155
87
105
126
102
12
146
151
58
270
28
32
104
156
0.70 (0.59-0.82)
0.72 (0.56-0.92)
0.66 (0.45-0.99)
0.69 (0.52-0.92)
0.58 (0.44-0.76)
0.79 (0.64-0.98)
0.63 (0.50-0.80)
0.75 (0.58-0.97)
0.68 (0.56-0.81)
0.83 (0.54-1.26)
0.71 (0.58-0.86)
0.60 (0.42-0.86)
1.12 (0.57-2.22)
0.67 (0.56-0.80)
0.90 (0.59-1.36)
0.45 (0.31-0.66)
0.84 (0.66-1.06)
0.70 (0.51-0.97)
0.72 (0.54-0.97)
0.61 (0.46-0.81)
0.74 (0.55-0.99)
0.94 (0.42-2.13)
0.70 (0.54-0.90)
0.72 (0.57-0.92)
0.71 (0.48-1.06)
0.69 (0.57-0.83)
0.57 (0.30-1.07)
0.99 (0.60-1.62)
0.70 (0.52-0.95)
0.63 (0.49-0.82)
0.938
0.082
0.339
0.391
0.299
0.207
0.024
0.597
0.787
0.846
0.422
3
0.5
12
HR ( 95% CI ) Interaction
P value
No.
Events
No.
Events
Abemaciclib + ET
ET alone
Favors
Abemaciclib + ET
Favors
ET alone
Nominal P < 0.0001
HR = 0.70 (95% CI 0.59-0.82)
Patients
2808
2829
Events
232
333
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 121518212427303336394245
Time (months)
Abemaciclib + ET
ET alone
2808 2680 2621 2579 2547 2508 2477 2430 1970 1287 919 522 275 67 8 0
2829 2700 2652 2608 2572 2513 2472 2400 1930 1261 906 528 281 64 10 0
Invasive disease−free survival (%)
Number at risk
Abemaciclib + ET
ET alone
2-year rate: 92.7%
2-year rate: 90.0% 3-year rate: 83.4%
3-year rate: 88.8%
A
B
Figure 1. Invasive disease-free survival (IDFS) in the intent-to-treat (ITT) population at additional follow-up 1 (AFU1).
CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; ET, endocrine therapy; HR, hazard ratio.
Annals of Oncology N. Harbeck et al.
6https://doi.org/10.1016/j.annonc.2021.09.015 Volume xxx -Issue xxx -2021
Collectively, these data suggest that 2 years of abemaci-
clib treatment provide a meaningful benefit for this patient
population. A 2-year abemaciclib treatment duration was
selected to manage patients through their period of highest
relapse-risk while simultaneously balancing the risk poten-
tial for side-effects.
21
Further follow-up is needed to
determine the impact of adjuvant abemaciclib on later
recurrences.
OS data remained immature and follow-up for survival
outcomes is ongoing. Given the substantial reduction in the
risk of developing invasive disease as well as distant
recurrence and the maintenance of the treatment benefit
over time, it is anticipated that the robust treatment benefit
will translate to survival benefit.
Two phase III studies investigating palbociclib, another
CDK4 and 6 inhibitor, in patients with HRþ, HER2EBC
have recently reported no improvement in IDFS with the
addition of adjuvant palbociclib to ET.
22,23
PALLAS enrolled
5760 patients with stage II-III disease and Penelope-B
enrolled 1250 patients with residual disease after neo-
adjuvant chemotherapy and a clinical pathological staging-
estrogen receptor grading score of 3, or score ¼2 and
tumor involvement in lymph nodes. The reasons for the
differences in outcomes between these studies and mon-
archE are unclear. While the studies enrolled patients with
different risks of recurrence, there was no numerical benefit
in the subgroup of high-risk patients (58.7%) in PALLAS
defined as having 4 positive nodes or 1-3 positive nodes
with either T3/T4 and/or grade 3 disease. The treatment
durations with the CDK4 and 6 inhibitors also differed be-
tween Penelope-B (1 year) and monarchE and PALLAS (2
years). In Penelope-B, the observed numerical difference
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 121518212427303336394245
1262 1221 1189 1167 1155 1139 1123 1094 870 546 377 203 109 25 2 0
1236 1197 1177 1158 1142 1114 1096 1041 827 520 367 198 107 25 3 0
Invasive disease−free survival (%)
Time (months)
Nominal P = 0.0006
HR = 0.66 (95% CI 0.52-0.84)
1262
1236
118
172
Abemaciclib + ET
ET alone
Patients Events
2-year rate: 91.9%
2-year rate: 87.9%
3-year rate: 86.8%
3-year rate: 80.8%
Number at risk
Abemaciclib + ET
ET alone
Nominal P = 0.0002
HR = 0.63 (95% CI 0.49-0.80)
1017
986
104
158
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Abemaciclib + ET
ET alone
1017 989 963 946 936 922 908 894 733 484 348 203 109 25 2 0
986 955 938 922 906 883 868 835 687 457 333 197 107 25 3 0
Invasive disease−free survival (%)
Time (months)
Number at risk
Abemaciclib + ET
ET alone
Patients Events
2-year rate: 91.5%
3-year rate: 86.1%
2-year rate: 86.4% 3-year rate: 79.0%
A
B
Figure 2. Invasive disease-free survival (IDFS) in (A) ITT Ki-67-high and (B) cohort 1 Ki-67-high populations at additional follow-up 1 (AFU1).
