Therapeutic strategies against EGFR exon 20 mutant lung cancer

EGFR外显子20突变肺癌的治疗策略

• 批准号: 10530622
• 负责人: John V. Heymach
• 金额: $ 54.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530622
• 关键词: Address; Bypass; Cancer Patient; Cell Line; Clinical; Clinical Research; Clinical Trials; Collaborations; DNA Sequence Alteration; Data; Development; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluable Disease; Exons; FDA approved; Future; Gefitinib; Generations; Genetically Engineered Mouse; Genomics; Goals; In Vitro; Induced Mutation; Insertion Mutation; Lead; Letters; Location; Malignant neoplasm of lung; Maps; Mediating; Medical Oncology; Medicine; Modeling; Molecular; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Point Mutation; Population; Pre-Clinical Model; Productivity; Proteomics; Publications; Regimen; Reporting; Research Personnel; Resistance; Resources; Retrospective Studies; Role; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; Study models; Testing; Therapeutic; Treatment Protocols; Tyrosine Kinase Inhibitor; aurora kinase A; combat; drug sensitivity; effective therapy; efficacy evaluation; experience; improved; in silico; in vivo; inhibitor; molecular modeling; molecular pathology; mouse model; multidisciplinary; mutant; objective response rate; partial response; patient population; phase II trial; pre-clinical; preclinical study; prevent; resistance mechanism; resistance mutation; response; screening; targeted agent; targeted treatment; treatment strategy; tumor; virtual

PROJECT SUMMARY Approximately 10-12% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor in-frame mutations or insertions within exon 20 of EGFR. Unlike NSCLC patients bearing “typical” EGFR mutations (L858R or exon 19 deletions), these patients with exon 20 mutations are highly resistant to FDA-approved first- generation tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, with an objective response rate of approximately 4-8% and a median PFS of 2 months; by comparison, first-generation TKIs lead to an objective response rate of ~60% and a PFS of ~10 months in patients with typical EGFR mutations. The population impacted by EGFR exon 20 mutations is sizable: approximately 2,000-3,000 patients per year in the US and approximately 27,000 patients per year worldwide. Until recently, no treatment strategies had been identified that were tailored for this patient population. We recently reported the results of a detailed structure-function analysis and screening effort that led to the identification of the TKI poziotinib as a potent and clinically active inhibitor of EGFR exon 20 mutant tumors. Based on our preclinical data we have conducted a phase II trial of poziotinib. Initial results indicate high anti-tumor activity with best objective response of PR (partial response) in 55% of 44 evaluable patients. However, some patients do not initially respond to treatment (primary resistance) and, for the patients who do respond initially, acquired resistance is a clinical challenge. Our goals are to elucidate the mechanisms of primary and acquired resistance to poziotinib and other potential EGFR exon 20- targeted therapies. We find that in preclinical models, primary resistance may be associated with size and location of the specific insertion, with a greater distance of the insertion from the α-c-helix associated with a lower sensitivity to poziotinib. Moreover, we have generated evidence from preclinical models and NSCLC patients indicating that acquired resistance may be mediated through multiple mechanisms, some EGFR-dependent (e.g. additional EGFR alterations) and others EGFR-independent (e.g. activation of alternate signal bypass pathways). We hypothesize that a) the sensitivity of different exon 20 insertions/mutations to specific TKIs will be dictated by the insertion size and location and treatment may be tailored based on this information; and b) that acquired resistance occurs through both EGFR-dependent and independent mechanisms that can be targeted. We will test these hypotheses through an integrative, multidisciplinary effort involving preclinical studies, molecular modeling, and ongoing clinical studies. In Aim 1, we will investigate primary resistance and the structure-function relationship between specific insertions and drug response; in Aim 2, we will investigate the mechanisms of EGFR-dependent acquired resistance, and in Aim 3 we will investigate EGFR-independent mechanisms. These studies will help guide the selection of TKIs based on a patients’ mutation, and will provide a road map for the future development of improved TKIs and more effective combinations to delay or prevent the emergence of drug resistance in this group of patients for which no targeted treatments currently exist.

项目摘要 EGFR突变的非小细胞肺癌（NSCLC）患者约有10-12％ EGFR的外显子20中的突变或插入。与具有“典型” EGFR突变的NSCLC患者不同 （L858R或外显子19缺失），这些外显子20突变患者对FDA批准的第一次突变具有高度抗性 产生的酪氨酸激酶抑制剂（TKI），例如厄洛替尼或吉非替尼，客观响应率为 大约4-8％的PFS为2个月；相比之下，第一代TKI导致了目标 典型EGFR突变患者的应答率〜60％，PFS约10个月。人口 受EGFR外显子20突变的影响很大：美国每年约2,000-3,000名患者 全球每年约有27,000名患者。直到最近，还没有确定治疗策略 是针对该患者人群量身定制的。我们最近报告了详细的结构功能的结果 分析和筛选工作导致TKI poziotinib鉴定为潜力和临床活动 EGFR外显子20突变肿瘤的抑制剂。根据我们的临床前数据，我们进行了II期试验 poziotinib。初始结果表明较高的抗肿瘤活性，PR（部分响应）在 在44名合格患者中，有55％。但是，一些患者最初对治疗没有反应（初级抗药性） 而且，对于最初反应的患者而言，获得的抵抗是临床挑战。我们的目标是 阐明对poziotinib和其他潜在EGFR外显子20-的抗性和获得性的机制20- 靶向疗法。我们发现，在临床前模型中，主要阻力可能与大小和 特定插入的位置，与较低的α-c螺旋插入更大距离 对poziotinib的敏感性。此外，我们已经从临床前模型和NSCLC患者中获得了证据 表明获得的抗性可以通过多种机制介导，而某些EGFR依赖性（例如 其他EGFR改变）和其他无关EGFR（例如激活替代信号的激活 途径）。我们假设a）不同外显子20插入/突变对特定TKI的敏感性将 可以根据这些信息来定制插入大小，位置和处理的决定；和b） 获得的抵抗是通过EGFR依赖性和独立机制发生的 目标。我们将通过涉及临床前的综合，多学科的工作来检验这些假设 研究，分子建模和正在进行的临床研究。在AIM 1中，我们将调查主要抵抗力和 特定插入与药物反应之间的结构功能关系；在AIM 2中，我们将调查 EGFR依赖性获得的抗性的机制，在AIM 3中，我们将研究EGFR独立的 机制。这些研究将有助于根据患者的突变指导TKI的选择，并将提供 未来开发TKI和更有效组合的路线图，以延迟或防止 目前尚无靶向治疗的这组患者中耐药性的出现。