新药介绍: 第三代EGFR TKI，EGF816-诺华和ASP8273-Astellas

EGF816, a novel covalent inhibitor of mutant-selective epidermal growth factor receptor, overcomes T790M-mediated resistance in NSCLC
EGF816，一种新型共价结合的突变选择型EGFR抑制剂，能够克服NSCLC患者中T790M介导的耐药性

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond to EGFR tyrosine kinase inhibitors (TKI) but ultimately develop resistance to these therapies. The most common mechanism of resistance is a second site gate-keeper mutation within exon 20 of EGFR (T790M), followed by MET and other receptor tyrosine kinase amplification/activation. We developed a covalent mutant-selective EGFR inhibitor, EGF816 that potently inhibits both activating EGFR mutations as well as the T790M resistance mutation while sparing wild-type EGFR. EGF816 demonstrated strong tumor regressions in several EGFR activating and resistant tumor models in vivo. These include H1975 (L858R; T790M), HCC827 (exon 19 del) and H3255 (L858R) that are representative of the relevant clinical settings. In all of the models EGF816 inhibited tumor growth in a dose dependent manner and achieved regressions of established tumors at well tolerated doses. In single dose studies, EGF816 showed sustained inhibition of pEGFR, consistent with the irreversible binding mechanism of EGF816. EGF816 also performs exceptionally well in long term dosing studies providing durable responses in the preclinical models. Together, this data indicates that EGF816 exhibits excellent anti-tumor activity in the relevant patient derived tumor cell lines at well tolerated doses and is expected to provide long term duration of responses compared to current EGFR TKI therapy in the clinic.

具有EGFR突变的NSCLC患者对EGFR TKI具有良好的初始响应，但最终会发展至耐药。最常见的耐药机制为第二位gate-keeper突变，该突变为发生在20号外显子的T790M，其他的耐药机制有MET和其他受体酪氨酸激酶的扩增和激活。我们开发了一种共价结合突变选择的EGFR抑制剂-EGF816,，其能有效抑制激活的EGFR突变以及T790M耐药突变，同时能避开野生型EGFR。EGF816在一些EGFR激活和耐药的体外肿瘤模型中，展现了强效的肿瘤缩小效果。这些模型包括H1975(L858R+T790M)、HCC827(外显子19缺失)、H3255(L858R)等在临床中具有代表性的细胞系。在所有的模型中，EGF816抑制肿瘤生长的效果与剂量相关，并且能够在良好耐受的剂量下缩小肿瘤。在单剂量研究中，EGF816显示了对pEGFR的持续抑制，这与EGF816的不可逆结合机制一致。同时，EGF816在亚临床模型持续响应的长效剂量研究中表现良好。综上所述，这些数据表明了EGF816在由相关的来源于肿瘤患者的肿瘤细胞系中，在良好耐受的剂量下展现了优异的抗肿瘤活性，并且对比当前临床中的EGFR TKI治疗，EGF816有望提供长效的持续响应。

In vitro characterization of EGF816, a third-generation mutant-selective EGFR inhibitor
第三代突变选择抑制剂-EGF816的体外特性

EGFR is a major oncogene in NSCLC. Patients with the oncogenic mutations L858R and Ex19Del are responsive to the first generation pan-EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. The associated dose-limiting toxicities (DLTs) are severe rash and GI tolerability due to WT EGFR inhibition. However, therapy is universally limited by the development of acquired drug resistance where EGFR gatekeeper mutation T790M accounts for 50% of incidence. Second generation irreversible pan-EGFR TKI afatinib was developed to overcome T790M resistance. Though effective in animal models, the efficacy of afatinib on T790M patients is largely limited by its DLTs due to potent inhibition of WT EGFR. A strong medical need still exists for better tolerated therapy to treat NSCLC patients harboring EGFR mutations. Here we report the discovery and development of a potent third generation, irreversible mutant-selective EGFR TKI that is expected to improve/maintain efficacy on oncogenic EGFR mutant patients while demonstrating reduced side effects. EGF816 potently inhibits both activating (L858R and Ex19Del) and T790M resistant mutations in various cellular assays; it is selective against a large panel of kinases in both Ambit and BaF3 profiling, and more importantly is selective against WT EGFR. EGF816 is efficacious in mutant EGFR-driven xenograft models, is well tolerated in IND-enabling toxicology studies, and is entering phase 1 trials.

