Received: 6 December 2020 | Revised: 4 March 2021 | Accepted: 7 March 2021

DOI: 10.1111/cas.14877

ORIGINAL ARTICLE

Abemaciclib in combination with endocrine therapy for East

Asian patients with HR+, HER2− advanced breast cancer:
MONARCH 2 & 3 trials

Masakazu Toi1 | Kenichi Inoue2 | Norikazu Masuda3 | Hiroji Iwata4 |

Joohyuk Sohn5 | In Hae Park6 | Seock-Ah Im7 | Shin-Cheh Chen8 | Sotaro Enatsu9 |
P. Kellie Turner10 | Valérie A. M. André11 | Molly C. Hardebeck10 | Sachi Sakaguchi9 |
Matthew P. Goetz12 | George W. Sledge Jr13
1
Breast Cancer Unit, Graduate School of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan
2
Division of Breast Oncology, Saitama Cancer Center, Saitama, Japan
3
National Hospital Organization Osaka National Hospital, Osaka, Japan
4
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
5
Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
6
Division of Hematology and Medical Oncology, Department of Internal Medicine, National Cancer Center, Goyang, Korea
7
Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
8
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University Medical College Taoyuan, Taoyuan, Taiwan
9
Eli Lilly and Company, Tokyo, Japan
10
Eli Lilly and Company, Indianapolis, IN, USA
11
Eli Lilly and Company, Paris, France
12
Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
13
Stanford University, Stanford, CA, USA

Correspondence
Masakazu Toi, Breast Cancer Unit, Kyoto Abstract
University Hospital, Breast Surgery, This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy,
Graduate School of Medicine, Kyoto
University, 54 Shogoin-Kawaracho, Sakyo- safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine
ku, Kyoto 606-8507, Japan. therapy (ET) in East Asian patients with hormone receptor positive (HR+), human
Email: [email protected]
epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer.
Funding information MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 stud-
Eli Lilly and Company, Indianapolis
ies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal
aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian
population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the
MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial.

Abbreviations: ABC, advanced breast cancer; AE, adverse events; ALT, alanine aminotransferase; CBR, clinical benefit rate; CDK, cyclin-dependent kinase; CI, confidence interval; CR,
complete response; ET, endocrine therapy; HER2−, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone receptor positive; ILD, interstitial lung disease;
ITT, intent-to-treat; NSAI, nonsteroidal aromatase inhibitor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PR, partial
response; SAE, serious adverse event; VTE, venous thromboembolic event.
Clinical Trial Register and Clinical Registration number: NCT02107703 and NCT02246621.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Cancer Science. 2021;112:2381–2392. wileyonlinelibrary.com/journal/cas | 2381

2382 | TOI eT al.

In the East Asian population, median progression-free survival (PFS) was significantly
prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (haz-
ard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median:
21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001;
median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3:
88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most fre-
quent adverse events observed in the East Asian populations. Abemaciclib exposures
and PK were similar in East Asians and the non-East Asian populations of both trials.
Abemaciclib in combination with ET in the East Asian populations of MONARCH 2
and MONARCH 3 provided consistent results with the ITT populations, demonstrat-
ing improvements in efficacy with generally tolerable safety profiles for patients with
HR+, HER2− advanced breast cancer.

KEYWORDS

abemaciclib, breast cancer, cyclin-dependent kinase inhibitor, East Asia, metastatic

1 | I NTRO D U C TI O N intent-to-treat (ITT) population (median PFS: 28.18 vs 14.76 months,

