背景:EGFR突变的非小细胞肺癌(NSCLC)和MET扩增作为一线奥希替尼耐药机制的患者几乎没有治疗选择。这里,我们报告了评估替泊替尼的2期INSIGHT2研究的主要分析,一种高度选择性的MET抑制剂,与奥希替尼联合治疗这一人群。
方法:这个开放标签,第二阶段研究在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岁或以上,东部肿瘤协作组表现状态为0或1,任何组织学的晚期或转移性EGFR突变NSCLC,通过组织活检荧光原位杂交进行MET扩增(FISH;MET基因拷贝数≥5或MET与CEP7比率≥2)或液体活检下一代测序(MET血浆基因拷贝数≥2·3),一线奥希替尼进展后。患者每天一次口服500mg托泊替尼加奥希替尼80mg。主要终点是通过Tepotinib联合奥希替尼治疗的中心FISH独立评估MET扩增患者的客观反应,随访至少9个月。在接受至少一个研究药物剂量的患者中分析安全性。这项研究在ClinicalTrials.gov注册,NCT03940703(注册完成)。
结果:在2020年2月13日至2022年11月4日之间,128名患者(74[58%]女性,54[42%]男性)入组,并开始使用替泊替尼+奥希替尼。主要活动分析人群包括98例经中央FISH证实的MET扩增患者,之前的一线奥希替尼和至少9个月的随访(中位数12·7个月[IQR9·9-20·3])。确认的客观缓解率为50·0%(95%CI39·7-60·3;98例患者中有49例)。最常见的治疗相关的3级或更严重的不良事件是外周水肿(128例患者中有6例[5%])。食欲下降(5[4%]),心电图QT间期延长(五[4%]),和肺炎(四[3%])。16例(13%)患者报告了严重的治疗相关不良事件。研究人员评估了四名(3%)患者因肺炎(两名[2%]患者)与任一试验药物可能相关的死亡。血小板计数减少(1[1%]),呼吸衰竭(1[1%]),和呼吸困难(1[1%]);1例死亡归因于肺炎和呼吸困难。
结论:Tepotinib联合奥希替尼在EGFR突变的NSCLC和MET扩增患者中显示出良好的活性和可接受的安全性,作为一线奥希替尼耐药机制,建议一种潜在的不含化疗的口服靶向治疗方案,应进一步研究.
背景:默克公司(CrossRefFunderID:10.13039/100009945)。
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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Merck (CrossRef Funder ID: 10.13039/100009945).