特泊替尼加奥西美替尼治疗一线奥西美替尼治疗进展后MET扩增的表皮生长因子受体突变非小细胞肺癌患者(INSIGHT 2):一项多中心、开放标签、2期试验。

IF 41.6 1区 医学 Q1 ONCOLOGY
Yi-Long Wu, Valentina Guarneri, Pei Jye Voon, Boon Khaw Lim, Jin-Ji Yang, Marie Wislez, Cheng Huang, Chong Kin Liam, Julien Mazieres, Lye Mun Tho, Hidetoshi Hayashi, Nguyen Viet Nhung, Puey Ling Chia, Filippo de Marinis, Jo Raskin, Qinghua Zhou, Giovanna Finocchiaro, Anh Tuan Le, Jialei Wang, Christophe Dooms, Terufumi Kato, Ernest Nadal, How Soon Hin, Egbert F Smit, Martin Wermke, Daniel Tan, Masahiro Morise, Aurora O'Brate, Svenja Adrian, Boris M Pfeiffer, Christopher Stroh, Dilafruz Juraeva, Rainer Strotmann, Kosalaram Goteti, Karin Berghoff, Barbara Ellers-Lenz, Niki Karachaliou, Xiuning Le, Tae Min Kim
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引用次数: 0

摘要

背景:表皮生长因子受体(EGFR)突变的非小细胞肺癌(NSCLC)患者,由于MET扩增是一线奥希替尼的耐药机制,因此可供选择的治疗方案很少。在此,我们报告了 INSIGHT 2 2 期研究的主要分析结果,该研究评估了特泊替尼(一种高选择性 MET 抑制剂)与奥西莫替尼在该人群中的联合应用:这项开放标签的 2 期研究在 17 个国家的 179 个学术中心和社区诊所进行。符合条件的患者年龄在18岁或18岁以上,东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现状态为0或1,任何组织学类型的晚期或转移性表皮生长因子受体(EGFR)突变NSCLC,经组织活检荧光原位杂交(FISH;MET基因拷贝数≥5或MET-to-CEP7比值≥2)或液体活检新一代测序(MET血浆基因拷贝数≥2-3)发现MET扩增,一线奥希替尼治疗进展。患者每天一次口服特博替尼 500 毫克,外加口服奥西美替尼 80 毫克。主要终点是独立评估经中心FISH检测有MET扩增的患者接受特泊替尼加奥希替尼治疗后至少9个月随访的客观反应。对至少接受过一次研究药物治疗的患者进行了安全性分析。该研究已在ClinicalTrials.gov注册,编号为NCT03940703(已完成注册):2020年2月13日至2022年11月4日期间,128名患者(74名[58%]女性,54名[42%]男性)入组并开始服用特泊替尼加奥希替尼。主要活性分析人群包括98名经中心FISH证实存在MET扩增、既往接受过一线奥希替尼治疗且随访至少9个月(中位数为12-7个月[IQR 9-9-20-3])的患者。确诊客观反应率为 50-0%(95% CI 39-7-60-3;98 例患者中有 49 例)。最常见的治疗相关 3 级或更严重不良事件是外周水肿(128 例患者中有 6 例[5%])、食欲下降(5 例[4%])、心电图 QT 间期延长(5 例[4%])和肺炎(4 例[3%])。有 16 例(13%)患者报告了与治疗相关的严重不良事件。经研究者评估,有4例(3%)患者的死亡可能与试验药物有关,分别是肺炎(2例[2%])、血小板计数下降(1例[1%])、呼吸衰竭(1例[1%])和呼吸困难(1例[1%]);1例死亡同时归因于肺炎和呼吸困难:在表皮生长因子受体(EGFR)突变的NSCLC患者中,特泊替尼加奥希替尼显示出良好的活性和可接受的安全性,MET扩增是奥希替尼一线治疗的耐药机制,这表明这是一种潜在的节省化疗的口服靶向治疗方案,应进一步研究:默克公司(CrossRefunder ID:10.13039/100009945)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population.

Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete).

Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.

Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.

Funding: Merck (CrossRef Funder ID: 10.13039/100009945).

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来源期刊
Lancet Oncology
Lancet Oncology 医学-肿瘤学
CiteScore
62.10
自引率
1.00%
发文量
913
审稿时长
3-8 weeks
期刊介绍: The Lancet Oncology is a trusted international journal that addresses various topics in clinical practice, health policy, and global oncology. It covers a wide range of cancer types, including breast, endocrine system, gastrointestinal, genitourinary, gynaecological, haematological, head and neck, neurooncology, paediatric, thoracic, sarcoma, and skin cancers. Additionally, it includes articles on epidemiology, cancer prevention and control, supportive care, imaging, and health-care systems. The journal has an Impact Factor of 51.1, making it the leading clinical oncology research journal worldwide. It publishes different types of articles, such as Articles, Reviews, Policy Reviews, Personal Views, Clinical Pictures, Comments, Correspondence, News, and Perspectives. The Lancet Oncology also collaborates with societies, governments, NGOs, and academic centers to publish Series and Commissions that aim to drive positive changes in clinical practice and health policy in areas of global oncology that require attention.
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