HR: 0.540; 95% CI: 0.418 to 0.698; P < .001) and ORR in patients
Recent advances in the treatment of hormone receptor posi- with measurable disease (61.0% [95% CI: 55.2% to 66.9%] vs 45.5%
tive (HR+), human epidermal growth factor receptor 2-negative [95% CI: 37.0% to 53.9%], P = .003) compared with placebo plus aro-
(HER2−) advanced breast cancer (ABC) have changed the standard matase inhibitor.18 Likewise, in MONARCH 2, abemaciclib in combi-
of care.1 Typically these patients have been treated with endo- nation with fulvestrant resulted in significant improvement in PFS
crine therapy (ET), such as an aromatase inhibitor in the first-line and OS compared with placebo plus fulvestrant (median PFS: 16.4
setting and fulvestrant in the second-line setting.1,2 However, vs 9.3 months, HR: 0.553, 95% CI 0.449- 0.681, P < .001; median
cyclin-dependent kinase 4 and 6 (CDK4 & 6) inhibitors, such as OS: 46.7 vs 37.3 months, HR: 0.757; 95% CI, 0.606- 0.945; P = .01). 5,8
abemaciclib, are now being combined with ET in these treatment In patients with measurable disease, the ORR was significantly im-
settings and have significantly improved outcomes in terms of proved in the abemaciclib arm compared with the placebo arm (ORR:
progression-free survival (PFS), objective response rate (ORR), and 48.1% [95% CI, 42.6% to 53.6%] vs 21.3% [95% CI, 15.1% to 27.6%],
overall survival (OS). 3-8 P < .001).5 The MONARCH trials also reported a consistent and tol-
Abemaciclib is a CDK4 & 6 inhibitor that targets the cyclin D/ erable safety profile of abemaciclib in combination with ET.5,18
CDK/retinoblastoma signaling pathway, creating a G1 cell cycle The incidence of breast cancer among East Asian women has
block resulting in apoptosis and senescence in preclinical models.9 increased rapidly in recent years and is one of the leading causes
In enzymatic assays, abemaciclib notably exhibited a 14-fold higher of cancer-related mortality in East Asian women.19-21 The growing
3,10
selectivity in kinases for cyclinD1/CDK4 than cyclinD3/CDK6. incidence in Asian women may be due to lifestyle changes, includ-
CDK4 & 6 inhibitors are commonly associated with hematological ing postmenopausal obesity, earlier menarche, later menopause,
toxicities which have been ascribed to the consequence of CDK6 decreased breastfeeding, and beginning child-bearing later in
inhibition, as this kinase plays a crucial role in the proliferation and life. 22 The age of occurrence varies between regions, with Asian
11,12
development of hematopoietic stem cells in the bone marrow. women having a greater incidence in their forties and fifties, while
However, the greater selectivity of abemaciclib toward CDK4 com- women in the western countries having a greater incidence in
pared with CDK6 may explain why abemaciclib is able to be dosed their sixties. 23 Response to cancer therapies and the AE profile
on a continuous schedule, unlike other CDK4 & 6 inhibitors which in the Asian population can also differ from other regions due to
require an intermittent schedule due to the dose-limiting toxicity of geographic variation in clinical practice, racial/ethnic background,
neutropenia.3,5,13-17 genetic variation, and differences in drug metabolism, among oth-
Abemaciclib is approved in combination with ET as initial ther- ers. Therefore, it is important to evaluate the efficacy and safety
apy and following progression on ET in the advanced setting based of cancer therapies within the Asian population. Here, we report
4,5,8,18
on the MONARCH 3 and MONARCH 2 trials, respectively. In a subgroup analysis evaluating the efficacy and safety of abe-
MONARCH 3, abemaciclib in combination with an aromatase in- maciclib in combination with ET in the East Asian patients of the
hibitor (anastrozole or letrozole) significantly improved PFS in the MONARCH 2 and 3 trials.
TOI eT al. | 2383

2 | M E TH O DS endpoints evaluated in both the studies are ORR (percentage of pa-

tients with best response of complete [CR] or partial response [PR]),
2.1 | Study design and population clinical benefit rate (CBR = CR + PR + SD ≥6 months), safety and
tolerability, and pharmacokinetics (PK).
The study design, procedures, and statistical methods for
MONARCH 2 and 3 have been previously published in detail.4,5
MONARCH 2 (NCT02107703) is a randomized, double-blind, phase 2.4 | Statistical analysis
3 study of abemaciclib/placebo + fulvestrant in women with HR+,
HER2− ABC whose disease had progressed while receiving neoad- Detailed statistical methods of both the studies have been previ-
juvant or adjuvant ET, ≤12 months from the end of adjuvant ET, or ously published.4,5,18 The East Asian population used for this sub-
while receiving first-line ET for metastatic disease. Patients must group analysis was defined based on the geographic region in which
not have received more than one ET or any prior chemotherapy in patients enrolled at study sites in Japan, Korea, and Taiwan. The data
the advanced setting.5 MONARCH 3 (NCT02246621) is a phase 3, are from the final PFS database lock from MONARCH 2 and 3 trials,
randomized, double-blind trial of abemaciclib/placebo + NSAI (anas- 14 February, 2017 and 03 November, 2017, respectively. At the time
trozole or letrozole per physician's choice) for initial therapy of HR+, of the final PFS analysis, results for prespecified subgroups includ-
HER2− ABC (prior neoadjuvant or adjuvant ET was permitted if the ing region (North America, Europe, and Asia) were reported.8,18 In
disease-free interval was >12 months from the completion of prior the present report, we further described the East Asian subgroup. In
ET). Patients must not have received systemic therapy for advanced both studies, the primary end point, PFS was analyzed using Kaplan-
disease.4 Randomly assigned patients in these studies were strati- Meier estimates and an unstratified Cox proportional hazards model.
fied by metastatic site: visceral, bone only, or other (MONARCH 2 In MONARCH 2, PK samples were collected cycle (C) 1, day (D) 1:
and 3); ET resistance (MONARCH 2); and prior ET: NSAI, no ET or 2 to 4 hours (h) post dose; C1D15: 4 and 7 h post dose; C2D1: prior
other (MONARCH 3). to dose and 3 h post dose; C3D1; prior to dose. In MONARCH 3, PK
Each center's institutional review board or independent ethics samples were collected C1D1: 2 to 4 h post dose; C2D1: 4 and 7 h
committee approved the trials. The study followed the guiding prin- post dose; C3D1: prior to dose and 3 h post dose; C4D1: 2 to 4 h post
ciples of the Declaration of Helsinki and the Good Clinical Practice dose. A population pharmacokinetic analysis was conducted using
Guidelines of the International Conference on Harmonization. All NONMEM 7.3.0 to evaluate the contribution of covariates such as
patients provided written informed consent before enrollment. race to the interindividual variability in abemaciclib PK. 25-27 In addi-
tion, the observed abemaciclib concentrations for East Asians and
the non-East Asian population were plotted versus time from the
2.2 | Study treatment first dose.

