Gefitinib (1) and erlotinib (2) are reversible small-molecule ATP analogues originally designed to inhibit the tyrosine kinase (TK) activity of wild-type EGFR. During their clinical development, these first-generation TK inhibitors (TKI) were serendipitously found to be most effective in patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor recurrent somatic activating mutations occurring in the exons encoding the kinase domain of EGFR, i.e., small multinucleotide in-frame deletions in exon 19 (ex19del) and a point mutation in exon 21 leading to substitution of leucine for arginine at position 858 (L858R; refs. 3–5). Tumors with these activating mutations (EGFRm+) account for approximately 10% to 15% and 40% of NSCLC in Western and Asian populations, respectively. Unfortunately, although patients with EGFRm+ tumors typically show good initial responses to first-generation TKIs, most patients who respond to therapy ultimately develop disease progression after about 9 to 14 months of treatment. Furthermore, these first-generation TKIs are associated with side effects that include skin rash and diarrhea that are due to the inhibition of wild-type EGFR in skin and gastrointestinal organs. Preclinical modeling and analysis of tumor tissue obtained from patients after the development of disease progression have led to the identification of a number of mechanisms that mediate EGFR TKI resistance. Such genetic and other signaling aberrations that drive resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, NF1 loss, and potentially FGFR signaling. In addition, resistant tumors have also been reported to show histologic changes such as small-cell lung cancer (SCLC) transformation or epithelial-to-mesenchymal transition (EMT). However, it is now well established that acquisition of a second mutation in EGFR, resulting in substitution of threonine at the "gatekeeper" amino acid 790 to methionine (T790M), is the most common resistance mechanism and is detected in tumor cells from more than 50% of patients after disease progression. The T790M mutation is believed to render the receptor refractory to inhibition by these reversible EGFR TKIs through exerting effects on both steric hindrance and increased ATP affinity. Current targeted therapeutic strategies for patients with acquired resistance are limited. Second-generation irreversible EGFR TKIs such as afatinib and dacomitinib are effective in untreated EGFR-mutant lung cancer. However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients , because concentrations at which these irreversible TKIs overcome T790M activity preclinically are not achievable in humans due to dose-limiting toxicity related to nonselective inhibition of wild-type EGFR. Furthermore, these inhibitors can drive resistance through acquisition of T790M in vitro and in patients, providing supportive evidence that they have low potency against T790M. One regimen that showed potential activity is afatinib plus the anti-EGFR antibody cetuximab, which induced a 29% confirmed response rate in a phase IB trial for patients with EGFRm+ lung cancer and acquired resistance to erlotinib. However, this combination has substantial skin toxicity, with 20% of patients reporting Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher rash. Therefore, there remains a significant unmet need for an EGFR TKI agent that can more effectively target T790M tumors while sparing the activity of wild-type EGFR. This has led to the development of "third-generation" EGFR TKIs that are designed to target T790M and EGFR TKI–sensitizing mutations more selectively than wild-type EGFR. WZ4002 was the first such agent to be published (34), although it has not progressed to clinical trials. A second agent closely related to the WZ4002 series, CO-1686, has been recently reportedand is currently in early phase II clinical trials. HM61713 is another "third-generation" agent that is currently in early phase I trials. Here, we describe identification, characterization, and early clinical development of AZD9291, a novel, irreversible, EGFR TKI with selectivity against mutant versus wild-type forms of EGFR. AZD9291 is a mono-anilino–pyrimidine compound that is structurally and pharmacologically distinct from all other TKIs, including CO-1686 and WZ4002.
