Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial.
Nat Med
; 30(8): 2242-2250, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38824244
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 .
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Receptores de Estrógenos
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Receptor ErbB-2
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Histona Acetiltransferasas
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Fulvestrant
Límite:
Adult
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Aged
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
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MEDICINA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Japón