入脑效果好的新药AZD3759

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AZD3759，阿斯利康的非小肺癌脑转新药，针对egfr突变耐药病人，50mg-100mg*2每天，无明显副作用，目前1期临床（与160mg每天的AZD9291对比治疗脑转效果，入组病人为egfr耐药的脑转非小细胞肺癌）。值得关注。
AZD3759的入脑特性：具有非常高的被动渗透率（29.5x10-6 cmc），不是跨膜糖蛋白(Pgp)和乳腺癌耐药蛋白(BCRP)的底物，在免子、小鼠和猴子体内的Kpuu,brain和 Kpuu,CSF > 0.5。
初步临床结果：4名脑转NSCLC病人，3名50mg*2每天，1名100mg*2每天，其中2名可评估病人中，1名肿瘤缩小，1名稳定，他们的脑脊髓液中药物浓度为7.7nM和6nM，约等于AZD3759的pEGFR IC50。临床中没有发现剂量限制副作用，有2名病人1级皮疹。
注：多药转运体如 PGP、MRP、LRP 和 BCRP,能够使细胞内药物外排增加或囊泡隔离导致细胞内药物浓度降低或药物分布改变。
Kpuu：血浆分配系数。
https://clinicaltrials.gov/show/NCT02228369
http://abstracts.asco.org/156/AbstView_156_146873.html
http://abstracts.asco.org/156/AbstView_156_147526.html

AZD3759, an EGFR inhibitor with blood brain barrier (BBB) penetration for the treatment of non-small cell lung cancer (NSCLC) with brain metastasis (BM): Preclinical evidence and clinical cases.

Subcategory:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Session Type and Session Title:
Poster Discussion Session, Lung Cancer—Non-Small Cell Metastatic
Abstract Number:
8016

Poster Board Number:
Board #338
Citation:
J Clin Oncol 33, 2015 (suppl; abstr 8016)
Author(s):
Dong-Wan Kim, James Chih-Hsin Yang, Kan Chen, Ziqiang Cheng, Lucy Yin, Paul David Martin, Zhenfan Yang, Haiyi Jiang, Myung-Ju Ahn; Seoul National University Hospital, Seoul, South Korea; Department of Oncology, National Taiwan University Hospital; Graduate Institute of Oncology & Cancer Research Center, National Taiwan University, Taipei, Taiwan; Innovation Center China, Innovative Medicines and Early Development, AstraZeneca, Shanghai, China; Innovation Center China, Innovative Medicines & Early Development, AstraZeneca, Shanghai, China; Innovation Center China, Innovative Medicines & Early Development, Shanghai, China; AstraZeneca, Alderley Park, Macclesfield, United Kingdom; AstraZeneca China, Shanghai, China; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea

Abstract Disclosures

Abstract:

Background: Increasing numbers of EGFRm+ NSCLC patients with BM have been reported, while effective treatment is lacking due to limited BBB penetration of currently available EGFR TKIs. Here we report preliminary data on AZD3759, an EGFR TKI with BBB penetration, for the treatment of BM. Methods: Preclinically, AZD3759 was assessed in both in vitro and in vivo assays, including MDCKII/Pgp and BCRP assays and CNS penetration in rats, mice and monkeys. PC-9 cells (Exon19Del) were transfected with luciferase and implanted through intra-carotid artery injection to establish a BM model in mice. Tumor growth was monitored weekly by a Xenogen Imaging System and the animal survival time was recorded. Blood and brain tissues were collected for pharmacokinetics, histopathology and pEGFR expression analyses. An ongoing, open label, dose escalation phase I study (NCT02228369; sponsor AstraZeneca) is investigating safety and tolerability of AZD3759 in patients with EGFRm+ advanced NSCLC. Results: AZD3759 has high passive permeability (29.5x10-6 cm/sec) and is not a substrate of the efflux transporters Pgp or BCRP at the BBB. In vivo, AZD3759 reached distribution equilibrium in rats, mice and monkey (Kpuu,brain and Kpuu,CSF > 0.5), suggesting BBB penetration. In the BM model, AZD3759 induced profound tumor regression and significantly improved animal survival. A correlation between free brain exposure and pEGFR modulation was also detected in tumor tissues on AZD3759 treatment. To date, 4 patients with measurable BM have been enrolled into 50mg bid and 100mg bid cohorts (3 patients and 1 patient, respectively). In the 2 evaluable patients with BM, one unconfirmed PR and one SD in the brain have been observed. Ctrough CSF concentrations of these patients were 7.7 and 6nM, respectively, close to the pEGFR IC50 of AZD3759. No DLTs were reported to date and two cases of grade I skin rash were observed. Conclusions: Preclinical and initial clinical evidence indicate that AZD3759 is an EGFR TKI with BBB penetration with potential to treat EGFRm+ NSCLC patients with BM. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369

Abstracts by Dong-Wan Kim:
AZD9291, a mutant-selective EGFR inhibitor, as first-line treatment for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): Results from a phase 1 expansion cohort.
Meeting: 2015 ASCO Annual Meeting | Abstract No: 8000 | First Author: Suresh S. Ramalingam
Category: Lung Cancer—Non-Small Cell Metastatic - Lung Cancer—Non-Small Cell Metastatic
Dynamic serial monitoring of EGFR mutations in plasma DNA samples in EGFR mutant NSCLC patients treated with EGFR TKI.
Meeting: 2015 ASCO Annual Meeting | Abstract No: 8078 | First Author: Myung-Ju Ahn
Category: Lung Cancer—Non-Small Cell Metastatic - Lung Cancer—Non-Small Cell Metastatic