CI, confidence interval; ET, endocrine therapy; HR, hazard ratio.
N. Harbeck et al. Annals of Oncology
Volume xxx -Issue xxx -2021 https://doi.org/10.1016/j.annonc.2021.09.015 7
favoring the palbociclib arm in the IDFS rates (4.3% and
3.5% at 2 and 3 years, respectively) was not sustained over
time and the study did not show a statistically significant
benefit. It remains unknown if the early separation of the
IDFS KM curves reflected a transient treatment effect from
palbociclib that diminished over time or could be attributed
to statistical variability related to a small number of events
at the earlier timepoints. In monarchE, the treatment
benefit of abemaciclib þET was statistically significant and
clinically meaningful. This benefit was maintained over time
and extended beyond the 2-year study treatment period.
Another potential explanation for the discordant out-
comes to date for monarchE, PALLAS, and Penelope-B are the
differences between drugs. Whereas abemaciclib is admin-
istered continuously daily, palbociclib is administered daily
for 3 weeks followed by 1-week rest. In preclinical studies,
abemaciclib has shown a tolerability profile that allows for a
continuous dosing required for sustainable G1/S arrest and
inhibition of tumor growth.
24,25
In addition, continuous in-
hibition of CDK4 and 6 by abemaciclib led to cell senescence
and apoptosis to a greater extent than was seen with pal-
bociclib.
25,26
It can be speculated that the differences in
mechanism of action and the continuous versus intermittent
dosing schedules may be more important in eradicating
micrometastatic cells in an adjuvant setting, as opposed to
established macrometastatic disease where both abemaci-
clib and palbociclib have shown relatively similar anticancer
activity in regard to progression-free survival. Differences,
however, in OS benefit between abemaciclib and palbociclib
have also been observed in the metastatic setting in combi-
nation with fulvestrant in patients who progressed after prior
ET. Whereas palbociclib in combination with fulvestrant failed
to show significant OS differences in the ITT population,
27
abemaciclib plus fulvestrant demonstrated a statistically
significant OS benefit in the ITT population.
28
The use of Ki-67 in clinical practice is historically
challenging due to the high inter-observer variability and
the lack of a standard threshold for determining high
versus low values.
29
In monarchE, Ki-67 was measured at
a central laboratory using a validated assay that was
shown to be highly reproducible across different pathol-
ogists and laboratories using an automated staining
protocol with a standardized scoring method.
17
This is
the first phase III registration trial that has prospectively
analyzed the utility of a prespecified, centrally confirmed
Ki-67 threshold of 20% using a standardized assay and
methodology. Abemaciclib þET significantly improved
IDFS in patients with Ki-67-high tumors in the ITT and
cohort 1 populations. Within cohort 1, the benefitof
abemaciclib was consistently observed regardless of Ki-67
index, suggesting Ki-67 is not predictive of abemaciclib
treatment benefit. Because patients in cohort 1 with Ki-
67-high tumors had a greater risk of recurrence than
those with Ki-67-low tumors, we concluded that Ki-67
index was prognostic of recurrence. Overall, these data
support use of Ki-67 20% together with high-risk
||
1017
986
946
968
104
158
62
86
70
75
80
85
90
95
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time
(
months
)
Invasive disease–free survival (%)
Abemaciclib + ET
ET alone
Abemaciclib + ET
ET alone
Cohort 1 Ki-67-high
Cohort 1 Ki-67-low
EventsPatients
2-year rate: 91.5%
2-year rate: 86.4%
2-year rate: 94.4%
2-year rate: 92.9%
HR = 0.63 (95% CI 0.49-0.80)
HR = 0.70 (95% CI 0.51-0.98)
3-year rate: 79.0%
3-year rate: 86.1%
3-year rate: 91.7%
3-year rate: 87.2%
Figure 3. Kaplan-Meier curves of invasive disease-free survival in Cohort 1 Ki-67 high versus Ki-67 low at additional follow-up 1 (AFU1).
