This phase II trial tests the how well a precision medicine approach (serial measurements of molecular and architectural response to therapy [SMMART])-adaptive clinical treatment [ACT]) works in treating patients with sarcoma, prostate, breast, ovarian or pancreatic cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). SMMART testing uses genetic and protein tests to learn how cancer changes and to understand what drugs may work against a person's cancer or why drugs stop working. These test results are reviewed by a group of physicians and scientists during a SMMART tumor board who then recommend precision therapy.

开始日期2025-01-01

申办/合作机构

OHSU Knight Cancer Institute

[+3]

100 项与 EGFR L858R x EGFR T790M 相关的临床结果

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100 项与 EGFR L858R x EGFR T790M 相关的转化医学

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0 项与 EGFR L858R x EGFR T790M 相关的专利（医药）

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项与 EGFR L858R x EGFR T790M 相关的文献（医药）

2024-10-01·Journal of Thoracic Oncology

Mutational Characteristics and Clinical Outcomes for Lung Adenocarcinoma With EGFR Germline Mutations

Article

作者: Cascone, Tina ; Skoulidis, Ferdinandos ; Elamin, Yasir ; Zhang, Jianjun ; Negrao, Marcelo V ; Fossella, Frank ; Le, Xiuning ; Pan, Kelsey ; Heymach, John V ; Pozadzides, Jenny ; Owens, Jennifer ; Altan, Mehmet ; Routbort, Mark ; Ostrin, Edwin ; Tsao, Anne ; Lu, Charles

INTRODUCTIONGermline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer.METHODSWe perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing.RESULTSWe identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval [CI]: 6.3-not reached [NR]). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3-NR) and median overall survival was 82.0 months (95% CI: 28.4-NR).CONCLUSIONSBased on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC.

2024-07-12·Medicine

Dacomitinib overcomes acquired resistance to osimertinib in advanced NSCLC patients with EGFR L718Q mutation: A two-case report

Article

作者: Jin, Meizi ; Diao, Yuzhu ; Li, Xiaoling ; Li, Jielin

Rationale:Acquired resistance still inevitably occurs in patients treated with third-generation TKI osimertinib. Although the EGFR L718Q mutation has been reported as a scarce mechanism of osimertinib resistance, advanced therapeutic strategies are still in development. In this report, we included 2 cases of patients who acquired EGFR L858R/L718Q mutation after osimertinib and were overcome by dacomitinib.Patient concerns:Case 1: A 77-year-old woman was diagnosed with stage IV lung adenocarcinoma. Case 2: A 64-year-old woman was diagnosed with stage IV lung adenocarcinoma.Diagnoses:Case 1: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Since then, treatment with gefitinib was administrated, leading to a progression-free survival of 18 months. The treatment was switched to osimertinib based on the detection of EGFR T790M mutation, resulting in a progression-free survival of 24 months. Subsequently, EGFR L718Q mutation was detected. Case 2: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Icotinib was used as the first-line treatment for 7 months. Osimertinib was applied as the second-line treatment for 13 months based on the EGFR T790M mutation. Subsequently, EGFR L718Q mutation was detected.Interventions:Case 1: Dacomitinib was administered. Case 2: Dacomitinib was administered.Outcomes:Case 1:The progression-free survival was 8 months. Case 2: The progression-free survival was 3 months.Lessons:Dacomitinib is a potential treatment option for NSCLC patients with EGFR L718Q mutation after resistance to Osimertinib. Further research is needed to validate the efficacy of Dacomitinib in this context.

2024-07-01·Bioorganic & Medicinal Chemistry

Exploring the structural activity relationship of the Osimertinib: A covalent inhibitor of double mutant EGFRL858R/T790M tyrosine kinase for the treatment of Non-Small Cell Lung Cancer (NSCLC)

Review

作者: Ahmad, Iqrar ; Agrawal, Yogesh J ; Dhangar, Mayur S ; Patel, Harun M ; Patil, Bhatu R ; Bhadane, Kunal V ; Shimpi, Amit A

