This phase 3 trial investigated adding abemaciclib to standard adjuvant endocrine therapy in patients with hormone receptor-positive, HER2-negative, lymph node-positive, high-risk early breast cancer. At the interim analysis, the addition of abemaciclib resulted in a statistically significant improvement in invasive disease-free survival compared to endocrine therapy alone. The most common adverse events with abemaciclib were diarrhea, neutropenia, and fatigue. Additional follow-up is still needed to determine if the benefit persists for later recurrences and overall survival.

1. Journal Club ,monarchE-phase III

2. Out lines of presentation
Introduction
Method
Result
Discussion
Conclusion

3. 1. Introduction
• More than 90% of pts with breast ca are Dx with
early stage disease, of whom approximately 70%
have cancers that are hormone receptor positive
(HR+) & human epidermal growth factor
receptor 2 negative (HER2-).
• Standard Rx varies depending on risk of
recurrence but includes combinations of Sx, RT,
adjuvant/neoadjuvant chemo, & endocrine
therapy (ET)

4. 1. Introduction…
• Adjuvant ET (aromatase inhibitors and/or
antiestrogens with or without ovarian
suppression) is standard treatment of HR+,
HER2- early breast cancer (EBC) and has been
associated with a significant ↓ in risk of
recurrence & death
• Although many pts with HR+,HER2- disease not
experience recurrence with standard therapies
alone, up to 20% of pts may experience disease
recurrence in the first 10 yrs, often with distant
met.

5. 1. Introduction…
• For those pts with high-risk clinical and/or
pathologic features, risk of recurrence is higher,
especially during the first few yrs on adjuvant ET.
• It is therefore critical to optimize adjuvant Rx to
prevent early recurrences & met for these pts!!

6. 1. Introduction…
• Abemaciclib is an oral, continuously dosed, cyclin
dependent kinase 4 & 6 (CDK4/6) inhibitor
approved in combination with ET for the Rx of
HR+, HER2- advanced breast ca (ABC) on the
basis of significant improvements in:
 PFS & OS in combination with fulvestrant
 PFS in combination with non steroidal AIs
• As such, exploration of the combination of
abemaciclib & ET is warranted in adjuvant
setting.

7. 1. Introduction…
• MonarchE is an open label, global, randomized,
phase III trial that investigated the addition of
abemaciclib to standard adjuvant ET in pts with
HR+, HER2-, LN+, high risk EBC.
• The design of monarchE was motivated by large
clinical datasets in EBC, which all noted a subset
of HR+, HER2- pts with high risk clinical features
and/or highly proliferative disease that were
likely to experience recurrence quickly

8. 1. Introduction…
• The goal in monarchE was to treat the pts with
primary endocrine-resistant disease who were
likely to experience recurrence earlier in the
course of their disease, especially in the first 5
yrs.
• This report describes the first results from
MonarchE following a preplanned interim
analysis.

9. 2. Methods
• 2.1. Trial oversight
• This study was funded by the sponsor (Eli Lilly)
• The study was performed in compliance with the
Declaration of Helsinki.
• The study protocol & all amendments received
approval from ethical/institutional review boards
before implementation, & all pts gave written
informed consent.

10. 2. Methods
• 2.2. patients
• Female (any menopausal status) and male pts
≥18 yrs of age with HR+ & HER2- disease were
eligible.
• High risk was defined as pts with:
 ≥ 4+ve pathologic axillary LNs or
1-3 +ve axillary LNs & at least one of the
following:
tumor size ≥5 cm
histologic grade 3
Centrally assessed Ki-67≥20%

11. 2. Methods
• 2.2. patients
• Pts may have received up to 12 wks of ET before
randomization & must have been randomly
assigned within 16 months of definitive breast
cancer surgery.
• RT & both adjuvant & neoadjuvant chemo were
allowed, but not required

12. 2. Methods
• 2.2. patients
• Pts excluded from randomizations are:
With occult breast ca
metastatic disease
node-negative breast ca
after a protocol amendment
Pts with inflammatory breast ca
Pts who had received Rx with ET for breast ca
prevention, raloxifene, and/or a CDK4/6 inhibitor
Pts with history of VTE events .

