Phase 2 Randomized Study of PF-07220060 and Letrozole Versus Letrozole in Postmenopausal Women with HR-Positive, HER2-Negative Breast Cancer

The primary objective of this study is to evaluate the effects of **PF-07220060** in combination with letrozole, compared to letrozole alone, on **Ki-67 expression** in tumors after 2 weeks of treatment. This is clinically relevant as Ki-67 is a marker of cell proliferation, and changes in its expression can provide insights into the efficacy of the treatment in reducing tumor growth in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer.

Secondary objectives include:

• Evaluating the safety and tolerability of PF-07220060 plus letrozole and letrozole alone after 2 weeks of treatment.
• Assessing the **ctDNA** response on treatment after 2 weeks of treatment, which can indicate the molecular response to therapy.
• Determining steady-state plasma concentrations of PF-07220060 in combination with letrozole, which is important for understanding the pharmacokinetics of the drug.
• Determining changes in Ki-67 expression, further supporting the primary objective by providing additional data on the treatment's impact on tumor cell proliferation.

The clinical trial involves a total of **55 participants** diagnosed with **hormone receptor-positive, HER2-negative breast cancer**. The study population is exclusively female, aged 18 years and older, who are either naturally or surgically postmenopausal. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of HR-positive and HER2-negative breast cancer, a Ki-67 score of 10% or higher, and an ECOG performance status of 0 or 1. The trial excludes male participants and does not involve a vulnerable population. Participants must have unilateral, invasive T1c-T4c, N0-N2, M0 breast cancer, as per the AJCC Version 8 classification. Lifestyle factors such as diet and physical activity are not specified in the trial data provided. The selection process ensures that participants are willing to undergo both a baseline and an on-treatment biopsy, as required by the study protocol.

The clinical trial is designed as an **open-label**, randomized, multicenter, Phase 2 study to evaluate the effects of **PF-07220060** in combination with **letrozole** compared to letrozole alone in postmenopausal women aged 18 years or older with hormone receptor-positive, HER2-negative breast cancer in the neoadjuvant setting. The primary objective is to assess the impact on Ki-67 expression in tumors after two weeks of treatment. The trial is expected to commence recruitment on October 15, 2024, and conclude by December 15, 2025, with a total treatment period of 14 days 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, menopausal status, and specific cancer characteristics. The inclusion criteria require a histologically confirmed diagnosis of hormone receptor-positive, HER2-negative breast cancer, a Ki-67 score of at least 10%, and an ECOG performance status of 0 or 1. Participants must also be willing to undergo baseline and on-treatment biopsies. The trial will include follow-up visits to monitor safety and efficacy, with assessments of adverse events, serious adverse events, and any adverse events leading to study drug discontinuation. The end-of-study visit will occur after the 14-day treatment period, where primary and secondary endpoints, including Ki-67 staining and ctDNA measurements, will be evaluated.

The expected length of participant involvement is approximately two weeks, with conditions for early termination including the occurrence of unacceptable adverse events or withdrawal of consent. The trial will utilize oral administration of the investigational product, with a maximum daily dose of 600 mg for PF-07220060 and 2.5 mg for letrozole. The study is not classified as a low-intervention trial, and the investigational products are not pediatric formulations. The trial will adhere to study-specific repacking and relabeling requirements as per regulatory guidelines.

The clinical trial involves the administration of **PF-07220060 monohydrate**, an experimental medication developed by Pfizer Inc. This medication is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 600 mg, with a total treatment period of 14 days. The active substance, PF-07220060 monohydrate, is of chemical origin. Participants are required to adhere to the dosing schedule, and compliance is monitored throughout the trial.

In addition to the experimental treatment, the study includes the administration of **Letrozole**, a non-experimental comparator treatment. Letrozole is provided as a **film-coated tablet** by UAB SanoSwiss and is also administered orally. The maximum daily dose for Letrozole is 2.5 mg, with a treatment duration of 14 days. Letrozole is a well-established chemical compound used in the treatment of hormone receptor-positive, HER2-negative breast cancer. The study-specific repacking and/or relabelling of Letrozole is conducted in accordance with Annex 13 to ensure consistency and compliance with trial protocols.

Efficacy in this clinical trial will be assessed by evaluating the effects of PF-07220060 plus letrozole compared to letrozole alone on **Ki-67** expression in tumors after 2 weeks of treatment. The primary endpoint is the rate of centrally assessed **Ki-67** expression at or below 2.7% on Day 14, determined through biopsy. Secondary endpoints include the incidence of adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation, as well as circulating tumor DNA (ctDNA) measurements at baseline and Day 14. Additionally, the trial will measure the trough and peri-biopsy plasma concentrations of PF-07220060 and perform **Ki-67** staining.