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