Gefitinib

First and only EGFR inhibitor and targeted treatment approved in the EU in unresectable NSCLC Approval based on LAURA Phase III trial results which showed Tagrisso extended median progression-free survival to more than three years LONDON, UK I December 23, 2024 I AstraZeneca’s Tagrisso (osimertinib) has been approved in the European Union (EU) for the treatment of adult patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor ( EGFR ) exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has not progressed during or following platinum-based chemoradiation therapy (CRT). The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the LAURA Phase III trial, which were published in The New England Journal of Medicine . In the trial, Tagrisso reduced the risk of disease progression or death by 84% compared to placebo (hazard ratio 0.16; 95% confidence interval 0.10-0.24; p<0.001) as assessed by blinded independent central review. Median progression-free survival (PFS) was 39.1 months in patients treated with Tagrisso versus 5.6 months for placebo. Overall survival (OS) results remain immature, and the trial is continuing to assess OS as a secondary endpoint. Each year in Europe, there are more than 450,000 people diagnosed with lung cancer, and approximately 80-85% have NSCLC. 1-3 Among those with NSCLC in Europe, about 10-15% have tumours with an EGFR mutation. 4-6 Manuel Cobo, MD, Specialist Physician of the Medical Oncology Service at the Carlos Haya University Hospital, Malaga, Spain, and investigator for the trial, said: “Today’s approval marks a major breakthrough for patients in the EU with unresectable, EGFR -mutated non-small cell lung cancer, delivering the first targeted treatment in this setting. Osimertinib reduced the risk of disease progression or death by an unprecedented 84 per cent in the LAURA trial, setting a new benchmark for outcomes and underscoring the importance of testing for EGFR mutations upon diagnosis.” Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “ Tagrisso is now the first and only EGFR inhibitor and targeted treatment approved in the EU for locally advanced, unresectable lung cancer, providing a new standard of care to patients who have historically experienced early progression after chemoradiation therapy. The powerful results from the LAURA trial show Tagrisso improves outcomes for patients in the unresectable setting, reinforces the importance of timely EGFR testing and solidifies Tagrisso as the backbone therapy in EGFR -mutated non-small cell lung cancer.” The safety and tolerability of Tagrisso in the LAURA trial was consistent with its established profile and no new safety concerns were identified. This is the fifth major approval for Tagrisso based on the LAURA trial following recent approvals in the US, Switzerland, South Korea and Australia. Regulatory applications are also currently under review in China, Japan and several other countries. Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. Approved indications include 1st-line treatment of patients with locally advanced or metastatic EGFR m NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFR m NSCLC. Tagrisso is also approved in combination with chemotherapy in the US, China and several other countries for 1st-line treatment of patients with locally advanced or metastatic EGFR m NSCLC. Notes Lung cancer Each year, an estimated 2.4 million people are diagnosed with lung cancer globally. 7 Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 7 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer. 2,3 The majority of all NSCLC patients are diagnosed with advanced disease. 8 ​Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFR m NSCLC. 