Detailed methods for randomization, treatment, dose adjustments,

and treatment discontinuation for MONARCH 2 and 3 trials were 3 | R E S U LT S
4,5
previously described. In MONARCH 2, patients were randomized
in a 2:1 ratio to receive either abemaciclib + fulvestrant or placebo 3.1 | Patients
+ fulvestrant. 5,24 In MONARCH 3, patients were randomly assigned
in a 2:1 ratio to receive either abemaciclib + NSAI or placebo + Of the 669 overall ITT patients in the MONARCH 2 trial, 212 (31.7%)
NSAI. In MONARCH 2, at study initiation, patients in the abemaci- patients were enrolled at sites in the East Asian countries (Japan,
clib arm received 200 mg twice daily. Following a review of safety Korea, and Taiwan); 147 (69.3%) were randomized to receive abe-
data and dose reduction rates, the protocol was amended to reduce maciclib + fulvestrant and 65 (30.7%) to receive placebo + fulves-
the starting dose to 150 mg for new patients, and all patients who trant. A total of 57 (39%) East Asian patients received 200 mg of
were receiving 200 mg underwent a mandatory dose reduction to abemaciclib as initial dose prior to the mandatory dose reduction
150 mg twice daily. A total of 178 patients (26.6%) were enrolled at amendment in MONARCH 2. In the MONARCH 3 trial, a total of
the 200 mg starting dose. Patients in the abemaciclib + fulvestrant 493 patients were enrolled globally, of which 144 (29.2%) were East
arm received a median of 34 days of treatment at the 200-mg start- Asians; 102 (70.8%) patients were randomized to the abemaciclib +
ing dose prior to dose reduction or discontinuation. In MONARCH 3, NSAI arm and 42 (29.1%) patients to the placebo + NSAI arm. As the
abemaciclib 150 mg was orally administered twice daily. stratification at randomization was applied to the ITT population and
not for each region or race, in the East Asian population, the num-
ber of patients with visceral disease was higher in the abemaciclib +
2.3 | Study endpoints fulvestrant arm compared with the placebo + fulvestrant arm in the
MONARCH 2 trial (61.9% vs 49.2%), and fewer in the abemaciclib +
The primary endpoint of MONARCH 2 and 3 was to compare PFS of NSAI arm compared with the placebo + NSAI arm in the MONARCH
the experimental arm with that of the control arm. Key secondary 3 trial (49.0% vs 59.5%). Of note, in MONARCH 2 there were more
2384 | TOI eT al.

pre/perimenopausal East Asian patients (35.4%) compared with the 3: 74.3%) compared with ITT (MONARCH 2: 59.8%; MONARCH 3:
ITT (17.0%). In both trials, there were more East Asian patients with 60.0%). Complete baseline and disease characteristics in the East
an ECOG performance status of 0 (MONARCH 2: 79.2%; MONARCH Asian population are presented in Table 1.

TA B L E 1 Baseline characteristics of East Asian patients in the MONARCH 2 and 3 trials

