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卡培他滨在乳腺癌中的新作用。

"The emerging role of capivasertib in breast cancer".

机构信息

Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens, 11528, Greece.

Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion hospital, 76, Vassilisis-Sofias Ave., 11528 Athens, Greece.

出版信息

Breast. 2022 Jun;63:157-167. doi: 10.1016/j.breast.2022.03.018. Epub 2022 Apr 1.

Abstract

Over 50% of breast tumors harbor alterations in one or more genes of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%). While PI3K and mTOR inhibitors are already approved in advanced breast cancer, AKT inhibitors have been recently developed as a new therapeutic approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated efficacy of capivasertib in breast cancer cell lines as a single agent or in combination with anti-HER2 agents and endocrine treatment, especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. The recommended phase II dose of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and maculopapular rash (11-16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer.

摘要

超过 50%的乳腺癌肿瘤携带有一个或多个磷脂酰肌醇 3-激酶 (PI3K) 通路基因的改变,包括 PIK3CA 突变 (31%)、PTEN 缺失 (34%)、PTEN 突变 (5%)和 AKT1 突变 (3%)。虽然 PI3K 和 mTOR 抑制剂已在晚期乳腺癌中获得批准,但 AKT 抑制剂最近已被开发为一种新的治疗方法。Capivasertib (AZD5363) 是一种新型、选择性的 ATP 竞争性泛 AKT 激酶抑制剂,对三种 AKT 同工型 AKT1、AKT2 和 AKT3 具有相似的活性。临床前研究表明,Capivasertib 作为单一药物或与抗 HER2 药物和内分泌治疗联合应用于乳腺癌细胞系具有疗效,尤其是在 PIK3CA 或 MTOR 改变的肿瘤中。I/II 期研究表明,Capivasertib 与紫杉醇、氟维司群联合应用于激素受体 (HR) 阳性、HER2 阴性乳腺癌或奥拉帕利时疗效更大。Capivasertib 作为单药治疗的推荐 II 期剂量为 480mg bid,给药方案为 4 天 ON,3 天 OFF。高血糖症(20-24%)、腹泻(14-17%)和斑丘疹皮疹(11-16%)是最常见的≥3 级不良事件,毒性谱易于控制。正在进行的 Capivasertib 联合氟维司群 (CAPItello-291)、CDK4/6 抑制剂 palbociclib (CAPItello-292) 和紫杉醇 (CAPItello-290) 的 III 期试验将更好地阐明 Capivasertib 在乳腺癌中的治疗作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a10a/9011110/4b7270064490/gr1.jpg

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