A Phase 3, Randomized, Open-Label Study of Imlunestrant, Investigator*s Choice of Endocrine Therapy, and Imlunestrant plus Abemaciclib in Patients with Estrogen Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer Previously Treated with Endocrine Therapy

There remains an unmet medical need for novel, improved, and tolerable ETs for
the management of ER+, HER2- mBC, that can overcome the PK and resistance
limitations of ETs currently used in the clinic. To this end, promising
clinical data have been observed with the oral SERD, imlunestrant, in heavily
pretreated ER+ mBC patients. Along with this, abemaciclib has well established
clinical benefit in CDK4/6-naïve patients in the 1st and 2nd line setting and
has the potential for benefit in CDK4/6-pre-treated patients . The clinical and
the preclinical results outlined in Section 2.1 support further investigation
of imlunestrant and imlunestrant plus abemaciclib for patients with ER+, HER2-
locally advanced or mBC.The purpose of this study, in patients with ER+, HER2-
locally advanced or mBC previously treated with an AI with or without a CDK4/6
inhibitor, is to determine whether: imlunestrant prolongs PFS compared to
Investigator*s Choice of Endocrine Therapy; and if imlunestrant plus
abemaciclib prolongs PFS compared to imlunestrant monotherapy.Patient
randomization within this study will be stratified by known prognostic factors
to reduce the potential for bias and improve the power of the analyses.
Randomization minimizes systematic bias in the selection and assignment of
patients to study therapy and provides justification for inferential
statistical methods to be used on data from
this study. Using an appropriate concurrent control arm enables direct
statistical estimation of benefits and harms due to study therapy and minimizes
bias in the assessment and interpretation of observed treatment effects.

This study has been transitioned to CTIS with ID 2023-506786-63-00 check the CTIS register for the current data.

Main objective:
•To compare the progression-free survival of imlunestrant (Arm A) to the
standard comparator of Investigator's Choice Endocrine Therapy of
either fulvestrant or exemestane (Arm B) in the ITT population
•To compare the PFS of Arm A to Arm B in the ESR1-mutation detected population
•To compare the progression-free survival of imlunestrant plus abemaciclib
(Arm C) to imlunestrant (Arm A) in the ITT population

Secondary objectives:
•To compare OS of Arm A to Arm B in the ITT population
•To compare OS of Arm A to Arm B in the ESR1-mutation detected population
•To compare OS of Arm C to Arm A in the ITT population
•To assess the safety and tolerability of each treatment arm
•To evaluate the effectiveness of Arm A compared to Arm B and Arm C
compared to Arm A based on PROs of pain using the Worst Pain NRS
•To assess the PK of imlunestrant (Arm A and Arm C)
•To assess the PK of abemaciclib and its metabolites (Arm C)

Participants will be randomized 1:1:1 between 3 treatment arms (Arm A: Arm B:
Arm C) and will be treated until disease progression or other discontinuation
criteria are met
* Arm A: Imlunestrant 400 mg orally QD on Days 1 to 28 of a 28-day cycle
* Arm B:Investigator*s Choice Endocrine Therapy
o Exemestane 25 mg orally QD on Days 1 to 28 of a 28-day cycle OR
o Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1
of Cycle 2 and beyond
* Arm C: Imlunestrant + Abemaciclib
o Imlunestrant 400 mg orally QD on Days 1 to 28 of a 28-day cycle
o Abemaciclib 150 mg orally BID on Days 1 to 28 of a 28-day cycle

Imlunestrant will be administered orally, 400 mg QD on Days 1 to 28 on a 28-day
cycle. The imlunestrant doses will be administered at approximately the same
times on each day. Patients should follow the fasting guidance provided in the
patient diary.
The Investigator*s Choice of Endocrine Therapy will be limited to fulvestrant
or exemestane.
Fulvestrant will be administered 500 mg intramuscularly into the buttocks
slowly (1 to 2 minutes per injection) as two 250 mg injections, one in each
buttock on Days 1 and 15 of Cycle 1 of a 28-day cycle, then on Day 1 of Cycle 2
and beyond. However, for patients with moderate hepatic
impairment (defined as Child-Pugh Class B), including any patient who develops
moderate hepatic impairment during study treatment, fulvestrant 250 mg should
be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one
250-mg injection.
Exemestane will be supplied as 25 mg and administered orally, 25 mg QD.
Abemaciclib will be administered orally, 150 mg BID on Days 1 to 28 on a 28-day
cycle. The
abemaciclib doses will be administered at approximately the same times on each
day

Imlunestrant toxicology studies demonstrate an acceptable safety profile, with
toxicities that are generally monitorable and/or reversible and are clinically
manageable in the EMBER-3 patient population.

Although the study procedures are generally consistent with standard of care,
increased monitoring of vital signs(including blood pressure), haematology,
hepatic panels, and electrocardiograms (ECGs) occur in the initial cycles to
monitor for potential toxicities of interest.
Additionally, a data monitoring committee (DMC) will assess unblinded safety
data during the trial on a regular basis. The DMC will evaluate all
safety-related data provided for each meeting to determine whether a change in
the conduct of the trial is warranted for the safety of patients.

Given the high unmet need for additional therapies to treat ER+, HER2- locally
advanced or mBC, the clinical safety profile of imlunestrant, and the clinical
efficacy observed in patients in other studies, the risk/benefit assessment
supports evaluation of imlunestrant in the proposed patient population.