MONARCH 2 MONARCH 3

Abemaciclib + fulvestrant Placebo + fulvestrant Abemaciclib + NSAI Placebo +

Characteristics n = 147 n = 65 n = 102 NSAI n = 42

Age, n (%)
Median (range) 55 (32-76) 56 (32-81) 60 (45-78) 62 (46-85)
<65 y 118 (80.3) 48 (73.8) 66 (64.7) 27 (64.3)
≥65 y 29 (19.7) 17 (26.2) 36 (35.3) 15 (35.7)
Country, n (%)
Japan 64 (43.5) 31 (47.7) 38 (37.3) 15 (35.7)
Korea 58 (39.5) 20 (30.8) 41 (40.2) 18 (42.9)
Taiwan 25 (17.0) 14 (21.5) 23 (22.5) 9 (21.4)
Menopausal status
Postmenopausal 96 (65.3) 41 (63.1) NA NA
Pre- or perimenopausal 51 (34.7) 24 (36.9)
Measurable disease, n (%)
Yes 122 (83.0) 47 (72.3) 86 (84.3) 37 (88.1)
No 25 (17.0) 18 (27.7) 16 (15.7) 5 (11.9)
Metastatic site, n (%)
Visceral 91 (61.9) 32 (49.2) 50 (49.0) 25 (59.5)
Bone-only 28 (19.0) 20 (30.8) 21 (20.6) 7 (16.7)
other 28 (19.0) 13 (20.0) 31 (30.4) 10 (23.8)
a
Disease setting, n (%)
Recurrent locally advanced 6 (4.1) 0 4 (3.9) 1 (2.4)
Metastatic 141 (95.9) 65 (100.0) 98 (96.1) 41 (97.6)
Prior neoadjuvant systemic therapy, n (%)
Endocrine therapy 4 (2.7) 2 (3.1) 0 1 (2.4)
Chemotherapy 23 (15.6) 13 (20.0) 4 (3.9) 7 (16.7)
Prior adjuvant systemic therapy, n (%)
Endocrine 116 (78.9) 55 (84.6) 40 (39.2) 20 (47.6)
Chemotherapy 73 (49.7) 37 (56.9) 36 (35.3) 14 (33.3)
Most recent endocrine therapy
Neoadjuvant/adjuvant metastatic 82 (55.8) 41 (63.1) NA NA
64 (43.5) 23 (35.4)
PgR status, n (%)b
Positive 110 (74.8) 55 (84.6) 77 (75.5) 31 (73.8)
Negative 37 (25.2) 9 (13.8) 25 (24.5) 11 (26.2)
ECOG PS, n (%)
0 114 (77.6) 54 (83.1) 74 (72.5) 33 (78.6)
1 33 (22.4) 11 (16.9) 28 (27.5) 9 (21.4)
d
Sensitivity to ET, n (%)
Primary resistance 35 (23.8) 19 (29.2) NA NA
Secondary resistance 111 (75.5) 45 (69.2)

Abbreviations: AI, aromatase inhibitor; ET, endocrine therapy; NA, not available; NSAI, nonsteroidal aromatase inhibitor; PgR, progesterone receptor.
a
Derived based on baseline tumor lesion locations; bOne patient in MONARCH 2 placebo arm had unknown PgR status.
TOI eT al. | 2385

3.2 | Efficacy 3.2.2 | MONARCH 3

3.2.1 | MONARCH 2 In the East Asian population, 36 (35.3%) PFS events occurred in the abemaci-
clib + NSAI arm, and 30 (71.4%) occurred in the placebo + NSAI arm. Median
A total of 70 (47.6%) PFS events in the abemaciclib + fulves- PFS was not reached in the abemaciclib + NSAI arm and was 12.82 months
trant arm and 51 (78.5%) in the placebo + fulvestrant arm in the placebo + NSAI arm (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001)
occurred by the data cutoff in East Asian patients. Median (Figure 1B). Patients with measurable disease achieved an ORR of 69.8%
PFS was 21.2 months in the abemaciclib + fulvestrant arm (95% CI, 60.1% to 79.5%) in the abemaciclib + NSAI arm and 45.9% (95% CI,
and 11.6 months in the placebo + fulvestrant arm (HR, 0.520; 30% to 62%) in the control arm (Table 2). The CBR for East Asian patients
95% CI, 0.362 to 0.747; P < .001) (Figure 1A). Patients with was 87.3% (95% CI, 80.8% to 93.7%) in the abemaciclib + NSAI arm and
measurable disease achieved an ORR of 47.5% (95% CI, 38.7% to 73.8% (95% CI, 60.5% to 87.1%) in the placebo + NSAI arm (Table 2). East
56.4%) in the abemaciclib + fulvestrant arm and 23.4% (95% CI, Asian patients treated with abemaciclib + NSAI experienced greater tumor
11.3% to 35.5%) in the placebo + fulvestrant arm (Table 2). The CBR shrinkage compared with those in the placebo + NSAI arm (Figure 2B).
for East Asian patients was 76.2% (95% CI, 69.3% to 83.1%) for the
abemaciclib + fulvestrant arm and 75.4% (95% CI, 64.9% to 85.9%)
for the placebo + fulvestrant arm. For East Asian patients, as ob- 3.3 | Treatment exposure and PK
served in the waterfall plot, greater tumor shrinkage was achieved
in the abemaciclib + fulvestrant arm compared with the placebo + The median abemaciclib dose intensity of East Asian patients in
fulvestrant arm (Figure 2A). MONARCH 2 and 3 was 263 and 239 mg/d, respectively. The median

F I G U R E 1 Kaplan-Meier plot of
progression-free survival for East
Asian patients in MONARCH 2 (A) and
MONARCH 3 (B) trials. CI, confidence
interval; HR, hazard ratio; NR, not
reached; NSAI, nonsteroidal aromatase
inhibitor; PFS, progression-free survival
2386 | TOI eT al.

