C4551002 - An Interventional, Open-Label, Randomized, Multicenter, Phase 3 Study of PF-07248144 Plus Fulvestrant Compared to Investigator’s Choice of Therapy in Adult Participants with Hormone Receptor-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Whose Disease Progressed After Prior CDK4/6 Inhibitor-based Therapy

The primary objective is to demonstrate superiority of PF-07248144 plus fulvestrant (Arm A) versus investigator's choice of therapy (Arm B) with respect to progression-free survival (PFS). This endpoint is clinically relevant for evaluating treatment efficacy in patients with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer who have experienced disease progression following prior CDK4/6 inhibitor-based therapy.

The secondary objectives include:

• To compare Arm A versus Arm B with respect to overall survival (OS)

• To assess Arm A versus Arm B with respect to measures of tumor control and to evaluate duration of response (DoR) within each treatment arm

• To assess safety and tolerability in Arm A and Arm B

• To characterize trough plasma concentrations of PF-07248144 when given in combination with fulvestrant

The clinical trial enrolled a total of **247 participants** diagnosed with **hormone receptor-positive**, **HER2-negative advanced or metastatic breast cancer**. The study population included both female and male subjects aged 18 years or older. Participants were required to have histologically confirmed disease that was not amenable to curative surgical resection or radiation therapy. All enrolled individuals had previously received **CDK4/6 inhibitor** therapy, either in combination with endocrine therapy in the advanced or metastatic setting, or as adjuvant treatment with documented disease progression or recurrence during or within 12 months after completing CDK4/6 inhibitor therapy. Participants with prior exposure to therapies targeting **estrogen receptor 1 (ESR1)** or **BRCA1/2** mutations were also eligible. The trial required availability of adequate tumor tissue specimens for analysis and the presence of measurable disease or non-measurable bone-only disease according to **RECIST v1.1** criteria. Participants were required to have an **Eastern Cooperative Oncology Group (ECOG) Performance Status** of 0 or 1, with consideration for ECOG 2 in select cases based on investigator judgment and adequate organ function. The study population included vulnerable groups as defined by regulatory standards.

This is an interventional, open-label, randomized, multicenter, phase 3 clinical trial evaluating PF-07248144 in combination with fulvestrant compared to investigator's choice of therapy in adult participants with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who experienced disease progression following prior CDK4/6 inhibitor-based therapy. The primary objective is to demonstrate superiority of PF-07248144 plus fulvestrant versus investigator's choice of therapy with respect to progression-free survival. The trial employs a randomized design with participants allocated to either the test arm receiving PF-07248144 plus fulvestrant or the comparator arm receiving investigator's choice of therapy, which may include exemestane, fulvestrant, or everolimus. The study is not classified as a low-intervention clinical trial.

Eligible participants must be at least 18 years of age at screening and have histological confirmation of hormone receptor-positive, HER2-negative breast cancer with evidence of locally advanced or metastatic disease that is not amenable to surgical resection or radiation therapy with curative intent. Participants must have received prior CDK4/6 inhibitor therapy either in combination with endocrine therapy in the advanced or metastatic breast cancer setting, or as adjuvant therapy with documented disease progression or recurrence during or within 12 months after the last dose. Previous therapy targeting estrogen receptor 1 or BRCA1/2 is permitted. Participants must provide sufficient representative formalin-fixed, paraffin-embedded tumor tissue specimens and have either measurable disease or non-measurable bone-only disease as defined by RECIST v1.1. An Eastern Cooperative Oncology Group Performance Status of 0 or 1 is required, with ECOG 2 considered eligible under specific circumstances with investigator judgment and sponsor agreement.

The investigational medicinal products include PF-07248144 administered as a film-coated tablet via the oral route at a maximum daily dose of 5 mg, with a maximum total dose of 3650 mg over the treatment period. Fulvestrant is administered as a solution for injection via the intramuscular route at a maximum daily dose of 500 mg, with a maximum total dose of 12,500 mg. Comparator therapies include exemestane as a tablet administered orally at a maximum daily dose of 25 mg (maximum total dose 18,250 mg) and everolimus as a tablet administered orally at a maximum daily dose of 10 mg (maximum total dose 7,300 mg). The maximum treatment period for all medicinal products is 24 months. All investigational products undergo study-specific repacking or relabeling in accordance with regulatory requirements where applicable.

