III 期研究阿法替尼或顺铂加培美曲塞治疗 EGFR 突变的转移性肺腺癌患者。

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.

机构信息

Lecia V. Sequist, Massachusetts General Hospital and Harvard Medical School, Boston, MA; James Chih-Hsin Yang, National Taiwan University Hospital; Chun-Ming Tsai, Taipei Veterans General Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Nobuyuki Yamamoto, Shizuoka Cancer Center, Shizuoka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; Kenneth O'Byrne, St James' Hospital, Dublin, Ireland; Vera Hirsh, McGill University, Montreal, Quebec, Canada; Tony Mok, Prince of Wales Hospital, Hong Kong, China; Sarayut Lucien Geater, Songklanagarind Hospital, Songkla, Thailand; Sergey Orlov, Pavlov State Medical University, St Petersburg; Vera Gorbunova, GU Russian Oncological Research Centre, Moscow, Russia; Michael Boyer, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Jaafar Bennouna, Institut de Cancérologie de l'Ouest-site René Gauducheau, Nantes, France; Ki Hyeong Lee, Chungbuk National University Hospital, Cheongju, South Korea; Riyaz Shah, Maidstone and Tunbridge Wells National Health Service Trust, Maidstone Hospital, Maidstone; Dan Massey, Victoria Zazulina, and Mehdi Shahidi, Boehringer Ingelheim, Bracknell, United Kingdom; and Martin Schuler, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.

出版信息

J Clin Oncol. 2013 Sep 20;31(27):3327-34. doi: 10.1200/JCO.2012.44.2806. Epub 2013 Jul 1.

DOI:10.1200/JCO.2012.44.2806

PMID:23816960

Abstract

PURPOSE

The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

PATIENTS AND METHODS

In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

RESULTS

A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

CONCLUSION

Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

摘要

目的

LUX-Lung 3 研究调查了化疗与 afatinib 的疗效比较，afatinib 是一种选择性的、口服生物利用的 ErbB 家族阻滞剂，可不可逆地阻断表皮生长因子受体（EGFR/ErbB1）、人表皮生长因子受体 2（HER2/ErbB2）和 ErbB4 的信号传导，并且对 EGFR 突变具有广谱的临床前活性。一项 afatinib 治疗 EGFR 突变阳性肺腺癌的 II 期研究显示出高缓解率和无进展生存期（PFS）。

患者和方法

在这项 III 期研究中，筛选出 IIIB/IV 期肺腺癌患者进行 EGFR 突变检测。突变阳性患者按突变类型（外显子 19 缺失、L858R 或其他）和种族（亚裔或非亚裔）分层，然后按 2:1 随机分配至每天 40mg afatinib 或标准剂量顺铂加培美曲塞化疗，每 21 天为一个周期，最多 6 个周期。主要终点为独立评估的 PFS。次要终点包括肿瘤反应、总生存期、不良事件和患者报告的结局（PROs）。

结果

共筛选了 1269 例患者，其中 345 例患者随机分配接受治疗。afatinib 组和化疗组的中位 PFS 分别为 11.1 个月和 6.9 个月（风险比[HR]，0.58；95%CI，0.43 至 0.78；P=0.001）。在具有外显子 19 缺失和 L858R EGFR 突变的患者中（n=308），afatinib 组和化疗组的中位 PFS 分别为 13.6 个月和 6.9 个月（HR，0.47；95%CI，0.34 至 0.65；P=0.001）。最常见的与治疗相关的不良事件为 afatinib 组的腹泻、皮疹/痤疮和口腔炎，以及化疗组的恶心、疲劳和食欲下降。PROs 有利于 afatinib，可更好地控制咳嗽、呼吸困难和疼痛。