TA B L E 2 Summary of best overall response in the MONARCH 2 and 3 trials (East Asian population)

MONARCH 2 MONARCH 3

Abemaciclib + fulvestrant Placebo + fulvestrant Abemaciclib + NSAI Placebo +

Best overall response n = 147 n = 65 n = 102 NSAI n =42

All patients
CR, n (%) 3 (2.0) 0 1 (1.0) 0
PR, n (%) 55 (37.4) 11 (16.9) 59 (57.8) 17 (40.5)
SD, n (%) 74 (50.3) 47 (72.3) 36 (35.3) 20 (47.6)
≥6 mo, n (%) 54 (36.7) 38 (58.5) 29 (28.4) 14 (33.3)
PD, n (%) 9 (6.1) 6 (9.2) 1 (1.0) 4 (9.5)
Overall response rate (CR + PR), n 58 (39.5) (31.6-47.4) 11 (16.9) (7.8-26.0) 60 (58.8) (49.3-68.4) 17 (40.5)
(%) 95% CI (25.6-55.3)
Clinical benefit rate (CR + PR + SD 112 (76.2) (69.3-83.1) 49 (75.4) (64.9-85.9) 89 (87.3) (80.8-93.7) 31 (73.8)
≥6 mo), n (%) 95% CI (60.5-87.1)
Measurable disease population
(n) 122 47 86 37
CR, n (%) 3 (2.5) 0 1 (1.2) 0
PR, n (%) 55 (45.1) 11 (23.4) 59 (68.6) 17 (45.9)
SD, n (%) 50 (41.0) 31 (66.0) 22 (25.6) 15 (40.5)
≥6 mo, n (%) 32 (26.2) 24 (51.1) 16 (18.6) 9 (24.3)
PD, n (%) 9 (7.4) 4 (8.5) 1 (1.2) 4 (10.8)
Overall response rate (CR + PR), n 58 (47.5) (38.7-56.4) 11 (23.4) (11.3, 35.5) 60 (69.8) (60.1-79.5) 17 (45.9)
(%) 95% CI (29.9-62.0)
Clinical benefit rate (CR + PR +SD 90 (73.8) (66.0-81.6) 35 (74.5) (62.0-86.9) 76 (88.4) (81.6-95.1) 26 (70.3)
≥6 mo), n (%) 95% CI (55.5-85.0)

Abbreviations: CI, confidence interval; CR, complete response; NSAI, nonsteroidal aromatase inhibitor; PD, progressive disease, PR; partial response,
SD; stable disease.

duration of abemaciclib treatment in the East Asian population was in MONARCH 2 were 67.8% in the abemaciclib + fulvestrant arm
65.07 weeks in MONARCH 2 and 96.72 weeks in MONARCH 3. A versus 21.5% in the placebo + fulvestrant arm; similar rates were ob-
total of 20 (13.7%) and 30 (29.4%) East Asian patients in the abe- served in MONARCH 3, with 61.8% in the abemaciclib + NSAI arm
maciclib arm discontinued any study drug (discontinuation of one and 26.2% in the placebo + NSAI arm (Table 3). In the abemaciclib
or more study drug) due to an AE in MONARCH 2 and 3, respec- arm, a total of 28 (19.2%) East Asian patients in MONARCH 2 and 22
tively, whereas none of the patients discontinued any study drug in (21.6%) in MONARCH 3 experienced at least one serious adverse
the placebo arms. The dose reduction rate of abemaciclib due to an event (SAE), and the most frequently reported SAEs were pyrexia
AE in East Asian patients was 51.4% in MONARCH 2 and 46.1% in (three [2.1%]) and embolism (three [2.1%]) in MONARCH 2 and lung
MONARCH 3. In population pharmacokinetic analysis, race, includ- infection (six [5.9%]) in MONARCH 3. Among the East Asian patients
ing Asian, was not a significant covariate on any of the PK param- who died in the abemaciclib arms, two (1.4%) patients in MONARCH
eters. Furthermore, abemaciclib concentration time profiles for East 2 (cerebral infarction, abnormal hepatic function) and one (1%) pa-
Asian patients are similar to the global population (Figure 3). tient in MONARCH 3 (lung infection) died due to an AE while on
In order to investigate the effect of East Asian race on abemaciclib treatment or within 30 days of treatment discontinuation, whereas
PK or abemaciclib exposure, a population PK analysis was tested. This no deaths occurred during this period in the placebo arms of the East
demonstrated that race was not a significant covariate for any parame- Asian patients in both trials.
ter. Therefore, abemaciclib PK or exposure are not expected to be asso- The most common AE of any grade reported among East Asian
ciated with the observations related to East Asian race reported here. patients in the abemaciclib arm was diarrhea (MONARCH 2: 90.4%;
MONARCH 3: 88.2%), followed by neutropenia (MONARCH 2:
67.8%; MONARCH 3: 57.8%). Neutropenia was the most common
3.4 | Safety grade ≥ 3 AE observed among East Asian patients in both MONARCH
2 and 3 trials (MONARCH 2: 44.5%; MONARCH 3: 29.4. Of note, the
The overall abemaciclib safety profile of East Asians in MONARCH incidence of ALT increase (any grade; ≥20% in East Asian patients)
2 and 3 was similar. Rates of grade ≥ 3 AEs in East Asian patients was 23.3% and 32.4% (n = 102) in MONARCH 2 and 3, respectively.
TOI eT al. | 2387

