科學創新
Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study
來源:The Lancet | 作者:晨泰醫藥 | 發布時間: 2017-11-05 | 732 次瀏覽 | 分享到:

2017年:AZD3759登上《柳葉刀》呼吸醫學分冊

 

AZD3759治療EGFR突變型NSCLCCNS轉移的活性和安全性

一期非盲劑量遞增和劑量擴大研究(BLOOM

 

  表皮生長因子受體突變型非小細胞肺癌的中樞神經系統轉移包括腦轉移和軟腦膜轉移,其預后不良。AZD3759為新型表皮生長因子受體酪氨酸激酶抑制劑,具有較高的血腦屏障穿透能力。

  2017111日,英國《柳葉刀》呼吸醫學分冊正式發表韓國成均館大學三星首爾醫院、首爾大學醫院、延世大學醫學院、蔚山大學首爾峨山醫院、首爾大學盆唐醫院、中國臺灣大學醫院和成功大學醫院、澳大利亞墨爾本奧利維亞牛頓約翰癌癥中心、悉尼克里斯奧布萊恩癌癥中心、美國洛杉磯加利福尼亞大學醫學中心、洛杉磯西奈雪松醫學中心、阿斯利康英國劍橋研發中心、阿斯利康中國上海研發中心的BLOOM研究報告,探討了AZD3759對表皮生長因子受體突變型非小細胞肺癌腦轉移和軟腦膜轉移患者的安全性、耐受性、藥物代謝動力學、有效性。

  該非盲多中心一期臨床研究于20141118日~201697日在澳大利亞、韓國、中國、美國的11個中心和醫院進行,經過組織學確診,入組晚期表皮生長因子受體突變型非小細胞肺癌患者共計67例,其中:

  劑量遞增階段入組29例表皮生長因子受體酪氨酸激酶抑制劑治療后疾病進展患者29例,口服AZD3759每天2次,每次劑量分別為50100200300500毫克,以確定最佳安全劑量。

  劑量擴大階段入組38例從未接受表皮生長因子受體酪氨酸激酶抑制劑治療的腦或軟腦膜轉移患者和曾經接受表皮生長因子受體酪氨酸激酶抑制劑治療的軟腦膜轉移患者,口服AZD3759每天2次,每次劑量為200300毫克。

  主要研究目標為安全性和耐受性,根據美國國家癌癥研究所不良事件通用術語標準(CTCAE4.03版,對不良事件的嚴重程度進行評定。該研究已在美國政府臨床研究網站注冊,編號:NCT02228369

  結果,截至20161212日,3例(10%)劑量遞增階段患者和20例(53%)劑量擴大階段患者仍在接受治療。

  劑量遞增階段有3例患者每天2次口服500毫克,其中2例(67%)發生劑量相關毒性反應(13級痤瘡、1例不可耐受的2級黏膜炎);因此,劑量擴大階段選擇每天2次口服200300毫克進一步評定。

  劑量擴大階段未發生4級病變,發生13級藥物相關皮膚病變35例(92%)、胃腸病變29例(76%),其中200毫克組3級轉氨酶升高1例(4%)、300毫克組3級腹瀉和3級皮疹各1例(13%)中斷治療。3級皮膚和胃腸病變分別發生于4例(17%)和2例(9%200毫克組、6例(40%)和4例(27%300毫克組。其他3級病變包括200毫克組肝膽腎臟病變3例(13%)、300毫克組乏力1例(7%)和感染寄生1例(7%)、200毫克組1例(4%)和300毫克組1例(7%)代謝及營養障礙。

  對于大多數患者,AZD3759的血漿游離濃度與腦脊液濃度非常接近(圖1),AZD3759治療前后相比,中樞神經系統轉移病灶、顱外轉移病灶的大小均有顯著減少(圖2)。

  對于從未接受酪氨酸激酶抑制劑治療的患者,所有轉移病灶、中樞神經系統轉移病灶、顱外轉移病灶的客觀緩解率分別為65%83%72%,疾病控制率分別為90%89%94%,具體參見表1

  對于曾經接受酪氨酸激酶抑制劑治療的患者,客觀緩解率、疾病控制率分別為28%78%,具體參見表2

  因此,對于從未接受酪氨酸激酶抑制劑治療或曾經接受酪氨酸激酶抑制劑治療的非小細胞肺癌伴中樞神經系統轉移患者,AZD3759每天2次每次200毫克的安全性可耐受。由于AZD3759的血腦屏障滲透性良好、臨床活性令人鼓舞,故有必要開展下一步研究對該化合物進行評定。

 

Lancet Respir Med. 2017 Nov;5(11):891-902.

Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study.

Ahn MJ, Kim DW, Cho BC, Kim SW, Lee JS, Ahn JS, Kim TM, Lin CC, Kim HR, John T, Kao S, Goldman JW, Su WC, Natale R, Rabbie S, Harrop B, Overend P, Yang Z, Yang JC.

Samsung Medical Centre, Seoul, South Korea; Seoul National University Hospital, Seoul, South Korea; Yonsei University College of Medicine, Seoul, South Korea; Asan Medical Centre, Seoul, South Korea; Seoul National University Bundang Hospital, Seongnam, South Korea; National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; Olivia Newton-John Cancer Wellness & Research Centre, Austin Health, Melbourne, VIC, Australia; Chris O'Brien Lifehouse, Sydney, NSW, Australia; UCLA Medical Center, Santa Monica, CA, USA; National Cheng-Kung University Hospital, Tainan, Taiwan; Cedars-Sinai Medical Center, Los Angeles, CA, USA; AstraZeneca, Cambridge, UK; AstraZeneca, Shanghai, China; National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.

BACKGROUND: CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases.

METHODS: This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced- stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369.

FINDINGS: Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day).

INTERPRETATION: AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies.

FUNDING: AstraZeneca.

PMID: 29056570

DOI: 10.1016/S2213-2600(17)30378-8


1、對于大多數患者,AZD3759的血漿游離濃度與腦脊液濃度非常接近。

 

2、對于大多數患者,AZD3759治療前后相比,中樞神經系統轉移病灶、顱外轉移病灶的大小均有顯著減少。


1、從未接受酪氨酸激酶抑制劑治療的患者                       



2、曾經接受酪氨酸激酶抑制劑治療的患者

 

 
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