阿斯利康的T790M牛逼新药AZD9291的1期临床结果出来了

Investigational EGFR Inhibitor May Hold Promise for Some Patients With Treatment-Resistant NSCLC

Approximately 50% of non–small cell lung cancer (NSCLC) patients who develop resistance to inhibitors of the epidermal growth factor receptor (EGFR) have acquired a second mutation, T790M, which no current EGFR inhibitors target. This may change if the AstraZeneca investigational compound AZD9291 proves as effective in patients as it appears in preclinical studies.

At the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston, Susan Galbraith, MD, PhD, Head of the Oncology Innovative Medicines Unit at AstraZeneca, reported early results at a press briefing (Abstract B212).

Current treatments are essentially lacking for advanced NSCLC of the resistant “double-mutation” type, and “this remains a key area of unmet need,” she said.

AZD9291 Potent Against T790M

AZD9291 is an oral, irreversible, third-generation, selective inhibitor of both EGFR-activating mutations and resistance (T790M) mutations.

“AstraZeneca chemists designed a compound that overcomes the limitations of earlier therapies. We developed a novel scaffold that could overcome the double-mutant kinase,” she said. “The innovative breakthrough was finding a series of molecules that could target both the activating and resistant mutant forms of EGFR more potentially than normal EGFR, which led to the development of the new EGFR kinase inhibitor AZD9291.”

The mechanistic and functional activity of AZD9291 was characterized in vitroand in vivo across a number of cell lines harboring various EGFR mutations or wild-type EGFR. Wild-type EGFR inhibition is believed to drive the observed dose-limiting toxicities seen with current EGFR inhibitors, such as skin rash and diarrhea.

AZD9291 potently inhibits EGFR phosphorylation in activating mutations and resistance cell lines in vitro, with much less activity against wild-type EGFR lines. Additionally, AZD9291 causes “profound regression” of tumors, she reported. Growth inhibition of 178% has been observed in activating cell lines, and 119% growth inhibition has been noted in resistance (double-mutation) models.

“Assuming that human tumors and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7 to 17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR-activating and T790M (resistant) mutations,” Dr. Galbraith said.

Preliminary Phase I Trial Results Impressive

At the 2013 European Cancer Conference in Amsterdam, preliminary results from an ongoing phase I study (Abstract 33) demonstrated partial tumor shrinkage in 12 of 26 (46%) patients receiving the drug. Twelve of these patients had tumors that carried the T790M mutation, and seven (58%) responded, with many other patients achieving stable disease.

“As for durability, I can tell you that the first patient we dosed in March continues to respond. It’s difficult to say, at this early stage, what the median progression-free survival will be, but we do see patients continuing to respond,” Dr. Galbraith said.

The global study is enrolling additional patients, and higher doses of AZD9291 are being tested. “The trial is going very well, and we are excited by the data,” she told the media

http://www.ascopost.com/ViewNews.aspx?nid=8673

期待新药！谢谢马哥！

感谢老马和υīСКī，期待。。。

AZD9291 and 2 active metabolites (AZ5104 and AZ7550)

唉,看不懂啊!

lliyany 发表于 2013-10-7 10:48

                               
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不知还能不能用上，妈妈加油。马哥，组织合成吧。时间就是生命

目前反馈的消息是9291的结构式还没公布，正在申请专利呢。等结构出来了才会有人去研究合成路线。

9291的专利肯定已经申请了，正处于保密期，估计要等到1期结束后，才会公布。

找个一个可能是来源于动物实验结果的肿瘤生长抑制效果对照表，作用对象是带19del突变的PC9细胞系增殖产生的异种移植物，剂量就是WCLC那篇摘要里面描述的5mg/kg：

Abstract Number:         A109
Presentation Title:        AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Presentation Time:         Sunday, Oct 20, 2013, 12:30 PM - 3:00 PM
Location:         Exhibit Hall C-D
Author Block:         Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
Abstract Body:         The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need. AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; <25nM) and EGFRm+/T790M (e.g. H1975; <25nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; >500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients. Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
http://www.abstractsonline.com/P ... 9-82a0-e4d68ac8a74a

2013 AACR Molecular Targets Conference in Boston
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19–23
BOSTON — The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19–23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the “resistance mutation.”
“There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working,” said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. “The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
“AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines,” she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
“Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects,” said Galbraith. “The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting.”
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).