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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-03060-0

摘要内容如下：

抑制组蛋白赖氨酸乙酰转移酶（KAT6A和KAT6B）在雌激素受体阳性（ER+）乳腺癌临床前模型中显示出抗肿瘤活性。PF-07248144是KAT6A和KAT6B的选择性催化抑制剂。在本研究中，我们报道了PF-07248144单药治疗和氟维司群联合治疗重度预处理ER+人表皮生长因子受体阴性（HER2-）转移性乳腺癌（MBC）的安全性、药代动力学（PK）、药效学、疗效和生物标志物的首次人体1期剂量递增和剂量扩展研究（n=107）结果。达到了评估PF-07248144作为单药治疗和与氟维司群联合治疗的安全性和耐受性以及确定推荐剂量的主要目标。次要终点包括PK特征和抗肿瘤活性评估，包括客观缓解率（ORR）和无进展生存期（PFS）。常见的治疗相关不良事件（任何级别；3-4级）包括味觉障碍（83.2%，0%）、中性粒细胞减少症（59.8%，35.5%）和贫血（48.6%，13.1%）。暴露量大致与剂量成比例。单药治疗时观察抗肿瘤活性。对于PF-07248144-氟维司群组合（n=43），ORR（95%可信区间（CI））为30.2%（95%CI=17.2-46.1%），中位PFS为10.7（5.3-不可评价）个月。PF-07248144在重度预处理的ER+HER2-MBC中表现出可耐受的安全性和持久的抗肿瘤活性。这些发现确立了KAT6A和KAT6B作为可用药的癌症靶标，提供了概念的临床证据，并揭示了治疗MBC的潜在途径。ClinicalTrial.gov注册：NCT04606446。

英文原文如下：

Abstracts

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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