A open-label multicenter Phase?/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile and Preliminary Efficacy of SYS6010 in combination with Enlonstobart ± chemotherapy in patients with EGFR and ALK wild type locally advanced or metastatic NSCLC and other advanced solid tumor

开始日期2024-09-30

申办/合作机构

上海市东方医院

ChiCTR2400089300 / Suspended临床1期IIT

An open-label and multicenter Phase ? Clinical Study to Evaluate the Safety and Efficacy of SYS6010 in combination with Enlonstobart and Simmitinib in patients with advanced esophageal cancer

开始日期2024-09-13

申办/合作机构-

100 项与 EGFR C797S x EGFR T790M 相关的临床结果

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100 项与 EGFR C797S x EGFR T790M 相关的转化医学

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0 项与 EGFR C797S x EGFR T790M 相关的专利（医药）

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项与 EGFR C797S x EGFR T790M 相关的文献（医药）

2024-01-01·JTO Clinical and Research Reports

The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors

Article

作者: Kobayashi, Susumu S ; Rangachari, Deepa ; Costa, Daniel B ; VanderLaan, Paul A ; Viray, Hollis ; Kobayashi, Ikei S ; Shaffer, William

IntroductionMechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib.MethodsWe identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S.ResultsMobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib.ConclusionsThis report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

2023-12-01·European Journal of Medicinal Chemistry

Design and synthesis of 4th generation EGFR inhibitors against human triple (Del19/T790M/C797S) mutation

Article

作者: Ahn, Young Gil ; Kim, In Su ; Singh, Pargat ; Jang, Sun Young ; Kim, Yu-Yon ; Lee, Sun Hoe ; Moon, Kyeongwon ; Kwak, Eun Joo ; Jeon, Jiyoung ; Byun, Joo-Yun

Epidermal growth factor receptor (EGFR)-targeted therapy is used to treat EGFR mutation-induced non-small cell lung cancer (NSCLC). However, its efficacy does not last beyond a certain period due to the development of primary and secondary resistance. First and second-generation inhibitors (e.g., gefitinib, erlotinib, and afatinib) induce EGFR T790M mutations, while third-generation inhibitors (e.g., osimertinib) induce C797S as a major target resistance mutation. Therefore, the C797S mutation is being actively researched. In this study, we investigated the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against the C797S mutation. We identified a compound 13k that displayed nanomolar potency and high selectivity. Moreover, we used a triple mutant xenograft mouse model to evaluate the in vivo efficacy of 13k in inhibiting EGFR C797S, which demonstrated exceptional profiles and satisfactory EGFR C797S inhibition efficacy. Based on its excellent in vitro and in vivo profiles, compound 13k can be considered a promising candidate for treating EGFR C797S mutations.

2023-05-01·Cancer Treatment Reviews

Acquired resistance mechanisms to osimertinib: The constant battle

Review

作者: Planchard, David ; Eid, Roland ; Hachem, Samir ; Raphael Kourie, Hampig ; Kassis, Yara ; Zalaquett, Ziad ; Catherine Rita Hachem, Maria

Lung cancer is the leading cause of cancer-related mortality worldwide. Detectable driver mutations have now changed the course of lung cancer treatment with the emergence of targeted therapy as a novel strategy that widely improved lung cancer prognosis, especially in metastatic patients. Osimertinib (AZD9291) is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat stage IV EGFR-mutated non-small-cell lung cancer. It was initially designed to target both EGFR-activating mutations and the EGFR T790M mutation as well, which is the most common resistance mechanism to first- and second-generation EGFR-TKIs. Following the FLAURA trial, osimertinib is now widely used in the first-line setting. However, resistance to osimertinib inevitably develops, with numerous mechanisms leading to its resistance, classified into two main categories: EGFR-dependent and EGFR-independent mechanisms. While EGFR-dependent mechanisms consist mainly of the C797S EGFR mutation, EGFR-independent mechanisms include bypass pathways, oncogenic fusions, and phenotypic transformation, among others. This review summarizes the molecular resistance mechanisms to osimertinib, with the aim of identifying novel therapeutic approaches to overcome osimertinib resistance and improve patient outcome.

项与 EGFR C797S x EGFR T790M 相关的新闻（医药）

2024-10-10

·Pharma CMC

石药集团ADC新药获FDA授予第二项快速通道资格认定

10月8日，石药集团发布公告，公司控股子公司巨石生物申报的注射用CPO301获得美国FDA授予的用于治疗表皮生长因子受体（EGFR）高表达，接受含铂化疗和抗PD-（L1）治疗期间或之后出现进展的复发或转移性鳞状非小细胞肺癌（Sq-NSCLC）患者的快速通道资格（FTD）。据悉，CPO301是一款靶向EGFR肿瘤相关抗原的抗体药物偶联物（ADC），通过与肿瘤细胞表面的靶抗原结合，使得药物被内吞进入细胞后释放小分子毒素杀伤肿瘤细胞。目前，该药物在中国和美国均已获得临床试验许可，均在开展I期临床试验。此为该药物获得美国FDA授予的第二项快速通道资格认定，第一次被授予用于治疗复发/难治性或EGFR靶向治疗（如第三代EGFR抑制剂，包括奥希替尼）无效的转移性EGFR突变非小细胞肺癌患者。内容来源于网络，如有侵权，请联系删除。

快速通道抗体药物偶联物

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。