奥希替尼联合或不联合化疗治疗伴EGFR及并发TP53突变的晚期非小细胞肺癌：一项随机临床试验
Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.
作者
作者单位
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
- Department of Pulmonary Oncology, Foshan Key Laboratory of Precision Therapy in Oncology and Neurology, the First People's Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Foshan, China.
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.
- The Fourth Department of Medical Oncology, Central Hospital of Guangdong Provincial Nongken, Zhanjiang Cancer Hospital, Zhanjiang, China.
- Department of Oncology, Shengli Oilfield Central Hospital, Dongying, China.
- Department of Hematology and Oncology, the First People's Hospital of Taizhou, Taizhou, China.
- Department of Oncology, the Third Affiliated Hospital of Soochow University, the First People's Hospital of Changzhou, Changzhou, China.
- Department of Respiratory and Critical Care Medicine, Taizhou Central Hospital, Taizhou, China.
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Department of Medical Oncology, Rui'an People's Hospital, the Third Affiliated Hospital of Wenzhou Medical University, Rui'an, China.
- Department of Medical Oncology, Yidu Central Hospital of Weifang, Weifang, China.
- Department of Medical Oncology, the First Affiliated Hospital of Xiamen University, Xiamen, China.
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, Kunming, China.
- Department of Respiratory Medicine, Sun Yat-Sen University Cancer Center Gansu Hospital, Lanzhou, China.
- Department of Respiratory, the First Affiliated Hospital of Hebei North University, Zhangjiakou, China.
- Department of Clinical Pharmacological Study Ward, Linyi People's Hospital, Linyi, China.
- Department of Clinical Trials Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
摘要
中文
联合治疗已成为表皮生长因子受体（EGFR）突变非小细胞肺癌（NSCLC）患者有前景的治疗方法。然而，其临床获益-风险特征仍是持续争论的焦点。识别最可能从此类方案中获益的患者仍是未满足的临床需求。本研究前瞻性比较一线奥希替尼联合化疗与奥希替尼单药治疗携带并发TP53突变的EGFR突变晚期NSCLC患者的疗效和安全性。这是一项在中国17个中心开展的多中心、随机、开放标签、3期研究。2021年3月25日至2024年7月11日期间，共入组294例初治、IV期或复发性非鳞NSCLC且携带并发TP53和EGFR敏感突变符合条件的患者。患者按1:1随机分配接受奥希替尼联合化疗（培美曲塞和卡铂每3周1次，共4个周期，之后奥希替尼联合培美曲塞维持治疗；n=146）或奥希替尼单药治疗（n=148）。主要终点是研究者评估的无进展生存期。次要终点包括总生存期、缓解、安全性和生活质量。在294例入组患者中，中位年龄57岁（范围26-79岁），159例（54.1%）为女性。数据截止日期为2025年11月11日。奥希替尼联合化疗组中位随访25.1个月，奥希替尼单药组中位随访26.1个月，奥希替尼联合化疗组的中位无进展生存期显著长于奥希替尼单药组（34.0 vs 15.6个月；差异18.4个月[95% CI, 9.9-22.3]；风险比0.44[95% CI, 0.32-0.60]；P<.001）。这一获益在预设亚组中一致，包括脑转移和L858R突变患者。总生存期数据尚未成熟（成熟度30.6%）；但观察到联合治疗的总生存期获益趋势。联合治疗组3级或更高治疗相关不良事件的发生率更高，未发现新的安全信号。在这项随机临床试验中，奥希替尼联合化疗显著提高了携带并发TP53突变的EGFR突变晚期NSCLC患者的无进展生存期。这些发现为EGFR突变NSCLC患者的个体化联合策略提供了临床依据。临床试验注册号：NCT04695925。
English
Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. ClinicalTrials.gov Identifier: NCT04695925.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 65.4
- 新锐分区
- 1区