特罗凯、易瑞沙、凯美纳三药比较 来源：生物谷 2014-08-18 08:57 近年来，涉及表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗晚期非小细胞肺癌（NSCLC）的各类研究层见叠出，证据亦越来越多。各类指南推荐的TKI治疗范围涵盖了晚期NSCLC的二、三线治疗，一线治疗甚至维持治疗，由此推断极大比例的晚期NSCLC患者在其治疗过程中的某个阶段必然会接受EGFR-TKI治疗。当然，个指南也明确指出，接受EGFR-TKI治疗的患者在治疗前需做EGFR基因检测，EGFR阳性患者才能从中受益，并且不同的突变类型对EGFR-TKI的敏感度也有所差异。作为患者，在确定EGFR阳性的情况下应当如何选择EGFR抑制剂药物呢？他们之间有何区别？医生为何推荐我用其中的一种？笔者是药物研发人员，在这里对常见的特罗凯（厄洛替尼）、易瑞沙（吉非替尼）、凯美纳（埃克替尼）做个简单的比较和分析。
一、药物化学结构 三药均有相同的喹唑啉母环，埃克替尼与厄洛替尼的差别仅在侧链的开环与闭环，上市最早的是易瑞沙，其次是特罗凯和凯美纳。
二、药代动力学 血药浓度与药效的关系呈线性相关，随着血药浓度增加，药效也逐渐增强。达到同样血药浓度厄洛替尼剂量为150mg，埃克替尼为375mg，吉非替尼为1000mg 。厄洛替尼半衰期是埃克替尼的6倍，每天仅需服药一次，埃克替尼每天需服用三次。推荐剂量下，厄洛替尼治疗浓度是吉非替尼的4倍，并优于埃克替尼，谷底浓度也最高。埃克替尼峰谷浓度波动大，血药浓度不稳定。厄洛替尼较吉非替尼生物利用度高(F值)。时量曲线下面积(AUC)是表示药物吸收入血液循环量的最好指标。厄洛替尼的AUC是吉非替尼的5倍。厄洛替尼在每日口服150mg时有最高血浆浓度，而150mg厄洛替尼与700mg吉非替尼有相同药物动力学。IC50值可以用来衡量药物诱导凋亡的能力，即诱导能力越强，该数值越低。厄洛替尼IC50值最低，诱导能力最强，疗效作用更好。
三、临床疗效 从临床研究的的数量上来看，上市较早的厄洛替尼和吉非替尼一线，二线，维持等研究多，而上市较晚的埃克替尼仅有二线ICOGEN研究。厄洛替尼临床实验数量是吉非替尼2倍，结论相对更全面可靠。在一线治疗晚期NSCLC患者上，厄洛替尼较吉非替尼有一定优势。埃克替尼目前在此方面并无相关一线研究。在台湾晚期非小细胞肺癌易瑞沙和特罗凯的比较的多中心逆溯型研究中， 1122个患者入组，其中厄洛替尼组407人，吉非替尼组715人。该研究表明，厄洛替尼组生存优于吉非替尼组。厄洛替尼组和吉非替尼组的疾病控制率分别是65.8% 和58.9%（P=0.025）；厄洛替尼组和吉非替尼组的中位无进展生存期分别是4.6月和3.6月（P=0.027）；厄洛替尼组和吉非替尼组的中位总生存期分别是10.7月和9.6月（P=0.013）。在埃克替尼vs吉非替尼III期临床双盲对照试验（ICOGEN试验）中，埃克替尼与吉非替尼疗效相似，埃克替尼在PFS、ORR、OS及不良反应上均优于吉非替尼。
四、不良反应及价格 三药的不良反应类似，包括皮疹、腹泻、恶心呕吐、食欲不振、皮肤溃烂、肝功能异常、出血、呼吸困难、间质性肺炎等，不良反应严重程度从高到低依次为特罗凯、易瑞沙、凯美纳。从每月服用费用比较，从高到低依次为特罗凯（每月费用约2万）、易瑞沙（每月费用约1.6万）、凯美纳（每月费用约1.2万）。
五、总结及思考 平均9个月左右，EGFR-TKI治疗即会出现耐药迹象，患者耐药后疾病往往迅速进展。因此，EGFR-TKI耐药是一个非常棘手的，也迫切需要解决的临床问题。随着研究的深入，EGFR-TKI耐药的分子机制逐渐清晰，越来越多的针对肿瘤耐药机制或作用于其他相关信号通路的靶向药物逐渐进入临床。被称为EGFR-TKI第一耐药机制的T790M突变耐药研究甚多，2014年的ASCO会议也发表了针对T790M突变耐药药物AZD9291、CO-1686的研究成果，这些药物预计在2016年可以上市。另一种耐药机制就是C-Met，目前关于C-Met抑制剂的I期临床研究已经启动，疗效明确，在未来的II期临床中，将特异选择C-Met扩增或者高度表达的患者，预期C-Met抑制剂的有效率会达到40%以上。此外，KRAS突变耐药也引起关注。KRAS是EGFR通路下游的效应因子，突变型KRAS基因编码异常的蛋白会促进肿瘤细胞的生长和扩散，且不受上游EGFR信号影响。目前关于KRAS抑制剂药物安卓健（Antroquinonol）的II期临床研究也正在进行中，安卓健作为全球针对RAS基因唯一在研靶向药物，该试验吸引了全球医学界的关注，预计2015年年底可发表研究成果。（生物谷Bioon.com）