Inhibition of lysine acetyltransferase KAT6 in ER + HER2 - metastatic breast cancer: a phase 1 trial
Published report from the trial registered as NCT04606446, in Nature Medicine (2024), chosen as the most cited paper whose own text cites the registry id.
Overview
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.
Indexed on Europe PMC as PubMed record 38824244 (DOI 10.1038/s41591-024-03060-0). Its abstract cites the registry id NCT04606446, which is how it was matched to this trial; no figure has been checked by an editor.
This is the paper Europe PMC returns for registry id NCT04606446 with the most citations, so it is the natural first reading for anyone following the trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.