The USFDA granted regular approval to Osimertinib (AZD9291) on March 2017, for treating individuals with metastatic Non-Small Cell Lung Cancer having EGFR T790M mutation. Clinically, Osimertinib stands at the forefront for the treatment of patients with Non-Small Cell Lung Cancer. Osimertinib forms a covalent bond with the Cys797 residue and predominantly spares binding to WT-EGFR, thereby reducing toxicity and enabling the administration of doses that effectively inhibit T790M. However, a high percentage of patients treated with Osimertinib (AZD9291) developed a tertiary cysteine797 to serine797 (C797S) mutation in the EGFR kinase domain, rendering resistance to it. This comprehensive review sheds light on the chemistry, computational aspects, structural features, and expansive spectrum of biological activities of Osimertinib and its analogues. The in-depth exploration of these facets serves as a valuable resource for medicinal chemists, empowering them to design better Osimertinib analogues. This exhaustive study not only provides insights into improving potency but also emphasizes considerations for mutant selectivity and optimizing pharmacokinetic properties. This review acts as a guiding beacon for the strategic design and development of next-generation Osimertinib analogues.

项与 EGFR L858R x EGFR T790M 相关的新闻（医药）

2024-10-29

·精准药物

药物筛选中心对外提供EGFR抑制剂筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶等相关靶标的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型 1）激酶：EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M) 2）肿瘤细胞模型：基于Ba/F3的敏感和耐药模型； 3）肿瘤移植瘤模型体内药效；对外服务 1）体外激酶活性； 2) 体外细胞活性； 3）体外降解活性； 4) 机制研究； 5）体内抗肿瘤药效； 6）小鼠、大鼠体内PK； 7）蛋白表达、共晶等。咨询合作

2024-09-24

·艾力斯医药科技

艾力斯新一代EGFR口服小分子抑制剂AST2303片药物临床试验获批

近日，上海艾力斯医药科技股份有限公司（以下简称“公司”）收到国家药品监督管理局（以下简称“国家药监局”）核准签发的《药物临床试验批准通知书》，同意AST2303片在EGFR突变的晚期非小细胞肺癌成人患者中开展临床试验。 AST2303 AST2303片（ABK3376片）是一款高选择、可入脑的新一代EGFR口服小分子抑制剂，可高效抑制EGFR C797S突变。根据临床前的研究成果显示，ABK3376具有四大优势： ABK3376对C797S突变伴随各种其他突变情况的活性都比较优异且较均衡。 ABK3376有对EGFR野生型抑制的良好选择性，在临床上可能带来更好的安全性。 ABK3376的潜在脱靶副作用小。 ABK3376具有高效穿透血脑屏障的特性，可在中枢神经系统获得有效的药物暴露，将可用于治疗或预防非小细胞肺癌的中枢神经系统转移。 AST2303片的临床前研究显示，无论单药还是与公司已上市的第三代EGFR抑制剂伏美替尼联用，都取得了积极的结果，有望成为精准治疗伴有EGFR C797S耐药突变非小细胞肺癌的新一代靶向治疗药物。第三代EGFR TKI已成为临床常规用药，并逐渐成为一线治疗标准疗法，虽然靶向治疗改善了EGFR驱动的非小细胞肺癌患者的治疗，但耐药依然不可避免，C797S是靶向治疗中极为常见的靶向耐药机制。此外，研究表明，在有基线脑转移的EGFR突变非小细胞肺癌患者中，多达40%的疾病进展涉及中枢神经(CNS)转移。杜锦豪艾力斯董事长兼总经理 “艾力斯深耕肺癌领域多年，核心产品伏美替尼是全球范围内唯一有临床数据证明对全部四种EGFR突变（包括敏感、T790M、Exon20ins、PACC）都有效的三代EGFR-TKI，伏美替尼已显示出同类最佳潜力，公司目前还在多个不同的非小细胞肺癌类型中进行药物研发和临床探索。新一代EGFR抑制剂AST2303的药物临床试验获批符合艾力斯发展策略，将进一步丰富艾力斯的产品管线并加强艾力斯在肺癌治疗领域的竞争力。艾力斯将不断推出创新产品、创新方案，以满足肿瘤患者日益增长的临床需求，为肿瘤患者带来福音。” 关于AST2303 AST2303是由上海和誉生物医药科技有限公司发现，并由上海艾力斯医药科技股份有限公司（以下简称“艾力斯”）开发的一种新分子实体，主要针对EGFR L858R+C797S或Del19+C797S的双位点突变的非小细胞肺癌。它具有口服、相较于野生型EGFR和其他激酶高选择性，以及可能进入中枢神经系统的特点。艾力斯计划开发ABK3376（AST2303），主要用于治疗第三代EGFR-TKI耐药后携带EGFR L858R+C797S或Del19+C797S的双位点突变的非小细胞肺癌。关于艾力斯上海艾力斯医药科技股份有限公司成立于2004年3月，是一家以全球医药市场需求为导向，专注于肿瘤治疗领域，集新药研发、生产和商业化为一体的创新型制药企业。艾力斯医药以科技关爱生命为发展理念，以开发首创药物和同类最佳药物为首要目标。历经20年坚持不懈的努力，艾力斯已经成功自主研发，获批两款创新药，具备持续创制具有自主产权的疗效确切、市场最优的抗肿瘤新药之综合实力。2020年12月2日，上海艾力斯医药科技股份有限公司正式在上海证券交易所科创板挂牌上市（股票代码：688578）。2024年上半年，艾力斯实现营收15.76亿元人民币，较去年同比增长110.57%，实现净利润6.56亿元，较去年同比增长214.82%。关于艾弗沙® 艾弗沙®是中国原研、具有自主知识产权的第三代EGFR-TKI。2021年3月获批上市，用于既往经EGFR酪氨酸激酶抑制剂（TKI）治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性NSCLC成人患者的治疗。2022年6月获批一线适应症，用于具有表皮生长因子受体（EGFR）外显子19缺失或外显子21（L858R）置换突变的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者的一线治疗。艾弗沙®肺癌一线及二线适应症均已纳入国家医保目录，惠及中国患者。目前开发用于EGFR敏感突变NSCLC辅助治疗、EGFR 20外显子插入突变等罕见突变的注册临床研究正顺利推进中。长按并识别二维码关注我们科技关爱生命 Advancing Long Life with Innovation of Science and Technology