13. 2. Methods
• 2.2. patients
• An interactive Web response system was used to
randomly assign pts (1:1) to receive either :
abemaciclib (150 mg PO twice daily on a continuous
dosing schedule) plus ET,or
ET alone.
• Stratification factors included:
 previous chemo (neoadjuvant, adjuvant, or none)
menopausal status(as determined at the time of Dx)
region (North America/Europe, Asia, or other).

14. 2. Methods…
• 2.2. patients
• Pts were treated for 2 yrs (Rx period) or until
meeting criteria for discontinuation.
• After the treatment period, all pts continued ET
for 5-10 yrs, as clinically indicated
• The 2-yr Rx duration was chosen based on
historical studies indicating recurrence events
peaked at 2 yrs for pts with EBC
• Post discontinuation treatment was at the
discretion of the investigator.
• Crossover was not permitted at any time

15. 2. Methods…
• 2.3. trial procedures:
• Visits occurred every:
2 weeks for the first 2 months,
monthly from months 3-6
 every 3 months until the end of year 2.
Thereafter every 6 months until year 5
then annually from years 6-10

16. 2. Methods…
• 2.3. trial procedures:
• All randomly assigned pts were followed for:
• local/regional and distant recurrence
• Over all survival
• At each visit, pts were assessed by a medically
qualified individual with:
History
Physical exam
Adverse effect
Hematology and chemistry
 tests to confirm recurrence if there are
sign/symptoms of recurrence

17. 2. Methods…
• 2.4. statistical analysis;
• The primary end point was invasive DFS & was
measured from the date of randomization to the
date of first occurrence of :
o ipsilateral invasive breast tumor recurrence,
o local/regional invasive breast ca recurrence,
o distant recurrence
o death attributable to any cause
o contralateral invasive breast cancer
o second primary non breast invasive cancer.

18. 2. Methods…
• 2.4. statistical analysis;
• All patients who experienced local recurrence
continued to be followed for distant recurrence.
• Distant relapse–free survival(DRFS), a secondary
end point, was defined as the time from
randomization to distant recurrence or death
from any cause, whichever occurred first

19. 2. Methods…
• 2.4. statistical analysis;
• Other secondary end points included
OS
 safety
pharmacokinetics (PK)
Patient reported outcomes (PROs)

20. 2. Methods…
• 2.4. statistical analysis;
• The study was powered at approximately 85% to
detect the superiority of abemaciclib (+) ET
versus ET in terms of IDFS, assuming HR of 0.73
at a cumulative two-sided ᾳ level of .05, with a 5-
year IDFS rate of 82.5% in the control arm for this
high-risk population.
• This required approximately 390 IDFS events in
the ITT population at the time of the primary
analysis.

21. 2. Methods…
• 2.4. statistical analysis;
• There were two planned efficacy interim
analyses at approximately 50% and 75% of the
total required events.
• Efficacy analyses were performed on the ITT
population.
• The primary objective was to test the superiority
of abemaciclib plus ET versus ET on IDFS.

22. 2. Methods…
• 2.4. statistical analysis;
• Safety was analyzed in all randomly assigned pts
who received at least one dose of study
treatment.
• AEs were graded according to Common
Terminology Criteria Adverse Events v4.0

23. 3. Results
• 3.1. Patient and Rx
• From July 2017 to August 2019, 5,637 pts from 603
sites in 38 countries were randomly assigned 1:1 to
receive either abemaciclib plus ET or ET alone
• Base line characteristics were balanced between
study arms
• The population had a median age of 51 yrs
(12.6%pts ≤40 yrs) & was predominantly female
(99.4%),postmenopausal (56.5%) at the time of Dx.
• Nearly 60% of pts were eligible on the basis of four
or more nodes.

