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Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

2015-10-09

2017年:AZD3759登上《柳叶刀》呼吸医学分册


AZD3759治疗EGFR突变型NSCLC伴CNS转移的活性和安全性

一期非盲剂量递增和剂量扩大研究(BLOOM)

 

  表皮生长因子受体突变型非小细胞肺癌的中枢神经系统转移包括脑转移和软脑膜转移,其预后不良。AZD3759为新型表皮生长因子受体酪氨酸激酶抑制剂,具有较高的血脑屏障穿透能力。


  2017年11月1日,英国《柳叶刀》呼吸医学分册正式发表韩国成均馆大学三星首尔医院、首尔大学医院、延世大学医学院、蔚山大学首尔峨山医院、首尔大学盆唐医院、中国台湾大学医院和成功大学医院、澳大利亚墨尔本奥利维亚牛顿约翰癌症中心、悉尼克里斯奥布莱恩癌症中心、美国洛杉矶加利福尼亚大学医学中心、洛杉矶西奈雪松医学中心、阿斯利康英国剑桥研发中心、阿斯利康中国上海研发中心的BLOOM研究报告,探讨了AZD3759对表皮生长因子受体突变型非小细胞肺癌脑转移和软脑膜转移患者的安全性、耐受性、药物代谢动力学、有效性。


  该非盲多中心一期临床研究于2014年11月18日~2016年9月7日在澳大利亚、韩国、中国、美国的11个中心和医院进行,经过组织学确诊,入组晚期表皮生长因子受体突变型非小细胞肺癌患者共计67例,其中:


  剂量递增阶段入组29例表皮生长因子受体酪氨酸激酶抑制剂治疗后疾病进展患者29例,口服AZD3759每天2次,每次剂量分别为50、100、200、300、500毫克,以确定最佳安全剂量。


  剂量扩大阶段入组38例从未接受表皮生长因子受体酪氨酸激酶抑制剂治疗的脑或软脑膜转移患者和曾经接受表皮生长因子受体酪氨酸激酶抑制剂治疗的软脑膜转移患者,口服AZD3759每天2次,每次剂量为200或300毫克。


  主要研究目标为安全性和耐受性,根据美国国家癌症研究所不良事件通用术语标准(CTCAE)4.03版,对不良事件的严重程度进行评定。该研究已在美国政府临床研究网站注册,编号:NCT02228369。


  结果,截至2016年12月12日,3例(10%)剂量递增阶段患者和20例(53%)剂量扩大阶段患者仍在接受治疗。


  剂量递增阶段有3例患者每天2次口服500毫克,其中2例(67%)发生剂量相关毒性反应(1例3级痤疮、1例不可耐受的2级黏膜炎);因此,剂量扩大阶段选择每天2次口服200和300毫克进一步评定。


  剂量扩大阶段未发生4级病变,发生1~3级药物相关皮肤病变35例(92%)、胃肠病变29例(76%),其中200毫克组3级转氨酶升高1例(4%)、300毫克组3级腹泻和3级皮疹各1例(13%)中断治疗。3级皮肤和胃肠病变分别发生于4例(17%)和2例(9%)200毫克组、6例(40%)和4例(27%)300毫克组。其他3级病变包括200毫克组肝胆肾脏病变3例(13%)、300毫克组乏力1例(7%)和感染寄生1例(7%)、200毫克组1例(4%)和300毫克组1例(7%)代谢及营养障碍。


  对于大多数患者,AZD3759的血浆游离浓度与脑脊液浓度非常接近(图1),AZD3759治疗前后相比,中枢神经系统转移病灶、颅外转移病灶的大小均有显著减少(图2)。

1587455921307369.png

图1、对于大多数患者,AZD3759的血浆游离浓度与脑脊液浓度非常接近。


1587456045837412.png

图2、对于大多数患者,AZD3759治疗前后相比,中枢神经系统转移病灶、颅外转移病灶的大小均有显著减少。


  对于从未接受酪氨酸激酶抑制剂治疗的患者,所有转移病灶、中枢神经系统转移病灶、颅外转移病灶的客观缓解率分别为65%、83%、72%,疾病控制率分别为90%、89%、94%,具体参见表1。

1587456135513709.png

表1、从未接受酪氨酸激酶抑制剂治疗的患者


  对于曾经接受酪氨酸激酶抑制剂治疗的患者,客观缓解率、疾病控制率分别为28%、78%,具体参见表2。

1587456182650020.png

表2、曾经接受酪氨酸激酶抑制剂治疗的患者


  因此,对于从未接受酪氨酸激酶抑制剂治疗或曾经接受酪氨酸激酶抑制剂治疗的非小细胞肺癌伴中枢神经系统转移患者,AZD3759每天2次每次200毫克的安全性可耐受。由于AZD3759的血脑屏障渗透性良好、临床活性令人鼓舞,故有必要开展下一步研究对该化合物进行评定。

 

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