美国丹娜-法伯癌症研究所Pasi A. Jänne团队研究了奥希替尼加或不加化疗治疗EGFR突变晚期NSCLC的疗效与安全性。该项研究成果发表在2023年11月8日出版的《新英格兰医学杂志》上。

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-致敏和EGFR-T790M耐药性突变具有选择性。有证据表明，联合化疗可能会扩大EGFR-TKI治疗的益处。

在这个临床3期的国际开放标签试验中，研究组以1:1的比例随机分配患有EGFR突变（外显子19缺失或L858R突变）的晚期非小细胞癌症（NSCLC）患者，之前均没有接受过晚期疾病治疗，分别接受奥希替尼（80 mg，每日一次）+化疗（培美曲塞[每平方米体表面积500 mg]加顺铂[每平方米75 mg]或卡铂[药理学指导剂量]）或接受奥希替尼单药治疗（80mg，每天一次）。主要终点是研究者评估的无进展生存期。还评估了缓解率和安全性。

共有557名患者接受了随机分组。研究者评估的奥希替尼-化疗组的无进展生存期明显长于奥希替尼组（疾病进展或死亡的危险比为0.62；P<0.001）。在24个月时，奥希替尼-化疗组57%的患者和奥希替尼组41%的患者存活且无进展。根据双盲独立中心审查评估的无进展生存率与主要分析一致（危险比为0.62）。

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）缓解；中位缓解持续时间分别为24.0个月和15.3个月。任何原因引起的3级或更高级别不良事件的发生率，联合用药均高于单药治疗——这一发现是由已知的化疗相关不良事件引起的。奥希替尼加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。

研究结果表明，在EGFR突变的晚期NSCLC患者中，奥希替尼一线化疗的无进展生存期明显长于奥希替尼单药治疗。

附：英文原文

Title: Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

Author: David Planchard, Pasi A. Jnne, Ying Cheng, James C.-H. Yang, Noriko Yanagitani, Sang-We Kim, Shunichi Sugawara, Yan Yu, Yun Fan, Sarayut L. Geater, Konstantin Laktionov, Chee K. Lee, Natalia Valdiviezo, Samreen Ahmed, Jean-Marc Maurel, Igor Andrasina, Jonathan Goldman, Dana Ghiorghiu, Yuri Rukazenkov, Alex Todd, Kunihiko Kobayashi

Issue&Volume: 2023-11-08

Abstract:

Background

Osimertinib is a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI–sensitizing and EGFR 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 EGFR-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 EGFR-mutated advanced NSCLC.

DOI: 10.1056/NEJMoa2306434

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2306434