Molecular features impacting drug resistance in atypical EGFR exon 18 and exon 20 mutant non-small cell lung cancers and the development of novel mutant-selective inhibitors

项目总结 大约20%带有EGFR突变的非小细胞肺癌患者存在不典型 突变。与携带典型的EGFR突变(L858R或外显子19缺失)的非小细胞肺癌患者不同，患者 具有外显子18或20非典型突变的患者对FDA批准的第一代酪氨酸激酶抑制剂具有耐药性 (TKIS)，外显子20患者的应答率仅为4-8%，中位无进展生存期 (MPFS)基于回顾研究的2个月。同样，带有非典型EGFR外显子18突变的患者 在使用常见的EGFR-TKI治疗时，与经典的EGFR突变患者相比，临床获益较少。 受非典型EGFR NSCLC突变影响的人群规模相当大：每年约有5,000名患者 在美国，全球每年有41,600名患者，非小细胞肺癌以外的患者甚至更多。我们 最近报道了一项详细的结构和功能分析的结果，这导致了对 TKI，poziotinib，作为EGFR和HER2外显子20突变肿瘤的有效和临床活性抑制物。基于 这些数据我们已经进行了一项研究人员启动的第二阶段试验，测试poziotinib在EGFR和HER2外显子20中的作用 突变的非小细胞肺癌患者，表明它是一种对客观反应确认的高度有效的药物 在43%的患者中观察到。这显然代表着这些患者的进步，然而，这种药物已经 明显的局限性。Poziotinib治疗的有效时间有限，MPFS为5.5个月， 在外显子20的“远环”突变的患者中观察到的活性甚至更低。 与经典的EGFR突变相比，奥西美替尼的MPFS为18.9个月。此外，许多患者接受了 Poziotinib出现3级不良反应，腹泻和皮疹，与该药的抗肿瘤活性有关 野生型EGFR，导致60%的患者剂量减少。为了解决这些限制，我们提出了一种 综合分析了解EGFR外显子18和20突变的结构特征，使其更具效力 可以开发抑制剂，并且可以增强突变体对WT受体的特异性。为了实现这一目标，我们 提出以下目标：目标1)我们将研究EGFR外显子20突变的结构特征 对TKI的差异敏感性，以指导具有更高效力的新化合物的开发。目标2)我们 将分析非典型EGFR外显子18突变的结构特征，以利用这些信息进行合理设计 具有增强功效的新化合物。目的3)我们将开发具有改进的EGFR突变体与野生型的TKIs 类型特异性，以增加EGFR外显子18和外显子20突变患者的药物耐受性和临床益处。 我们组建了一支由内科医生、实验室科学家、结构生物学家和 拥有无与伦比的临床前和临床资源的药物化学家将合作获得 深入了解EGFR外显子18和20突变癌症的结构特征并将其转化为临床前研究 以及潜在的临床测试。此外，从这项研究中获得的见解有助于加快努力 在全球范围内，旨在针对EGFR外显子18和20肿瘤以及其他EGFR突变癌。

PROJECT SUMMARY Approximately 20% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor atypical mutations. Unlike NSCLC patients bearing “classical” EGFR mutations (L858R or exon 19 deletions), the patients with atypical mutations in exon 18 or 20 are resistant to FDA-approved first-generation tyrosine kinase inhibitors (TKIs), with exon 20 patients presenting response rates of only 4-8% and a median progression free survival (mPFS) of 2 months based on retrospective studies. Similarly, patients with atypical EGFR exon 18 mutations have less clinical benefit than patients with classical EGFR mutations when treated with common EGFR- TKIs. The population impacted by atypical EGFR NSCLC mutations is sizable: approximately 5,000 patients per year in the US, 41,600 patients per year worldwide, and an even greater number of patients outside of NSCLC. We recently reported the results of a detailed structural and functional analysis that led to the identification of the TKI, poziotinib, as a potent and clinically active inhibitor of EGFR and HER2 exon 20 mutant tumors. Based on this data we have conducted an investigator-initiated phase II trial testing poziotinib in EGFR and HER2 exon 20 mutant NSCLC patients, demonstrating that it is highly active drug for with confirmed objective responses observed in 43% of patients. This clearly represents an advance for these patients, however, the drug has significant limitations. Responses to poziotinib treatment were of limited duration, with a mPFS of 5.5 months, and even less activity was observed in patients with mutations in the “far loop” of exon 20. Whereas patients with classical EGFR mutations have a mPFS of 18.9 months to osimertinib. Furthermore, many patients receiving poziotinib experienced >grade 3 adverse events, diarrhea and rash, related to the activity of this drug against wild-type EGFR, resulting in dose reduction in >60% of patients. To address these limitations, we propose an integrative analysis to understand the structural features of EGFR exon 18 and 20 mutations, so that more potent inhibitors can be developed and that specificity for mutant to WT receptor can be enhanced. To achieve this, we propose the following aims: Aim 1) we will study the structural features of EGFR exon 20 mutations that drive differential sensitivity to TKIs to guide the development of novel compounds with increased potency. Aim 2) we will analyze the structural features of atypical EGFR exon 18 mutations to use this information to rationally design new compounds with enhance efficacy. Aim 3) we will develop novel TKIs with improved EGFR mutant vs wild- type specificity to augment drug tolerability and clinical benefit of EGFR exon 18 and exon 20 mutant patients. We have assembled a unique, multi-disciplinary team of physicians, laboratory scientist, structural biologist, and medicinal chemists with unparalleled pre-clinical and clinical resources for who will work cooperatively to gain insights into the structural features of EGFR exon 18 and 20 mutant cancers and to translate this into preclinical and potentially clinical testing. Furthermore, insights gained from this study can help to accelerate efforts worldwide aiming to target EGFR exon 18 and 20 tumors as well as other EGFR mutant caners.