卡匹色替（AZD5363）是一种强有力的AKT选择性抑制剂，由英国阿斯利康研发。AKT是对肿瘤的葡萄糖代谢、转录、增殖、转移、凋亡等多种细胞过程发挥重要作用的丝氨酸/苏氨酸蛋白质激酶，有3种异构酶：AKT1、AKT2、AKT3，都可以被卡匹色替抑制。
2020年2月5日，英国《柳叶刀》肿瘤学分册在线发表卡迪夫大学维林德雷癌症中心、威尔士大学医院、北威尔士医疗委员会、黑潭教学医院、哈德斯菲尔德医院、莫克姆湾大学医院、利兹大学、利兹教学医院、伊普斯维奇医院、阿斯利康、曼彻斯特大学克里斯蒂医院的FAKTION研究报告，比较了雌激素受体选择性降解剂氟维司群±卡匹色替治疗雌激素受体阳性晚期乳腺癌芳香酶抑制剂耐药患者的无进展生存。
FAKTION (Fulvestrant +/- Akt Inhibition in Advanced Aromatase Inhibitor Resistant Breast Cancer): A Phase 1b/2 Randomised Placebo Controlled Trial of Fulvestrant +/- AZD5363 in Postmenopausal Women With Advanced Breast Cancer Previously Treated With a Third Generation Aromatase Inhibitor (NCT01992952)
该多中心随机化双盲安慰剂对照二期临床研究于2015年3月16日～2018年3月6日从英国19家医院入组年龄≥18岁、美国东部肿瘤学协作组体力状态评分0～2、雌激素受体阳性、HER2阴性、转移或局部晚期无法手术乳腺癌、芳香酶抑制剂治疗期间复发或进展的绝经后女性140例，按1∶1的比例随机分入两组：氟维司群＋卡匹色替69例、氟维司群＋安慰剂71例。每个周期28天的第1天肌肉注射氟维司群500毫克（第1个周期的第15天加500毫克），从第1个周期的第15天开始每周第1～4天每天2次口服卡匹色替400毫克或安慰剂，直至疾病进展、毒性反应无法耐受、失访或退出研究。通过交互式网络反馈系统完成治疗分组，按照最小化法对20%的随机化因素（可测量或不可测量的病变、原发或继发芳香酶抑制剂耐药、PIK3CA基因状态、PTEN基因状态）进行最小化。主要终点为无进展生存，单侧α预设0.20，对全部意向治疗患者进行有效性和安全性分析。目前已经完成入组，正在进行随访。
结果，截至2019年1月30日，无进展生存中位随访4.9个月（四分位：1.6～11.6）期间，发生进展或死亡事件112例。
卡匹色替组与安慰剂组相比：
进展或死亡人数：49比63例
进展或死亡比例：71%比89%
中位无进展生存：10.3比4.8个月（95%置信区间：5.0～13.2、3.1～7.7）
进展或死亡风险：低42%（未校正风险比：0.58，95%置信区间：0.39～0.84，双侧P=0.0044，单侧对数秩检验P=0.0018）
3～4级高血压：22比17例（32%比24%）
3～4级皮疹：14比0例（20%比0）
3～4级腹泻：10比3例（14%比4%）
3～4级感染：4比2例（6%比3%）
3～4级疲劳：1比3例（1%比4%）
严重腹泻：3比0例
严重皮疹：2比0例
急性肾损伤：2比0例
严重呕吐：1比0例
意识丧失：1比0例
严重高血糖：1比0例
严重脓毒症：1比0例
不典型肺部感染所致死亡：1比0例
不明原因死亡：1比0例
病变所致死亡：19比31例
因此，该研究结果表明，对于晚期乳腺癌芳香酶抑制剂耐药患者，氟维司群＋卡匹色替与氟维司群＋安慰剂相比，无进展生存显著较长，故有必要开展三期临床研究进一步证实。
对此，美国匹兹堡大学发表同期评论：卡匹色替可以抑制晚期乳腺癌的关键通路。
相关链接
Lancet Oncol. 2020 Feb 5. [Epub ahead of print]
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.
Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, Madden TA, Bale C, Bezecny P, Joffe J, Moon S, Twelves C, Venkitaraman R, Waters S, Foxley A, Howell SJ.
Cardiff University, Cardiff, UK; Velindre Cancer Centre, Cardiff, UK; University Hospital of Wales, Cardiff, UK; Betsi Cadwaladr University Health Board, Bangor, UK; Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK; Calderdale & Huddersfield NHS Foundation Trust, Huddersfield, UK; University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK; University of Leeds and Leeds Teaching Hospitals Trust, Leeds, UK; The Ipswich Hospital NHS Trust, Ipswich, UK; AstraZeneca, Cambridge, UK; The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK.
BACKGROUND: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.
METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0.20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.
FINDINGS: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4.9 months (IQR 1.6-11.6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10.3 months (95% CI 5.0-13.2) in the capivasertib group versus 4.8 months (3.1-7.7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0.58 (95% CI 0.39-0.84) in favour of the capivasertib group (two-sided p=0.0044; one-sided log rank test p=0.0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related.
INTERPRETATION: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.
FUNDING: AstraZeneca and Cancer Research UK.
PMID: 32035020
DOI: 10.1016/S1470-2045(19)30817-4
Lancet Oncol. 2020 Feb 5. [Epub ahead of print]
Capivasertib inhibits a key pathway in metastatic breast cancer.
Nasrazadani A, Brufsky AM.
University of Pittsburgh, Pittsburgh, PA, USA.
PMID: 32035019
DOI: 10.1016/S1470-2045(19)30857-5
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