EGF816目前开了I/II期临床：
http://clinicaltrials.gov/ct2/show/NCT02108964

ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations

BACKGROUND: Reversible EGFR TKIs, gefitinib and erlotinib, have shown antitumor efficacy in NSCLC patients with activating mutations in EGFR kinase domain. But the clinical efficacy of these agents is limited by the development of acquired drug resistance, which is most commonly caused by T790M resistance mutation in EGFR. This mutation has been detected in approximately 50% to 60% of patients. The 2nd generation irreversible EGFR inhibitors inhibit EGFR with T790M, but their clinical efficacy to NSCLC patients with T790M appears to be limited due to severe adverse effects caused by concomitant WT EGFR inhibition. Therefore, an EGFR TKI which inhibits T790M mutant EGFR selectively with less activity against WT EGFR may be beneficial. Here we report ASP8273, a novel, small molecule EGFR TKI that inhibits the kinase activity of EGFR containing the activating and T790M resistance mutations with less activity against WT EGFR.

METHODS: The inhibitory effect and the selectivity of ASP8273 were evaluated against mutant EGFR (L858R, del ex19, L858R/T790M and del ex19/T790M) and WT EGFR using in vitro enzymatic and cell-based assay. Binding mode of ASP8273 to EGFR was assessed by mass spectrometry. Antitumor activity of ASP8273 was evaluated in xenograft models using PC-9 (del ex19), HCC827 (del ex19), NCI-H1975 (L858R/T790M) and PC-9ER (Erlotinib Resistant)(del ex19/T790M) NSCLC cells.

RESULTS: ASP8273 inhibited mutant EGFR containing del ex19 or L858R activating mutations as well as the T790M resistance mutation with lower IC50 values than WT EGFR. Mass spectrometry analysis revealed that ASP8273 is covalently bound to a mutant EGFR(L858R/T790M) via C797 in the kinase domain of EGFR. In NCI-H1975 cells, ASP8273 induced long-lasting inhibition of EGFR phosphorylation for 24 h after washout of compound.
In assays using endogenously EGFR-dependent cells, ASP8273 inhibited the growth of PC-9(del ex19), HCC827(del ex19), NCI-H1975(del ex19/T790M) and PC-9ER(del ex19/T790M) with IC50 values of 8-33 nM, more potently than that of NCI-H1666(WT) with IC50 value of 230 nM.
In mouse xenograft studies, ASP8273 induced tumor regression in NCI-H1975 (L858R/T790M), HCC827 (del ex19) and PC-9 (del ex19) xenograft models by repeated oral dosing in a dose-dependent manner. Dosing schedules did not affect the efficacy of ASP8273. In an NCI-H1975 xenograft model, complete regression of tumor was achieved after 14-days of ASP8273 treatment. Complete regression was maintained in 50% of mice more than 85 days after cessation of ASP8273 treatment.

CONCLUSIONS: ASP8273 inhibits the growth of NSCLC cells with EGFR activating and T790M resistance mutations with evidence of tumor regression. Therefore, ASP8273 may show therapeutic efficacy in NSCLC patients with EGFR mutations. Clinical trials of ASP8273 in NSCLC patients are planned in the US/EU and Asia.

ASP8273目前开了I期临床：
http://clinicaltrials.gov/show/NCT02113813

粗粗看了一下，好像跟9291是一类药吧？抵制T790的同时有E的靶点。

新药层出不穷

谁翻译下是什么药?

期待临床数据

文盲啊，有英语好的翻译一下吧，

有没有高人，给翻译一下，让我们也见识了解这些新的信息。