Phase 3 Randomized Open-label Study of Imlunestrant, Abemaciclib, and Endocrine Therapy in ER+ HER2- Advanced Breast Cancer Post-Endocrine Treatment

The primary objective of the study is to evaluate the **progression-free survival** (PFS) of patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have been previously treated with endocrine therapy. The study aims to compare the PFS of patients receiving **imlunestrant** (Arm A) against those receiving the standard comparator of the investigator's choice of endocrine therapy, either **fulvestrant** or **exemestane** (Arm B), in the intention-to-treat (ITT) population. Additionally, the study will compare the PFS of Arm A to Arm B in the population with detected **ESR1 mutation**. Furthermore, the study will assess the PFS of patients receiving imlunestrant plus **abemaciclib** (Arm C) compared to those receiving imlunestrant alone (Arm A) in the ITT population. These comparisons are clinically relevant as they aim to determine the most effective treatment regimen for improving PFS in this patient population.

The clinical trial involves a total of **611 participants** diagnosed with **breast cancer**, specifically focusing on those with HR+ HER2- subtypes. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are required to have advanced cancer that has metastasized, and they must have previously received treatment that inhibits estrogen production. The trial population was selected based on their ability to maintain adequate body organ function and their overall health status, which should be fair to good. Additionally, participants must be capable of swallowing capsules or tablets. The trial also considers vulnerable populations, ensuring a comprehensive evaluation across diverse demographic groups. Lifestyle factors such as diet and physical activity are not specified, but the inclusion criteria emphasize the necessity for participants to have a certain level of health and functional capability.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of imlunestrant, either alone or in combination with **abemaciclib**, compared to the investigator's choice of endocrine therapy, which includes either **fulvestrant** or **exemestane**, in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic **breast cancer**. The trial aims to assess progression-free survival (PFS) in different patient populations, including the intention-to-treat (ITT) population and those with ESR1 mutations. The study is expected to conclude by February 2027, with recruitment having commenced in October 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having advanced breast cancer, previous treatment with estrogen-blocking drugs, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of disease progression, adverse events, and compliance with the treatment regimen. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed.

The expected duration of participant involvement is approximately one year, although this may vary depending on individual response to treatment and disease progression. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any situation where continued participation is deemed not in the participant's best interest by the investigator. The trial's methodology ensures rigorous monitoring and data collection to achieve its primary and secondary endpoints, contributing valuable insights into the treatment of advanced breast cancer.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Fulvestrant** is utilized as a comparator treatment in the study. It is a chemical substance administered as a solution for injection. The pharmaceutical form is identified as PHF00231MIG. Fulvestrant is administered via injection, with the specific dosage and frequency determined by the study protocol. The maximum treatment period for fulvestrant is one month, and it is not a pediatric formulation.

**Abemaciclib** is another experimental medication used in the trial. It is a chemical substance provided in a pharmaceutical form identified as PHF00082MIG. Abemaciclib is administered orally, with the dosage and frequency specified in the study protocol. The maximum treatment period is one month. The medication is packaged differently for the clinical trial compared to its marketing authorization, with specific clinical trial packaging and labeling.

**LY3484356** is an experimental medication in the form of a tablet, administered orally. It is a chemical substance developed by ELI LILLY AND COMPANY. The dosage and frequency of administration are determined by the study protocol, with a maximum treatment period of one month. This medication is not a pediatric formulation.

**Exemestane** is used as a comparator treatment in the study. It is a chemical substance administered orally, with the pharmaceutical form identified as PHF00009MIG. The dosage and frequency of administration are specified in the study protocol, with a maximum treatment period of one month. Exemestane is not a pediatric formulation.

Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the protocol. The trial aims to compare the progression-free survival (PFS) of the experimental medications against the standard comparator treatments in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine therapy.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. The primary endpoints include investigator-assessed PFS comparisons between different treatment arms: Arm A (imlunestrant) versus Arm B (standard comparator of Investigator’s Choice Endocrine Therapy, either **fulvestrant** or **exemestane**) in the Intent-to-Treat (ITT) population, Arm A versus Arm B in the ESR1-mutation detected population, and Arm C (imlunestrant plus **abemaciclib**) versus Arm A in the ITT population. These assessments will be conducted to determine the efficacy of the investigational treatments in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine therapy.