Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial

Publication Title

Nature medicine

Authors

Toru Mukohara
Yeon Hee Park
David Sommerhalder
Kan Yonemori
Erika Hamilton
Sung-Bae Kim
Jee Hyun Kim
Hiroji Iwata
Toshinari Yamashita
Rachel M Layman
Monica Mita
Timothy Clay
Yee Soo Chae
Catherine Oakman
Fengting Yan, Swedish Cancer Institute, First Hill-True Family Women's Cancer Center, Seattle, WA.Follow
Gun Min Kim
Seock-Ah Im
Geoffrey J Lindeman
Hope S Rugo
Marlon Liyanage
Michelle Saul
Christophe Le Corre
Athanasia Skoura
Li Liu
Meng Li
Patricia M LoRusso

Document Type

Article

Publication Date

6-1-2024

Keywords

washington; swedish; swedish cancer

Abstract

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

Clinical Institute

Cancer

Clinical Institute

Women & Children

Specialty/Research Institute

Oncology

DOI

10.1038/s41591-024-03060-0