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AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

晨泰医药2016-12-07

2016年:AZD3759亮相《科学》子刊


AZD3759:穿越血脑屏障,追踪肿瘤细胞

 

《科学》旗下《转化医学》编辑评论:虽然非小细胞肺癌的靶向疗法近年来取得进展,但是仍然难治,原因之一即中枢神经系统转移。抑制该癌症常见靶点表皮生长因子受体的药物无法有效穿透血脑屏障,意味着转移性肿瘤一旦转移至脑或脊髓,即可无限制地生长。现在,一种新药不仅可以与现有临床获批药物一样有效抑制表皮生长因子受体,而且可以穿过血脑屏障靶向治疗转移灶。该药对于多种不同小鼠模型表现出令人鼓舞的效果,而且对于人类患者也表现出抗肿瘤活性。


  对于表皮生长因子受体发生突变的非小细胞肺癌患者,现有的表皮生长因子受体抑制剂(例如厄洛替尼)治疗有效。不过,患者治疗期间经常发生中枢神经系统转移,即使其颅外肿瘤仍受控制。由于缺乏其他有效药物,为了在中枢神经系统内达到足够高的药物浓度,临床尝试更高剂量的表皮生长因子受体抑制剂。虽然该方法可见有限的肿瘤缓解,但是中枢神经系统以外的毒性太高而无法被耐受。


  2016年12月7日,美国科学促进会《科学》旗下《转化医学》正式发表阿斯利康亚洲创新医药中心、阿斯利康英国剑桥早期临床研发中心、韩国首尔大学医院和成均馆大学三星首尔医院、中国台湾大学医院和癌症中心的论文,报道了一种新型选择性表皮生长因子受体抑制剂AZD3759的发现和早期临床开发。


  AZD3759可以充分穿透血脑屏障,脑组织、脑脊液与血液的游离药物浓度比中位值分别为0.65、0.42,远远高于厄洛替尼的0.13、0.14。


  根据动物模型研究发现,AZD3759与空白对照和厄洛替尼相比,对于肺癌的软脑膜转移(图1)、脑转移(图2)、颅外皮下异种移植模型(图4),可以引起肿瘤显著缩小、生存率显著提高;对于无胸腺裸鼠,AZD3759可以预防脑转移发生(图3)。


  根据临床病例初步研究证实,AZD3759对于脑转移和软脑膜转移患者具有血脑屏障穿透性和抗肿瘤活性,治疗前后相比,肿瘤增殖指标(磷酸化表皮生长因子受体评分)、脑脊液肿瘤细胞数量、肿瘤大小显著减少(图5)。


  因此,以上结果表明AZD3759对于治疗脑转移和软脑膜转移的潜力,并且支持开展更大型研究进行临床评估。


Sci Transl Med. 2016 Dec 7;8(368):368ra172.

AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.

Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z, Xu Y, Yin X, Bai Y, Rabbie S, Kim DW, Ahn MJ, Yang JC, Zhang X.

Asia Innovative Medicines, AstraZeneca, Shanghai, China; Early Clinical Development, AstraZeneca, Cambridge, U.K; Seoul National University Hospital, Seoul, South Korea; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, China.

Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.

PMID: 27928026

DOI: 10.1126/scitranslmed.aag0976


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图3、预防肺癌脑转移模型:AZD3759与空白对照和厄洛替尼相比,脑转移发生率显著减少。


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图4、不同肺癌细胞颅外皮下异种移植模型:AZD3759与空白对照和厄洛替尼相比,颅外皮下异种移植肿瘤显著缩小。


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图5、临床病例初步研究:治疗前后相比,肿瘤增殖指标(pEGFR评分)、脑脊液肿瘤细胞数量、肿瘤大小显著减少。



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