24. 3. Results
• 3.1. Patient and Rx
• A total of 95.4% of pts had received RT, and 95.4% of
pts had received prior chemotherapy:
o 37.0% neoadjuvant
o 58.3%adjuvant
o 3.5% received both(counted in neoadjuvant total)
• AIs were prescribed as the first ET in 68.3% of pts
(including 14.2% treated with AI (+) ovarian function
suppression)
• tamoxifen in 31.4% (including7.6% treated with
tamoxifen (+) OFS.

25. 3. Results
• 3.1. Patient and Rx
• At the time of the data cutoff (March 16, 2020),
707 (12.5%)pts had completed the 2-year Rx
period, and 4,101 (72.8%) pts were still in the 2-
year Rx period.
• Median follow-up time was approximately 15.5
months in both arms

30. 3. Results
• 3.2. Efficacy ;
• With a total of 323 IDFS events observed at the
second efficacy interim analysis, the two-sided P
value boundary for positive efficacy was .026.
• At the time of data cut off IDFS events were:
 136 (4.8%) in the abemaciclib arm
187 (6.6%) in the control arm.
• Abemaciclib plus ET demonstrated a statistically
significant improvement in IDFS versus ET alone (P-
.01) with 2-year IDFS rates of:
o 92.2% -abemaciclib arm versus
o 88.7% -control arm

33. 3. Results
• 3.2. Efficacy ;
• Most IDFS events were distant recurrences (87 in
the abemaciclib arm and 138 in the control arm).
• The addition of abemaciclib to ET also resulted
in an improvement in DRFS compared with ET
alone (P-.01),with 2-year DRFS rates of :
93.6% -abemaciclib arm
 90.3% -control arm
• Common sites of distant recurrence were bone,
liver, and lung

35. 3. Results
• 3.2. Efficacy ;
• OS data were immature, with 39 (1.4%) deaths
observed in the abemaciclib arm and 37 (1.3%)
observed in the control arm.
• The study will continue to a final analysis of OS

36. 3. Results
• 3.3. safety;
• A total of 5,591 patients (2,791 in the
abemaciclib arm & 2,800 in the control arm)
were included in the safety analysis.
• The median duration of ET was approximately 15
months in each arm.
• The median duration of abemaciclib was 14
months

37. 3. Results
• 3.3. safety;
• Abemaciclib dose adjustments due to AEs occurred
in 1,901 patients(68.1%), with 56.9% having dose
omissions and 41.2% having reductions.
• In the abemaciclib arm, 463 patients (16.6%)
discontinued abemaciclib because of AEs, of whom
306 remained on ET when abemaciclib was
discontinued.
• A total of 172 patients (6.2%)discontinued both
treatments (157 at the same time) because of AEs.
• In the control arm, 21 patients (0.8%) discontinued
ET because of AEs.

38. 3. Results
• 3.3. Safety;
• A total of 5,141 pts experienced at least one treatment-
emergent AE (97.9% in the abemaciclib arm and 86.1% in
control arm).
• The most frequent AEs were:
• abemaciclib arm
o diarrhea
o Neutropenia
o fatigue
• control arm
 Arthralgia
 Hotflush
 fatigue

39. 3. Results
• 3.3. safety;
• Grade≥3 AEs occurred in :
45.9% of pts in the abemaciclib arm
12.9% of pts in the control arm.
• Serious adverse events (SAEs) occurred in :
12.3% of pts in the abemaciclib arm
7.2% of pts in the control arm, with the most
frequently reported SAE in both arms being
pneumonia (0.8% and 0.5%, respectively).