The primary endpoint is progression-free survival, defined as the time from randomization to the date of first documented disease progression as determined by blinded independent central review per RECIST v1.1, or death due to any cause in the absence of progressive disease, whichever occurs first. Secondary endpoints include overall survival defined as the time from randomization to death due to any cause, objective response by blinded independent central review per RECIST v1.1, duration of response by blinded independent central review per RECIST v1.1, and clinical benefit response defined as complete response, partial response, or stable disease/non-complete response/non-progression for at least 24 weeks by blinded independent central review per RECIST v1.1. Additional secondary endpoints assess the type, incidence, severity as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, seriousness of adverse events, laboratory test or electrocardiogram abnormalities, characterization of PF-07248144 effect on corrected QT interval from baseline, and trough plasma concentration of PF-07248144.

The estimated recruitment start date is November 26, 2025, with an estimated study completion date of January 6, 2027. The overall trial duration encompasses the screening period, treatment period of up to 24 months, and follow-up assessments. Participant involvement extends from the initial screening visit through the treatment phase and subsequent follow-up visits until study completion or early termination. Early termination from the study may occur due to disease progression, unacceptable toxicity, withdrawal of consent, death, or other protocol-specified criteria. Study visits include a screening visit for eligibility assessment, regular on-treatment visits for safety and efficacy evaluations, and an end-of-study visit for final assessments. The study design incorporates blinded independent central review for tumor response assessments to ensure objective evaluation of treatment efficacy.

The experimental medication **PF-07248144** is administered as a **film-coated tablet** containing the active substance 2-methoxy-n-{4-methoxy-6-[(1h-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide. The medication is administered via the **oral route** at a maximum daily dose of **5 mg**. The maximum total dose over the treatment period is **3650 mg**, with a maximum treatment duration of **24 months**. PF-07248144 serves as a test medication in this clinical trial and is manufactured by Pfizer Inc.

**Fulvestrant** is utilized in the study as both a test medication and a comparator treatment. It is formulated as a **solution for injection** and is administered via the **intramuscular route**. The maximum daily dose of fulvestrant is **500 mg**, with a maximum total dose of **12500 mg** over the treatment period. The maximum treatment duration is **24 months**. The product undergoes study-specific repacking and/or relabelling in accordance with Annex 13.

**Exemestane** is employed as a comparator treatment in the trial. It is available in **tablet** form and is administered via the **oral route**. The maximum daily dose is **25 mg**, with a maximum total dose of **18250 mg** over the course of treatment. The maximum treatment period is **24 months**. This product is also subject to study-specific repacking and/or relabelling in accordance with Annex 13.

**Everolimus** serves as a comparator treatment and is formulated as a **tablet** for **oral administration**. The maximum daily dose of everolimus is **10 mg**, with a maximum total dose of **7300 mg** throughout the treatment period. The maximum treatment duration is **24 months**. Similar to other comparator medications in this study, everolimus undergoes study-specific repacking and/or relabelling in accordance with Annex 13.

Efficacy will be assessed through multiple parameters in this clinical trial. The primary efficacy endpoint is progression-free survival (PFS), 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 RECIST v1.1, or death due to any cause in the absence of progressive disease, whichever occurs first. Secondary efficacy endpoints include overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause. Additional secondary endpoints comprise objective response by BICR per RECIST v1.1, duration of response by BICR per RECIST v1.1, and clinical benefit response (defined as complete response, partial response, or stable disease/non-complete response/non-progression for at least 24 weeks) by BICR per RECIST v1.1. Efficacy assessments will be conducted using RECIST v1.1 criteria with blinded independent central review for tumor response evaluation. Representative formalin fixed, paraffin embedded tumor tissue specimens will be collected from participants. The trial will utilize measurable disease or non-measurable bone only disease as defined by RECIST v1.1 for efficacy evaluation.