Title
An Interventional, Open-Label, Randomized, Multicenter Phase 3 Study of Pf-07220060 Plus Letrozole Compared to CDK4/6 Inhibitor Plus Letrozole in Participants Over 18 Years of Age With Hormone Receptor (HR)-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Who Have Not Received Any Prior Systemic Anticancer Treatment for Advanced/Metastatic Disease (Fourlight-3)

Description
The purpose of this study is to determine the safety and efficacy of PF-07220060 with letrozole compared to approved treatments (ie, palbociclib, ribociclib or abemaciclib with letrozole) in people with breast cancer:

-HR-positive (breast cancer cells that need estrogen or progesterone to grow)
-HER2-negative (cells that have a small amount or none of a protein called HER2 on their surface);
-locally advanced (that has spread from where it started to nearby tissue or lymph nodes) or metastatic disease (the spread of cancer to other places in the body)
-who have not received any prior systemic anti-cancer treatment for advanced/metastatic disease.

Approximately half of the participants will receive PF-07220060 plus letrozole while the other half of participants will receive the investigator's choice of treatment plus letrozole.

The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.

Objective
Primary:
1. To compare the efficacy of PF- 07220060 in combination with letrozole (Arm A) versus CDK4/6i (investigator s choice: abemaciclib, palbociclib, or ribociclib) in combination with letrozole (Arm B) with respect to progression-free survival (PFS).

Secondary:
1. To compare Arm A versus Arm B with respect to overall survival (OS).
2. To compare Arm A versus Arm B with respect to measures of tumor control and to evaluate duration of response within each treatment arm.
3. To compare safety and tolerability between Arm A and Arm B.
4. To evaluate patient-reported outcomes (PRO) of health-related quality of life, disease treatment related
symptoms, and general health status for each treatment arm
5. To evaluate the relationship between circulating tumor DNA (ctDNA) levels and clinical outcome.

Treatment Drug: PF-07220060
Drug: letrozole
Drug: abemaciclib
Drug: palbociclib
Drug: ribociclib

Key Eligibility Inclusion Criteria:

Histological confirmation of breast cancer with evidence of locally advanced or metastatic disease, which is not amenable to surgical resection or radiation therapy with curative intent.

Documented estrogen receptor (ER) and/or progesterone receptor (PR)-positive tumor

Documented HER2-negative tumor

Previously untreated with any systemic anticancer therapy for their locally advanced or metastatic disease.

Measurable disease or non-measurable bone only disease as defined by RECIST version 1.1

Applicable Disease Sites
Breast

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital