Background
Patients with hormone receptor–positive (HR+)/HER2-negative (HER2–) advanced/metastatic breast cancer who have tumors that progressed after CDK4/6 inhibitor (CDK4/6i) and endocrine therapy represent a high unmet medical need. Histone lysine acetyltransferases KAT6A and KAT6B regulate lineage-specific gene transcription via H3K23 acetylation. PF-07248144 (prifetrastat) is a selective inhibitor of KAT6A and KAT6B. PF-07248144 (5 mg once daily) in combination with fulvestrant has demonstrated encouraging and durable antitumor activity with a manageable safety profile in patients with heavily pretreated HR+/HER2– advanced breast cancer in a phase 1/2 study. The phase 3 study is designed to evaluate and confirm the efficacy and safety of PF-07248144 plus fulvestrant in patients with HR+/HER2– advanced breast cancer after tumor progression on CDK4/6i-based therapy, when compared to standard of care therapy.
Methods
KATSIS-1 is an open-label, randomized phase 3 trial, comparing PF-07248144 plus fulvestrant vs everolimus plus endocrine therapy (fulvestrant or exemestane) in patients with HR+/HER2– advanced breast cancer (NCT07062965). Key inclusion criteria are age 18 years or older; histologically confirmed HR+/HER2− advanced breast cancer; progression after prior CDK4/6i-based therapy; available tumor tissue; measurable disease or non-measurable bone-predominant disease, defined by RECIST v1.1; adequate organ function; ECOG PS 0 or 1. Key exclusion criteria are: presence of detectable PIK3CA/AKT1/PTEN alterations; prior chemotherapy or therapy targeting PIK3CA/AKT1/PTEN in ABC; >2 prior lines post-CDK4/6i of systemic anticancer therapy in advanced breast cancer; systemic anticancer therapy or radiation within 2 weeks of randomization. Up to 400 patients will be randomized (1:1) to receive either PF-07248144 plus fulvestrant vs everolimus plus endocrine therapy (fulvestrant or exemestane). Patients will be stratified by investigator choice of endocrine therapy with everolimus (fulvestrant vs exemestane), prior systemic lines of therapy in metastatic setting (1 vs 2), and disease site (visceral vs non-visceral). The primary end point is progression-free survival by blinded independent central review (BICR). Overall survival is a key secondary end point; other secondary end points include objective response, duration of response, clinical benefit rate, safety, and pharmacokinetics of PF-07248144.
ClinicalTrials.gov: NCT07062965
Funding Source: Pfizer Inc
Acknowledgement: Medical editorial support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Michael Riley, PhD of Oxford PharmaGenesis Inc, Wilmington, DE, USA with funding provided by Pfizer Inc, USA.
