Phase 3 Study of PF-07220060 and Fulvestrant Versus Investigator's Choice in HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Post-CDK 4/6 Inhibitor Therapy

The primary objective of this study is to compare the **efficacy** of PF-07220060 in combination with fulvestrant (Arm A) versus the investigator's choice of therapy (Arm B) in terms of progression-free survival (PFS) in participants with hormone receptor-positive, HER2-negative advanced or 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 worsening.

Secondary objectives include:

• Comparing Arm A versus Arm B with respect to overall survival (OS).
• Comparing Arm A versus Arm B with respect to measures of tumor control and evaluating the duration of response within each treatment arm.
• Comparing safety and tolerability between Arm A and Arm B.
• Evaluating patient-reported outcomes of health-related quality of life, disease-treatment-related symptoms, and general health status for each treatment arm.
• Determining trough plasma concentrations of PF-07220060 when given in combination with fulvestrant and exploring the relationship between exposure and efficacy/safety in this participant population.

The clinical trial involves a total of **326 participants** diagnosed with **hormone receptor-positive, HER2-negative advanced/metastatic breast cancer**. The study population includes both male and female subjects, aged 18 years and older, with no vulnerable populations selected. Participants were selected based on specific criteria, including a histological confirmation of breast cancer with evidence of locally advanced or metastatic disease, and a requirement for prior treatment with CDK4/6 inhibitors plus non-steroidal aromatase inhibitors. The trial does not focus on any particular lifestyle considerations such as diet or physical activity. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, indicating they are in relatively good health despite their condition. The selection process ensures that participants have measurable or non-measurable bone-only disease as defined by RECIST v1.1.

The clinical trial is designed as an **open-label**, randomized, multicenter Phase 3 study to evaluate the efficacy of PF-07220060 in combination with **fulvestrant** compared to the investigator's choice of therapy in participants with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer. The primary objective is to assess progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response, duration of response, and patient-reported outcomes. The trial is expected to commence recruitment on July 15, 2024, and conclude by November 13, 2028.

Participants will be randomly assigned to one of two arms: Arm A receiving PF-07220060 plus fulvestrant, and Arm B receiving the investigator's choice of therapy. The study will involve a series of visits, starting with a screening visit to confirm eligibility based on criteria such as age, histological confirmation of breast cancer, and prior treatment history. Participants must be at least 18 years old and have evidence of locally advanced or metastatic disease. The screening visit will also include the collection of a formalin-fixed, paraffin-embedded tumor tissue specimen.

Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety. These visits will include assessments of disease progression using RECIST v1.1 criteria, as well as evaluations of adverse events graded by the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE v5.0). The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent.

The expected duration of participant involvement is up to 24 months, with treatment continuing until disease progression or the occurrence of other conditions warranting early termination. These conditions include the development of severe adverse events or the participant's decision to withdraw from the study. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with data collected to support the evaluation of the study's primary and secondary endpoints.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The experimental medication, **PF-07220060 monohydrate**, is provided in the form of a film-coated tablet. The maximum daily dose is 600 mg, administered orally. The treatment period is up to 24 months. This investigational product is chemically derived and is not a pediatric formulation. The medication is repackaged and relabeled specifically for the study in accordance with Annex 13 guidelines.

**Afinitor** is used as a comparator in two different dosages: 5 mg and 10 mg tablets. Both are administered orally with a maximum daily dose of 5 mg and 10 mg, respectively. The treatment duration for both dosages is up to 24 months. Afinitor contains the active substance **everolimus**, which is chemically synthesized. The tablets are repackaged and relabeled for the study as per Annex 13.

Another comparator, **Aromasin**, is provided as 25 mg coated tablets. The active substance is **exemestane**, and the tablets are administered orally with a maximum daily dose of 25 mg. The treatment period is up to 24 months. Aromasin is also chemically derived and undergoes study-specific repackaging and relabeling in accordance with Annex 13.

**Faslodex** is administered as a 250 mg solution for injection, with the active substance being **fulvestrant**. The route of administration is intramuscular, with a maximum total dose of 500 mg. The treatment period extends up to 24 months. Faslodex is chemically synthesized and is repackaged and relabeled for the study in compliance with Annex 13.

All medications in this trial are chemically derived and are not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**. PFS is defined as the time from the date of randomization to the date of first documented disease progression, as determined by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause in the absence of progression of disease, whichever occurs first. Secondary endpoints include **Overall Survival (OS)**, which is the time from the date of randomization to the date of death due to any cause. Additional secondary endpoints involve PFS by investigator assessment, Objective Response (OR) by BICR and by investigator per RECIST v1.1, Duration of Response (DoR) by BICR and by investigator per RECIST v1.1, and Clinical Benefit Response (CBR) by BICR and by investigator per RECIST v1.1.

Patient-reported outcomes (PROs) will also be evaluated, focusing on global quality of life, symptoms, and functioning. These will be assessed using the European Quality of Life 5 Domain 5 Level Scale (EQ-5D-5L), the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30, and the EORTC QLQ Breast Cancer Module 23 (BR23). The type, incidence, severity, seriousness, and relationship to study interventions of adverse events (AEs) will be graded by the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE v5.0). Laboratory tests and electrocardiogram (ECG) abnormalities will also be monitored. The pharmacokinetic parameter C_trough of PF-07220060 will be measured as part of the efficacy assessment.