CI, confidence interval; ET, endocrine therapy; HR, hazard ratio.
Annals of Oncology N. Harbeck et al.
8https://doi.org/10.1016/j.annonc.2021.09.015 Volume xxx -Issue xxx -2021
clinicopathological features to identify patients with an
even greater risk of recurrence.
In conclusion, adjuvant abemaciclib combined with ET
showed statistically significant and clinically meaningful
improvement in IDFS for patients with HRþ, HER2, node-
positive, high-risk, EBC. Ki-67 index was a prognostic factor
for recurrence in this treatment setting but was not pre-
dictive of the treatment effect with abemaciclib benefit
being observed regardless of Ki-67 status. With 27 months
median follow-up, abemaciclib þET continued to provide a
clinically meaningful benefit in IDFS and DRFS that extended
beyond the 2-year treatment period, with a tolerable and
manageable safety profile.
ACKNOWLEDGEMENTS
The authors and Eli Lilly and Company would like to thank
the patients and their families/caregivers for participating in
this trial. monarchE would not have been possible without
the investigators and their support staff who participated in
this work. Finally, the authors are grateful for the time and
efforts of the monarchE Executive and Steering Commit-
tees. Medical writing support was provided by Trish Huynh,
employee of Eli Lilly and Company, and editorial assistance
provided by Dana Schamberger, employee of Syneos Health.
All writing, editorial assistance, and statistical analysis were
funded by Eli Lilly and Company.
FUNDING
This work was supported by the sponsor (Eli Lilly and
Company) and designed together with the study Executive
Committee (no grant number).
DISCLOSURE
NH reports research grants from Eli Lilly and Company to
her institution; personal fees and other for lectures and
consulting from Amgen, AstraZeneca, Daiichi-Sankyo, Eli
Lilly and Company, Merck Sharp & Dohme (MSD), Novartis,
Pfizer, Pierre-Fabre, Roche/Genentech, Sandoz, and SeaGen
outside the submitted work. SJ reports personal fees from
AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, and
Puma Biotechnology for consulting and advisory role; per-
sonal fees from AstraZeneca, Novartis, Pfizer, Eisai, and
Roche/Genentech for speaker’s bureau; personal fees and
other from AstraZeneca, Eli Lilly and Company, Novartis,
Pfizer, Puma Biotechnology, and Roche/Genentech for
research funding, outside the submitted work. PR reports
other compensation for travel/accommodations from Eli
Lilly and Company, AstraZeneca, and Roche/Genentech; and
other non-compensated fees for Ad Board participation,
outside the submitted work. MM reports grants from
Novartis and personal fees from Amgen, Roche, AstraZe-
neca, and Pfizer, outside of the submitted work. ZMS, MA,
RH, and KT have nothing to disclose. SMT reports grants and
personal fees from Eli Lilly and Company, during the
conduct of the study; grants and personal fees from
Immunomedics/Gilead, AstraZeneca, grants and personal
fees from Eli Lilly and Company, Odonate, grants and
personal fees from Merck, grants and personal fees from
Nektar, grants and personal fees from Novartis, grants and
personal fees from Pfizer, grants and personal fees from
Genentech/Roche, grants and personal fees from Exelixis,
grants and personal fees from Bristol Myers Squibb, grants
and personal fees from Eisai, Sanofi, and grants and per-
sonal fees from Nanostring; personal fees from Chugai
Pharma, Ellipses Pharma, 4D Pharma, BeyondSpring
Pharma, OncXerna, Infinity Therapeutics, OncoSec, Seattle
Genetics, Celldex, Certara, Mersana Therapeutics, Silverback
Therapeutics, Daiichi-Sankyo, G1 Therapeutics, CytomX,
Samsung Bioepis Inc., Athenex, OncoPep, Kyowa Kirin
Pharmaceuticals, and Puma; grants from Cyclacel, grants
and personal fees from Sanofi, personal fees from Celldex,
grants and personal fees from Odonate, personal fees from
Seattle Genetics, personal fees from Silverback Therapeu-
tics, personal fees from G1 Therapeutics, personal fees from
Athenex, personal fees from OncoPep, personal fees from
Kyowa Kirin Pharmaceuticals, personal fees from Daiichi-
Sankyo, personal fees from CytomX, personal fees from
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fees from Mersana Therapeutics, grants and personal fees
