Phase 3 Study of PF-07220060 and Letrozole Versus CDK4/6 Inhibitors and Letrozole in HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer

The primary objective of this study is to evaluate the **efficacy** of PF-07220060 in combination with letrozole (Arm A) compared to a CDK4/6 inhibitor (investigator’s choice: abemaciclib, palbociclib, or ribociclib) in combination with letrozole (Arm B) in terms of progression-free survival (PFS) in participants with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer. This is clinically relevant as progression-free survival is a critical endpoint in assessing the effectiveness of cancer therapies, providing insights into the duration a treatment can effectively control the disease without progression.

Secondary objectives include comparing Arm A versus Arm B with respect to overall survival (OS). Overall survival is a vital measure of a treatment's impact on extending a patient's life, offering a comprehensive view of the treatment's long-term benefits.

The clinical trial involves a total of **598 participants** diagnosed with **advanced/metastatic breast cancer**. The study population includes both male and female subjects, aged 18 years and older, with a documented estrogen receptor (ER) and/or progesterone receptor (PR)-positive tumor and a HER2-negative tumor. Participants are required to have either measurable disease or non-measurable bone-only disease as per RECIST v1.1 criteria and must have an ECOG Performance Status of 2 or less. The trial population was selected based on specific inclusion criteria, including the requirement for pre/perimenopausal female and male participants to receive therapy with an LHRH agonist prior to the first dose of study intervention. Participants must not have received any prior systemic anticancer therapy for their locally advanced or metastatic disease. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic.

The clinical trial is designed as an **interventional, open-label, randomized, multicenter Phase 3 study**. The primary objective is to compare the efficacy of **PF-07220060** in combination with **letrozole** against a **CDK4/6 inhibitor** (investigator's choice of **abemaciclib**, **palbociclib**, or **ribociclib**) combined with letrozole, focusing on progression-free survival (PFS) in participants with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer. The trial is expected to commence recruitment on February 11, 2025, and conclude by February 19, 2038, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, histological confirmation of breast cancer, and absence of prior systemic anticancer treatment for advanced/metastatic disease. Following successful screening, participants will be randomized into one of the two study arms. Regular follow-up visits will be scheduled to monitor treatment efficacy and safety, with assessments including progression-free survival evaluated by blinded independent central review. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 36 months, contingent upon disease progression or unacceptable toxicity. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or investigator decision based on clinical judgment. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity and reliability of the data collected.

The clinical trial involves the administration of **PF-07220060**, an experimental medication provided in the form of a film-coated tablet. The active substance, **PF-07220060 monohydrate**, is of chemical origin. The maximum daily dose is 600 mg, administered orally. The treatment period extends up to 36 months. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

**Letrozole** is used as a non-experimental treatment in the study. It is administered in the form of a film-coated tablet with a maximum daily dose of 2.5 mg, taken orally. Letrozole is a standard-of-care therapy for hormone receptor-positive, HER2-negative advanced/metastatic breast cancer.

**Ribociclib** is included as a comparator treatment. It is provided as a film-coated tablet with a maximum daily dose of 600 mg, administered orally. Ribociclib is a CDK4/6 inhibitor used in combination with letrozole for the treatment of advanced breast cancer.

**Palbociclib**, marketed as IBRANCE, is another comparator treatment available in hard capsule form. It is administered orally with a maximum daily dose of 125 mg. The treatment period is up to 36 months. Palbociclib is a CDK4/6 inhibitor used in combination with letrozole for advanced breast cancer.

**Abemaciclib** is also used as a comparator treatment, provided in the form of a film-coated tablet. The maximum daily dose is 300 mg, administered orally. Abemaciclib is a CDK4/6 inhibitor used in combination with letrozole for the treatment of advanced breast cancer.

All treatments are of chemical origin and are administered orally. The study aims to compare the efficacy of PF-07220060 in combination with letrozole against the combination of a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) with letrozole, focusing on progression-free survival in participants with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer.

The efficacy of the clinical trial will be assessed by comparing the **progression-free survival (PFS)** of participants receiving PF-07220060 in combination with letrozole (Arm A) versus those receiving a CDK4/6 inhibitor (investigator’s choice of abemaciclib, palbociclib, or ribociclib) in combination with letrozole (Arm B). The primary endpoint for efficacy evaluation is PFS, which will be measured by blinded independent central review (BICR). Additionally, overall survival (OS) will be evaluated as a secondary endpoint.