F I G U R E 2 Change in tumor size and response rate for East Asian patients in MONARCH 2 (A) and MONARCH 3 (B) trials. NSAI,
nonsteroidal aromatase inhibitor

Aspartate aminotransferase (AST) increase was also observed in The most frequent AE leading to discontinuation of any study
32.4% of East Asian patients in MONARCH 3. Tables comparing AEs drug was neutropenia (three [2.1%]) in MONARCH 2 and neutro-
among East Asian, non-East Asian, and the ITT populations are pro- penia (five [4.9%]) and alanine aminotransferase (ALT) increased
vided in the Supporting Information (Table S1 and S2). (five [4.9%]) in MONARCH 3. In MONARCH 2, discontinuations
2388 | TOI eT al.

F I G U R E 3 Abemaciclib plasma
concentration in MONARCH 2 and
MONARCH 3 in East Asian and global
populations. Each symbol represents
an observation. Red circles indicate the
East Asian population, and open triangles
represent the global population

due to ALT increase were infrequent (two [1.4%]). The most fre- consistent benefit/risk profile with the previously disclosed results
quent AEs leading to dose reduction were diarrhea (MONARCH 2: of the ITT population.
19.9%; MONARCH 3: 7.8%) and neutropenia (MONARCH 2: 18.5%; Baseline demographic and disease characteristics were gener-
MONARCH 3: 16.7%). ally similar between the East Asian and overall ITT populations in
In the abemaciclib arm, there were two (1.4%) East Asian patients both studies, but there were a few notable differences. As noted
in MONARCH 2 and 11 (10.8%) in MONARCH 3 who developed in- in the results section, in both trials, there were more East Asian pa-
terstitial lung disease (ILD) defined by selected treatment-emergent tients with an ECOG performance status of 0 (MONARCH 2: 79.2%;
AEs with the term of pneumonitis, ILD, organizing pneumonia, pul- MONARCH 3: 74.3%) compared with the ITT (MONARCH 2: 59.8%;
monary fibrosis, bronchiolitis obliterans, and obliterative bronchiol- MONARCH 3: 60.0%). Additionally, there was a higher percentage
itis. Among the 13 East Asian patients with ILD (Grade 1 or 2: n = 11; of pre/perimenopausal patients in MONARCH 2 (35.4%) versus the
Grade 3: n = 2), there were no fatal ILD events (Table S3). Due to ITT (17.0%), and in both trials, there were more East Asian patients
ILD, five patients received steroid therapy, two patients discon- under 65 years of age (MONARCH 2: 78.3%; MONARCH 3: 64.6%)
tinued study treatment, and two patients had a dose reduction of compared with the ITT (MONARCH 2: 63.4%; MONARCH 3: 55%).
abemaciclib. These findings are consistent with the literature, which reports that
Venous thromboembolic events (VTEs) of any grade occurred in Asian patients are being diagnosed with breast cancer at a younger
five patients (3.4%) and three patients (2.9%) of abemaciclib-treated age compared with Western countries. 23
East Asian patients in the MONARCH 2 and 3, respectively. Of these East Asian patients in both trials experienced an improvement
eight patients, four had a Grade 3 event (Table S4). All eight patients in PFS in the abemaciclib arms compared with the placebo arms.
received anticoagulation therapy and three discontinued abemaci- We see a numerically longer PFS and higher ORR compared with
clib or all study treatment. the ITT population in MONARCH 2 and 3. In MONARCH 3, there
was a smaller HR in East Asian patients (HR = 0.326) relative to the
ITT population (HR = 0.54); these results should be interpreted with
4 | D I S CU S S I O N caution due to the differences in important prognostic factors, such
as higher performance status observed in east Asian patients in both
The MONARCH 2 and MONARCH 3 registration trials met their studies and a greater number of patients in the placebo arm who
primary PFS endpoints, demonstrating statistically significant im- exhibited visceral disease, which may have contributed to the poor
provements in efficacy with a tolerable safety profile in the ITT performance of the placebo arm and the larger treatment effect.
populations. MONARCH 2 evaluated abemaciclib in combina- The safety profile of abemaciclib for East Asians was generally
tion with fulvestrant in patients who progressed on prior ET, and consistent with the ITT, with diarrhea being the most common AE,
MONARCH 3 evaluated abemaciclib in combination with NSAI as which was mostly low grade, manageable, and reversible. However,
initial therapy for advanced disease. As part of these pivotal stud- for patients in the abemaciclib arms, there were certain toxicities,
ies, it is important to consider the efficacy and safety of abemaci- such as neutropenia, leukopenia, and ALT increase that were more
clib within subgroups, including the East Asian population, which frequent in the East Asian patients compared with the ITT popula-
has demonstrated differences in efficacy and safety in response tion. Although the mechanism is unknown, the increased rates of
to other cancer therapies.6,28,29 Overall, data from the East Asian neutropenia and leukopenia are consistent with data from other
subpopulation of the MONARCH 2 and 3 trials showed a generally CDK4 & 6 inhibitors, where there is a precedent for increased
TA B L E 3 Most common adverse events observed in the East Asian population in the MONARCH 2 and 3 trials

MONARCH 2
TOI eT al.