临床2期申请上市临床结果临床1期

2024-09-19

·贝达药业

贝达药业CFT8919胶囊获批开展临床试验

9月19日，贝达药业和C4 Therapeutics, Inc. （C4T）合作开发的CFT8919胶囊获得国家药品监督管理局签发的《药物临床试验批准通知书》（通知书编号：2024LP02116、2024LP02117）,拟用于携带 EGFR 突变的非小细胞肺癌（NSCLC）患者。 CFT8919是一种具有口服生物利用度的变构 BiDAC™ （双功能蛋白）降解剂，在临床前研究中，CFT8919在EGFR L858R驱动的NSCLC的体内外模型中具有活性，可靶向广泛的在靶耐药突变并有颅内活性，具有预防或治疗患者脑转移的潜力。CFT8919通过与L858R突变的变构位点结合，展示出良好的选择性，同时对像T790M或C797S突变的EGFR继发耐药突变有效。2023年，CFT8919片获得美国FDA临床试验（IND）许可。多个大型随机对照试验亚组分析结果显示，一代、二代和三代EGFR-TKI治疗19del和21L858R突变患者显示出了不同的疗效，总体来看，19del突变患者的获益要明显高于21L858R突变的患者。对于携带21L858R突变NSCLC患者，临床上仍存在较大的未满足需求，期待更好的治疗方案。贝达药业副总裁、项目总负责人王三虎表示：很高兴看到CFT8919胶囊获批开展临床，这是本项目开发过程中的一个重要里程碑，贝达和C4T双方项目团队将继续携手同行，共同努力，积极推进临床研究，期待CFT8919胶囊能早日获批上市，给患者带来新的治疗选择。贝达药业董事长丁列明博士表示：贝达通过自主研发和战略合作相结合的方式丰富公司产品管线，CFT8919是公司在肺癌治疗领域引进的重点项目，是在靶向蛋白降解领域的一次全新探索。未来，贝达将继续立足民生需求，深耕新药研发领域，力争研制出更多的新药、好药，提高药物可及性，造福广大患者。内容来源于网络，如有侵权，请联系删除。