晚期三阴性乳腺癌患者一线治疗新方案 三阴性乳腺癌与其他乳腺癌相比，PI3K→AKT信号通路激活、PI3K催化亚基PIK3CA激活、PI3K→AKT信号通路抑制基因PTEN失活的发生率较高。临床前研究已经发现，口服小分子AKT 抑制剂卡匹色替对三阴性乳腺癌有效，尤其PI3K→AKT或PIK3CA激活或PTEN失活的三阴性乳腺癌。
凛开头的成语 2019年12月16日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国伦敦玛丽王后大学、皇家圣巴多罗买医院、卡迪夫大学韦林德癌症中心、诺丁汉大学医院、皇家康沃尔医院、斯塔福德郡大学北米德兰兹医院、英国癌症研究基金会剑桥大学中心、爱丁堡大学癌症研究中心、利兹大学教学医院、伦敦大学学院、阿斯利康、伦敦大学癌症研究院、皇家马斯登医院、格鲁吉亚临床肿瘤研究院、韩国成均馆大学三星首尔医院、匈牙利佩奇医科大学、法国安东尼拉卡萨涅中心、西班牙马德里大学拉蒙卡哈尔医院、巴塞罗纳大学肿瘤研究院、凯龙集团肿瘤研究院的PAKT研究报告，探讨了卡匹色替＋紫杉醇一线治疗晚期三阴性乳腺癌的安全性和有效性。
该国际多中心随机双盲安慰剂对照二期临床研究于2014年5月～2017年6月从英国、韩国、法国、匈牙利、罗马尼亚、格鲁吉亚42家学术型医疗中心入组尚未治疗的晚期三阴性乳腺癌女性患者140例，按1∶1的比例随机分入两组，每28天的第1、8、15天静脉注射紫杉醇90mg/m²＋第2～5和9～12和16～19天每天2次口服400mg卡匹色替或安慰剂，直至疾病进展或毒性反应无法耐受。主要研究终点为无进展生存。次要研究终点包括总生存、总缓解率、临床获益率、PIK3CA或AKT1或PTEN突变亚组无进展生
芦花鸡
存、安全性。预设统计学意义临界值为单侧P=0.10。两组患者特征相似，除了安慰剂组的内脏转移比例较高。
结果，中位随访18.2个月期间，卡匹色替＋紫杉醇与安慰剂＋紫杉醇相比：
中位无进展生存：5.9比4.2个月
进展或死亡风险：低26%（风险比：0.74，95%置信区间：0.50～1.08，单侧P=0.06）
双子座女明星中位总生存：19.1比12.6个月
总死亡风险：低39%（风险比：0.61，95%置信区间：0.37～0.99，双侧P=0.04）
对于28例PIK3CA或AKT1或PTEN突变患者，卡匹色替＋紫杉醇与安慰剂＋紫杉醇相比：中位无进展生存：9.3比3.7个月
进展或死亡风险：低70%（风险比：0.30，95%置信区间：0.11～0.79，双侧 P=0.01）
卡匹色替＋紫杉醇与安慰剂＋紫杉醇相比，发生比例最高的≥3级不良事件：
腹泻：13%比1%
开除孕妇
感染：4%比1%
中性粒细胞减少：3%比3%
晁新
皮疹：4%比0%
疲劳：4%比0%
与水有关的字
因此，该研究结果表明，AKT抑制剂卡匹色替与安慰剂相比，加入紫杉醇一线治疗以后，三阴性乳腺癌患者的无进展生存和总生存显著较长，尤其对于PIK3CA或AKT1或PTEN突变患者，故有必要开展卡匹色替治疗三阴性乳腺癌的三期临床研究：CapItello290。
CapItello290: Capivartib + Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC: A Pha III Double-blind Randomid Study Asssing the Efficacy and Safety of Capivartib + Paclitaxel vs Placebo + Paclitaxel as First-line Treatment for Patients With Locally Advanced (Inoperable) or Metastatic TNBC
(NCT03997123)
J Clin Oncol. 2019 Dec 16. [Epub ahead of print]
大地在我脚下Capivartib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.
Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall
PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC.
Queen Mary University of London, London, UK; Barts Hospital NHS Trust, London, UK; Velindre NHS Trust, Cardiff, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK; Royal Cornwall Hospitals NHS Trust, Truro, UK; University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK; Cancer Rearch UK Cambridge Centre, Cambridge, UK; Edinburgh Cancer Rearch Centre, University of Edinburgh, Edinburgh, UK; Leeds Teaching Hospitals NHS Trust, Leeds, UK; University College London, London, UK; AstraZeneca, Cambridge, UK; Institute of Cancer Rearch, London, UK; Royal Marsden Hospital, London, UK; AstraZeneca, Waltham, MA; Institute of Clinical Oncology, Tbilisi, GA; Samsung Medical Centre, Seoul, Korea; Medical University of Pécs, Pecs, Hungary; Centre Antoine Lacassagne, Nice, France; Ramon y Cajal University Hospit
al, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Institute of Oncology, Quiron Group, Madrid, Spain. PURPOSE: The phosphatidylinositol 3-kina (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivartib has shown preclinical activity in TNBC models, and drug nsitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivartib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized pha II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivartib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until dia progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with鬼故
PIK3CA/AKT1/PTEN alterations, tumor respon, and safety.
RESULTS: Median PFS was 5.9 months with capivartib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivartib plus paclitaxel an
d 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivartib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adver events in tho treated with capivartib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%).
CONCLUSION: Addition of the AKT inhibitor capivartib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivartib warrants further investigation for treatment of TNBC.
PMID: 31841354
DOI: 10.1200/JCO.19.00368