Abemaciclib + fulvestrant (N = 146) Placebo + fulvestrant (N = 65)

CTCAE Grade

≥20% in either arm All n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) All Grade 2 n (%) Grade 3 n (%) Grade 4 n (%)

Any 144 (98.6) 34 (23.3) 86 (58.9) 11 (7.5) 60 (92.3) 24 (36.9) 12 (18.5) 2 (3.1)
Diarrhea 132 (90.4) 49 (33.6) 21 (14.4) 0 13 (20.0) 2 (3.1) 1 (1.5) 0
Neutropenia 99 (67.8) 27 (18.5) 59 (40.4) 6 (4.1) 3 (4.6) 0 2 (3.1) 0
Leukopenia 60 (41.1) 33 (22.6) 19 (13.0) 1 (0.7) 2 (3.1) 1 (1.5) 0 0
Nausea 54 (37.0) 12 (8.2) 3 (2.1) 0 11 (16.9) 1 (1.5) 1 (1.5) 0
Anemia 54 (37.0) 31 (21.2) 16 (11.0) 1 (0.7) 3 (4.6) 0 2 (3.1) 0
Abdominal pain 45 (30.8) 8 (5.5) 1 (0.7) 0 11 (16.9) 1 (1.5) 0 0
Decreased appetite 42 (28.8) 13 (8.9) 4 (2.7) 0 10 (15.4) 1 (1.5) 0 0
Thrombocytopenia 37 (25.3) 11 (7.5) 7 (4.8) 5 (3.4) 2 (3.1) 0 0 1 (1.5)
Headache 36 (24.7) 9 (6.2) 1 (0.7) 0 10 (15.4) 2 (3.1) 0 0
Stomatitis 35 (24) 5 (3.4) 1 (0.7) 0 9 (13.8) 1 (1.5) 0 0
Vomiting 35 (24) 7 (4.8) 2 (1.4) 0 5 (7.7) 1 (1.5) 0 0
ALT increased 34 (23.3) 12 (8.2) 9 (6.2) 1 (0.7) 2 (3.1) 1 (1.5) 0 0
Pruritus 34 (23.3) 3 (2.1) 0 0 5 (7.7) 0 0 0

MONARCH 3

Abemaciclib + NSAI (N = 102) Placebo + NSAI (N = 42)

CTCAE Grade

≥20% in either arm All n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) All n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%)

Any 102 (100.0) 31 (30.4) 56 (54.9) 6 (5.9) 39 (92.9) 16 (38) 10 (23.8) 1 (2.4)
Diarrhea 90 (88.2) 20 (19.6) 5 (4.9) 0 12 (28.6) 1 (2.4) 0 0
Neutropenia 59 (57.8) 23 (22.5) 29 (28.4) 1 (1.0) 0 0 0 0
Anemia 36 (35.3) 16 (15.7) 13 (12.7) 0 1 (2.4) 1 (2.4) 0 0
Alopecia 34 (33.3) 2 (2) 0 0 4 (9.5) 0 0 0
Nausea 34 (33.3) 4 (3.9) 0 0 7 (16.7) 0 0 0
ALT increased 33 (32.4) 8 (7.8) 13 (12.7) 1 (1.0) 5 (11.9) 1 (2.4) 2 (4.8) 0
AST increased 33 (32.4) 7 (6.9) 9 (8.8) 0 4 (9.5) 1 (2.4) 1 (2.4) 0
Leukopenia 33 (32.4) 14 (13.7) 11 (10.8) 0 3 (7.1) 1 (2.4) 0 1 (2.4)
|
2389

(Continues)
 2390 | TOI eT al.

hematological toxicities in Asian patients.6 Likewise, in a phase 1b

Grade 4 n (%)
study exclusively in Asian patients, high incidences of liver toxicities

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, common terminology criteria for adverse events; n, number of patients in the safety population; N, number of
have been observed in Japanese patients treated with ribociclib.30
Despite these variations observed in East Asian patients, the dose

0
0
0
0
0
intensity and the discontinuation rates were similar between East
Asians and the ITT of MONARCH 2 and 3, suggesting that the AEs
were typically manageable.18,28 Per label recommendations, neu-
Grade 3 n (%)

tropenia monitoring should include blood counts assessed prior to

the start of abemaciclib, every 2 weeks for the first 2 months, and
1 (2.4)

monthly thereafter for 2 months as clinically indicated. It is also

suggested that liver function tests should be monitored prior to the
0
0
0
0 start of abemaciclib therapy, every 2 weeks for the first 2 months,
monthly for the next two months, and as clinically indicated. In the
event of hepatic transaminase elevation, dose modifications, omis-
Grade 2 n (%)

sions, or discontinuations should be considered as possible manage-

ment strategies.
Placebo + NSAI (N = 42)