40. 3. Results
• 3.3. safety;
• Deaths on study treatment or within 30 days of
discontinuation were balanced between the
arms, with 14 (0.5%)in each arm.
• In the abemaciclib arm, 11 were due to AEs(two,
diarrhea and pneumonitis, considered possibly
related to study treatment by the investigator)
versus seven as a result of AEs in the control arm

42. 4. Discussion
• In this global, open-label, randomized phase III
trial in pts with HR+, HER2-, LN+, high-risk EBC,
the addition of abemaciclib to standard adjuvant
ET resulted in a statistically significant
improvement in IDFS

43. 4. Discussion…
• The estimated 2-year IDFS rate in the monarchE
control arm indicates that 11.3% of pts with high-
risk clinicopathological features will develop an
invasive disease event within 2 yrs.
• The addition of abemaciclib resulted in a 25%
reduction in the risk of developing an IDFS event
relative to ET alone and an absolute
improvement of 3.5% in 2-year IDFS rates.
• This is a clinically meaningful result, and the
treatment effect was observed in all pre specified
subgroups.

44. 4. Discussion…
• Of note ,among the 43.5% of pts who were
premenopausal at Dx, there was a significant
37% ↓ in risk of recurrence relative to ET alone.
• This is relevant because there have been very
few Rx advances in adjuvant therapy for
HR+,HER2- EBC for nearly 20 yrs.

45. 4. Discussion…
• More than 75% of the early recurrences seen in
the control arm were distant recurrence.
• Overcoming endocrine resistance & ↓ the risk of
distant met is an essential objective for any novel
therapy in HR+ EBC.
• Abemaciclib is an approved CDK4/6 inhibitor in
HR+,HER2- ABC, with clinical efficacy both as
monotherapy in pretreated ABC and in
combination with ET

46. 4. Discussion…
• Significant improvement in OS was reported in
pts with endocrine resistant disease, including
patients with visceral met.
• The effect now seen in the EBC adjuvant setting
indicates a similar impact on preventing early
primary endocrine resistant recurrences & on
reducing the risk of metastatic recurrence by a
clinically meaningful 28% relative to ET alone,
especially in bone and liver metastases

48. 4. Discussion…
• At this preplanned interim analysis, 323 events
were observed, corresponding to 80% of the
total planned number of events (390).
• Although the median follow-up of 15 months at
this time is short for an EBC adjuvant study, the
positive outcome of abemaciclib in ↓ the risk of
invasive disease within 2 yrs is a critical outcome
for this high-risk population.

49. 4. Discussion…
• Additional follow-up in monarchE will determine
the persistence of this benefit on:
• later recurrences
• overall survival in node-positive, high-risk HR+
HER2- EBC, which is unknown at present.

50. 4. Discussion…
• understanding the subgroups of pts with
HR+,HER2- breast cancer for whom the addition
of a targeted therapy is most beneficial is an
important goal.
• In monarchE, a population with increased risk of
recurrence on the basis of disease characteristics
a clear efficacy benefit for the addition of
abemaciclib was demonstrated

51. 4. Discussion…
• Whether benefit of CDK4/6 inhibitor can be
demonstrated in pts at lower risk is unclear,
especially given that many of these patients
experience recurrence late(>10 years after Dx),
and extended adjuvant ET is increasingly used.

52. 4. Discussion…
• There are additional ongoing clinical trials
evaluating CDK4/6 inhibitors in EBC
(ClinicalTrials.gov identifiers:NCT03701334 &
NCT02513394).
• Results from these trials using different
compounds in different populations will further
determine the role of CDK4/6 inhibitors in EBC

53. 4. Discussion…
• Adherence to therapy is a challenge in the
adjuvant setting ,& a manageable toxicity profile
for any novel therapy is crucial.
• Of interest, arthralgia and hot flush are frequent
& often troublesome AEs related to ET.

54. 4. Discussion…
• The most frequently reported AE in the
abemaciclib arm was diarrhea.
• The frequency of diarrhea of grade ≥3 was 7.6%;
however a very low number of patients (4.8%)
discontinued abemaciclib because of diarrhea

55. 5. Conclusion
• In conclusion, monarchE has demonstrated that
abemaciclib added to standard adjuvant ET
significantly improves IDFS in women & men with
HR+, HER2-, LN+ EBC at high risk of early
recurrence
• If approved, abemaciclib added to standard
adjuvant ET could become a new standard of
care for patients with HR+, HER2- high-risk EBC.

57. Thank you!