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Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial.
- Mukohara, Toru;
- Park, Yeon;
- Sommerhalder, David;
- Yonemori, Kan;
- Hamilton, Erika;
- Kim, Sung-Bae;
- Kim, Jee;
- Iwata, Hiroji;
- Yamashita, Toshinari;
- Layman, Rachel;
- Mita, Monica;
- Clay, Timothy;
- Chae, Yee;
- Oakman, Catherine;
- Yan, Fengting;
- Kim, Gun;
- Im, Seock-Ah;
- Lindeman, Geoffrey;
- Rugo, Hope;
- Liyanage, Marlon;
- Saul, Michelle;
- Le Corre, Christophe;
- Skoura, Athanasia;
- Liu, Li;
- Li, Meng;
- LoRusso, Patricia
- et al.
Published Web Location
https://doi.org/10.1038/s41591-024-03060-0Abstract
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 .
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