Overall, safety findings were consistent across the

0
0
0
0
0

200-mg-starting-dose and 150-mg-starting-dose populations. Some

differences were observed in toxicities that were expected to occur
early in the course of treatment. Incidence of Grade 2 and 3 for
All n (%)

7 (16.7)

gastrointestinal toxicities like nausea, vomiting, or abdominal pain

2 (4.8)

2 (4.8)

2 (4.8)
4 (9.5)

was higher in patients starting at 200 mg than in patients starting

at 150 mg. Neutropenia Grade ≥ 3 was also observed in a higher
percentage of patients starting at 200 mg than in patients starting
at 150 mg, based on TEAE and central laboratory analyses. Overall,
Grade 4 n (%)

based on our review of the safety data, the higher starting dose
for the 178 patients who initially received 200 mg in MONARCH 2
contributed to the slightly higher toxicity rates in MONARCH 2. In
0
0
0
0
0

MONARCH 3, the rate of abemaciclib dose reductions due to an AE

in East Asian patients was comparable to the ITT population (46.5%);
whereas in MONARCH 2, dose reductions were slightly higher in
Grade 3 n (%)

East Asian patients than in the ITT population (42.9%). The higher
dose reduction rate due to an AE in MONARCH 2 may be partially
3 (2.9)

explained by the higher proportion of patients who started abe-

patients in the specified category; NSAI, nonsteroidal aromatase inhibitor.
0
0
0
0

maciclib with 200 mg twice daily in MONARCH 2 (39% vs 27.4%).5

However, efficacy was consistent with the overall population. This
finding corroborates the results of a previous exploratory analysis
Grade 2 n (%)

demonstrating that PFS was maintained irrespective of dose reduc-

tions.31 Moreover, as previously reported, race was not a significant
Abemaciclib + NSAI (N = 102)

4 (3.9)
4 (3.9)

4 (3.9)
8 (7.8)

5 (4.9)

covariate for abemaciclib PK parameters, 25-27 and in the present

study abemaciclib concentrations in East Asians were similar to the
ITT populations, indicating that the imbalance in toxicity rate is not
attributable to differences in abemaciclib disposition or exposure.
CTCAE Grade

The abemaciclib starting dose in combination with fulvestrant or

26 (25.5)
27 (26.5)

24 (23.5)
22 (21.6)
21 (20.6)
All n (%)

NSAI is 150 mg twice daily, regardless of race or ethnicity.

Interstitial lung disease and VTE were assessed as AEs of special
(Continued)

interest. Patients treated with abemaciclib developed serious lung

disease in an early postmarketing-phase pharmacovigilance survey
Decreased appetite
≥20% in either arm

conducted in Japanese patients after its approval in Japan.32 Due

Abdominal pain
MONARCH 3

to the small number of ILD and VTE events, it is difficult to assess

TA B L E 3

Vomiting

whether the risk of abemaciclib-induced ILD or VTE differs with

Pruritus
Rash

ethnicity or region. Further studies utilizing real-world data may be

needed.
TOI eT al. | 2391

One limitation of this analysis is that it is descriptive in nature V. A. M. is an employee of Eli Lilly and Company. V. A. M.’s spouse
and solely focused on the East Asian subgroup. No formal compar- (T. G.) is an employee of Eli Lilly and Company. M. C. H. is a full-time
isons were planned between East Asian and non-East Asian or the employee and stock shareholder of Eli Lilly and Company and shares
ITT population due to the relatively small number of patients in this income from Eli Lilly and Company with M. H. (spouse). S. S. is an
subgroup. However, the PFS results for prespecified subgroups in- employee and stock shareholder of Eli Lilly and Company. M. P. G.
cluding region (North America, Europe, and Asia) were previously receives research funds from Eli Lilly and Company and funds for
reported.8,18 travel expenses from Eli Lilly and Company and the JBCS. G. W. S.
In conclusion, the East Asian populations of MONARCH 2 and receives clinical trial funds from Eli Lilly and Company.
3 benefited from abemaciclib in combination with ET. As expected,
there was a greater occurrence of hematological toxicities in the East ORCID
Asian subgroup, but the overall safety profile was manageable and Masakazu Toi https://orcid.org/0000-0003-1488-9958
generally consistent with the ITT population. These findings sug- Norikazu Masuda https://orcid.org/0000-0002-7302-0278
gest that the benefit/risk profile of abemaciclib in combination with In Hae Park https://orcid.org/0000-0001-7894-8772
NSAIs (letrozole and anastrozole) or with fulvestrant is favorable and
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