4-6 Patients with EGFR m NSCLC are particularly sensitive to treatment with an EGFR -tyrosine kinase inhibitor ( EGFR -TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells. 9 LAURA LAURA is a randomised, double-blind, placebo-controlled, multi-centre, global Phase III trial in patients with unresectable, Stage III EGFR m NSCLC whose disease has not progressed following definitive platinum‑based CRT. Patients were treated with Tagrisso 80mg once-daily oral tablets until disease progression, unacceptable toxicity or other discontinuation criteria were met. Upon progression, patients in the placebo arm were offered treatment with Tagrisso . The trial enrolled 216 patients in more than 145 centres across more than 15 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS. Tagrisso Tagrisso (osimertinib) is a third-generation, irreversible EGFR -TKI with proven clinical activity in NSCLC, including against central nervous system metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFR m NSCLC. There is an extensive body of evidence supporting the use of Tagrisso as standard of care in EGFR m NSCLC. Tagrisso improved patient outcomes in early-stage disease in the ADAURA Phase III trial , Stage III, unresectable disease in the LAURA Phase III trial , late-stage disease in the FLAURA Phase III trial , and with chemotherapy in the FLAURA2 Phase III trial . As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial. The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca . References SOURCE: AstraZeneca

关注并星标CPHI制药在线 表皮生长因子受体（EGFR）是抗肿瘤领域的经典靶点，针对该靶点，目前已有多款药物上市，典型的如EGFR-TKI（EGFR酪氨酸激酶抑制剂），已上市三代药物，第四代呼之欲出。随着耐药现象出现，针对EGFR靶点药物的研发也在不断迭代。如今，该靶点研发进展如何？ EGFR-TKI迭代之战 EGFR是一种跨膜蛋白，具有胞外配体结合区，跨膜区和胞内激酶区三个结构元件。正常生理状态下，EGFR的激活表现为配体依赖型，EGFR与配体结合后，完成二聚化，调动酪氨酸激酶结构域中的关键调节元件，激活下游信号通路，促进细胞的生存、生长和增殖。 当EGFR发生突变时，如过表达，细胞表面会出现过量受体，使细胞不受控制地生长和分裂，诱导正常细胞逐渐转化为癌细胞。另外，EGFR突变会导致受体的行为方式发生变化，导致受体持续将表皮生长因子蛋白吸引到细胞表面，这同样可促进异常的细胞生长。 目前抗EGFR药物主要包括酪氨酸激酶抑制剂（TKI）和抗EGFR的单克隆抗体（mAb）。小分子TKI 通过与ATP竞争结合EGFR中的酪氨酸激酶结构域，从而抑制EGFR自身磷酸化和下游信号传导。 从2002年，吉非替尼作为第一款EGFR-TKI在日本获批上市起，截至目前，市面上已有一代、二代及三代EGFR-TKI上市。一代代表药物有吉非替尼、厄洛替尼、埃克替尼，这些药物与靶点的结合并不牢固，是可逆的。二代代表药物主要有阿法替尼和达克替尼，特点是与 EGFR 靶点的结合是不可逆的，永久性地锁住靶点。第一、二代EGFR-TKI虽然疗效显著，但多数患者都会在1-2年内出现耐药，为了克服耐药性，三代横空出世，其代表药物主要有奥希替尼和阿美替尼。 但第三代靶向药也不可避免的会产生耐药，其耐药原因主要为EGFR C797S耐药突变。为了克服耐药性，一部分药企正在研发第四代，其中以BDTX-1535的数据最为亮眼。BDTX-1535由Black Diamond Therapeutics研发，在II期临床试验中，接受每日1次200mg BDTX-1535治疗的EGFR突变型NSCLC患者有42%（8/19）实现了客观缓解。 抗EGFR抗体药物 与EGFR-TKI作用机制不同，抗EGFR单克隆抗体通过与EGFR的细胞外结构域结合来阻断配体诱导的EGFR酪氨酸激酶活化，从而与配体竞争性结合。目前已上市的抗EGFR单克隆抗体药物包括西妥昔单抗、尼妥珠单抗、帕尼单抗等，不过它们在NSCLC领域并未取得理想效果，研究人员开始将注意力集中到抗EGFR双抗的研发。 强生的Rybrevant（amivantamab-vmjw，埃万妥单抗）是一款靶向EGFR和MET的全人源双特异性抗体，已在美国、欧洲和全球其他市场获批作为单一疗法，用于治疗具有EGFR外显子20插入突变（EGFR ex20ins）的局部晚期或转移性NSCLC患者。2024年8月20日，强生再次宣布Rybrevant联合第三代EGFR-TKI Lazcluze（lazertinib，兰泽替尼）获FDA批准，用于一线治疗局部晚期或转移性NSCLC患者，该方案是第一个与奥希替尼相比，显示出更优的无进展生存期（PFS）的无化疗方案。 EGFR ADC 靶向EGFR的ADC产品的开发历时已久。2008年，雅培与Life Science Pharma达成一项合作协议，获得了后者4款靶向EGFR产品的全球开发和商业化许可权益，其中便包括了两款EGFR ADC：ABBV-321（Serclutamab talirine）和ABBV-414（Depatuxizumab mafodotin，ABT-414），这两款药物后来被艾伯维收入囊中，但是研发进展并不顺利，后续相继折戟。 目前，布局EGFR ADC赛道的多为国内公司。进度靠前的有乐普生物的维贝柯妥塔单抗（MRG003），这是一款靶向EGFR的ADC药物，目前已在国内申报上市。另外，MRG003与PD-1抑制剂普特利单抗的联合治疗也取得了积极进展。 百利天恒和BMS合作的靶向EGFR/HER3的双抗ADC产品BL-B01D1，目前已在六大瘤种中开展了III期研究，包括EGFR突变型和野生型非小细胞肺癌、鼻咽癌、食管鳞癌、三阴性乳腺癌以及HER2-/HR+乳腺癌，尽管当前仅报出部分I期和小II期探索数据，但其大III期的布局迅猛之势让市场充满期待。 百力司康开发的靶向EGFR的ADC产品BB-1705，目前处于临床II期阶段。 EGFR Protac 对于EGFR-TKI耐药难题，PROTAC或许是一个好的解决方案。它可以降解整个蛋白，而不仅仅是抑制酶活性，因此EGFR是一个理想的PROTAC靶标。 目前海思科的EGFR PROTAC药物HSK40118和贝达药业/C4 Therapeutics的EGFR PROTAC药物CFT8919，分别已获药监局批准开展临床试验，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。 随着对EGFR及其下游信号通路的不断探索，开启了肿瘤治疗新时代。近些年来，在抗体、ADC、Protac技术发展带动下，该经典靶点越来越受到关注。EGFR赛道，已翻开新的一页。 参考来源： 1.Yasheng Zhu, Xiuquan Ye, Hao Shen, Jiaxing Li, Zeyu Cai, Wenjian Min, Yi Hou, Haojie Dong, Yuxing Wu, Liping Wang, Xiao Wang, Yibei Xiao, and Peng Yang, Discovery of Novel Fourth-Generation EGFR Inhibitors to Overcome C797S-Mediated Resistance, J. Med. Chem. 2023, 66, 14633?14652. 2.https://investors.blackdiamondtherapeutics.com/press-releases. 3.Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP. doi.org/10.1021/acs.jmedchem.1c00649. J. Med. Chem.2021, 64, 11, 7839-7852. END 【智药研习社近期直播】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~