奥希替尼对比含铂化疗用于 - 突变型晚期 NSCLC。
Osimertinib with or without Chemotherapy in -Mutated Advanced NSCLC.
机构信息
From the Department of Medical Oncology, Institut Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, Villejuif, and the Faculty of Medicine, Paris-Saclay University, Paris - both in France (D.P.); the Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston (P.A.J.); the Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun (Y.C.), the Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin (Y.Y.), and the Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou (Y.F.) - all in China; the Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei (J.C.-H.Y.); the Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (N.Y.), the Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai (S.S.), and the Department of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka (K.K.) - all in Japan; the Department of Oncology, Asan Medical Center, Seoul, South Korea (S.-W.K.); the Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand (S.L.G.); the Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow (K.L.); the Department of Medical Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia (C.K.L.); the Department of Oncology, Instituto Nacional de Enfermedades Neoplásicas, Surquillo, Peru (N.V.); the Department of Medical Oncology, University Hospitals of Leicester, Leicester (S.A.), and Oncology Research and Development (D.G., Y.R.) and Oncology Biometrics (A.T.), AstraZeneca, Cambridge - both in the United Kingdom; the Department of Clinical Oncology, Rondebosch Oncology Centre, Cape Town, South Africa (J.-M.M.); the Department of Radiotherapy and Oncology, Východoslovenský Onkologický Ústav, Košice, Slovakia (I.A.); and the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.G.).
出版信息
N Engl J Med. 2023 Nov 23;389(21):1935-1948. doi: 10.1056/NEJMoa2306434. Epub 2023 Nov 8.
BACKGROUND
Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.
METHODS
In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.
RESULTS
A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.
CONCLUSIONS
First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).
背景
奥希替尼是一种第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），对 EGFR-TKI 敏感和 T790M 耐药突变具有选择性。有证据表明，化疗的加入可能会延长 EGFR-TKI 治疗的获益。
方法
在这项 3 期、国际、开放性试验中，我们以 1:1 的比例随机分配未接受过晚期疾病治疗的 -突变（外显子 19 缺失或 L858R 突变）的晚期非小细胞肺癌（NSCLC）患者接受奥希替尼（每日 80 mg）联合化疗（培美曲塞[500 mg/平方米体表面积]加顺铂[75 mg/平方米]或卡铂[药物指导剂量]）或接受奥希替尼单药治疗（每日 80 mg）。主要终点是研究者评估的无进展生存期。还评估了应答和安全性。
结果
共有 557 名患者接受了随机分组。与奥希替尼组相比，奥希替尼-化疗组的研究者评估无进展生存期显著延长（疾病进展或死亡的风险比，0.62；95%置信区间[CI]，0.49 至 0.79；P<0.001）。24 个月时，奥希替尼-化疗组中 57%（95%CI，50 至 63）的患者和奥希替尼组中 41%（95%CI，35 至 47）的患者存活且无疾病进展。根据盲法独立中心评估的无进展生存期与主要分析结果一致（风险比，0.62；95%CI，0.48 至 0.80）。奥希替尼-化疗组 83%的患者和奥希替尼组 76%的患者观察到客观（完全或部分）应答；中位缓解持续时间分别为 24.0 个月（95%CI，20.9 至 27.8）和 15.3 个月（95%CI，12.7 至 19.4）。与单药治疗相比，联合治疗的任何原因导致的 3 级或更高不良事件发生率更高-这一发现归因于已知的化疗相关不良事件。奥希替尼联合培美曲塞和铂类药物的安全性与各药物的既定安全性一致。
结论
在 -突变的晚期 NSCLC 患者中，奥希替尼联合化疗的一线治疗与奥希替尼单药治疗相比，无进展生存期显著延长。（由阿斯利康公司资助；FLAURA2 临床试验.gov 编号，NCT04035486）。
Zotero 插件