from Immunomedics/Gilead, personal fees from OncoSec,
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mitted work. PAH reports personal fees from Novartis,
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Company, Pierre Fabre, Seattle Genetics, Roche/Genentech,
and Hexal; and grants from Biontech, and Cepheid, outside
of the submitted work. CH reports grants and personal fees
for advisory role from Eli Lilly and Company; personal fees
and non-financial support for advisory role, speaker’s bu-
reaus, and travel expense from Amgen; and grants, personal
fees, and non-financial support for advisory role, speaker
bureaus, and travel expenses from Pfizer and Roche/Gen-
entech; grants and personal fees for speaker bureaus from
Novartis; grants, personal fees, and non-financial support
for travel expenses, and grants from EirGenix, OBI Pharma,
MSD, and Daiichi-Sankyo, outside the submitted work. GGJ
reports personal fees from Eli Lilly and Company, during the
conduct of the study; personal fees from Amgen, AstraZe-
neca, Clinigen, Egis, Eli Lilly and Company, Exact Sciences,
Novartis, Oncompass Medicine, Pfizer, Pierre Fabre, Roche/
Genentech, Sandoz, Samsung, and TLC Biopharmaceuticals,
outside the submitted work. AT reports personal fees and
non-financial support from Eli Lilly and Company, Bayer and
Novartis, Bristol Myers Squibb, MSD, Biocad, and Merck;
personal fees from AstraZeneca, Eisai Co., Ltd, and Amgen,
outside the submitted work. MPG receives consulting fees
to institution from Eagle pharmaceuticals, Eli Lilly and
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Pfizer, and Biotheranostics; and grants from Pfizer, and Eli
Lilly and Company; and grants to institution from Sermonix,
outside the submitted work. HSR reports grants to institu-
tion from Pfizer, Merck, Novartis, Eli Lilly and Company,
Roche/Genentech, OBI, Odonate, Daiichi-Sankyo, Seattle
N. Harbeck et al. Annals of Oncology
Volume xxx -Issue xxx -2021 https://doi.org/10.1016/j.annonc.2021.09.015 9
Genetics, Eisai, MacroGenics, Sermonix, Immunomedics,
and AstraZeneca; non-financial travel support for educa-
tional meeting from Daiichi-Sankyo, Mylan, Pfizer, Merck,
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Diamond, grants from Seattle Genetics, outside the sub-
mitted work. VA, RW, SB, SS, TF, SCN, BSA, MM, AS are full-
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sory role from Konica Minolta; other fees for honoraria and
advisory role from Bristol Myers Squibb; other fees for
advisory role from Athenex Oncology, Bertis, Terumo, and
Kansai Medical Net; and serves as a board of director for
JBCRG association, Organisation for Oncology and Trans-
lational Research, and Kyoto Breast Cancer Research
Network, outside the submitted work. JO reports personal
fees from Abbvie, Aptitude Health, AstraZeneca, Agendia,
Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics,
Genentech, Immunomedics, Eli Lilly and Company, Merck,
Novartis, Pfizer, Puma Biotechnology, Roche/Genentech,
and Seattle Genentech, outside the submitted work.
DATA SHARING
Lilly provides access to all individual participant data
collected during the trial, after anonymization, with the
exception of pharmacokinetic or genetic data. Data are
available to request 6 months after the indication studied
has been approved in the USA and EU or after primary
publication acceptance, whichever is later. No expiration
date for data requests is set once the data are made
available. Access is provided after a proposal has been
approved by an independent review committee identified
Annals of Oncology N. Harbeck et al.
10 https://doi.org/10.1016/j.annonc.2021.09.015 Volume xxx -Issue xxx -2021
for this purpose and after receipt of a signed data-sharing
agreement. Data and documents, including the study pro-
tocol, statistical analysis plan, clinical study report, and
blank or annotated case report forms, will be provided in a
secure data-sharing environment. For details on submitting
a request, see the online instructions.
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N. Harbeck et al. Annals of Oncology
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