阿法替尼用于经化疗、厄洛替尼/吉非替尼及阿法替尼治疗后病情进展的非小细胞肺癌患者：III期随机LUX-Lung 5试验
Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial.
作者信息
Schuler M, Yang J C-H, Park K, Kim J-H, Bennouna J, Chen Y-M, Chouaid C, De Marinis F, Feng J-F, Grossi F, Kim D-W, Liu X, Lu S, Strausz J, Vinnyk Y, Wiewrodt R, Zhou C, Wang B, Chand V K, Planchard D
机构信息
West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany
Department of Medical Research, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
出版信息
Ann Oncol. 2016 Mar;27(3):417-23. doi: 10.1093/annonc/mdv597. Epub 2015 Dec 8.
BACKGROUND
Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy.
PATIENTS AND METHODS
Patients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m(2)/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes.
RESULTS
Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent.
CONCLUSION
Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy.
TRIAL REGISTRATION NUMBER
NCT01085136 (clinicaltrials.gov).
背景
阿法替尼已在接受厄洛替尼/吉非替尼治疗后病情进展的非小细胞肺癌患者中显示出临床获益。这项III期试验前瞻性评估了在对厄洛替尼/吉非替尼和阿法替尼单药治疗产生耐药性的患者中，继续使用阿法替尼加紫杉醇进行不可逆的表皮生长因子受体（ErbB）家族阻断是否比单纯换用化疗具有更好的疗效。
患者与方法
接受过≥1线化疗后出现复发/难治性疾病，且在最初使用厄洛替尼/吉非替尼控制病情（≥12周）后疾病进展，随后使用阿法替尼（50毫克/天）治疗后病情仍进展的患者，按2:1随机分组，分别接受阿法替尼加紫杉醇（40毫克/天；80毫克/平方米/周）或研究者选择的单药化疗。主要终点为无进展生存期（PFS）。其他终点包括客观缓解率（ORR）、总生存期（OS）、安全性和患者报告的结局。
结果
202例在阿法替尼治疗后出现临床获益但病情仍进展的患者被随机分为阿法替尼加紫杉醇组（n = 134）或单药化疗组（n = 68）。阿法替尼加紫杉醇组的PFS（中位值5.6个月对2.8个月，风险比0.60，P = 0.003）和ORR（32.1%对13.2%，P = 0.005）显著改善。OS无差异。在整个治疗期间，阿法替尼加紫杉醇组维持了全球健康状况/生活质量。阿法替尼加紫杉醇组和单药化疗组的中位治疗持续时间分别为133天和51天；接受阿法替尼加紫杉醇治疗的患者中有48.5%、接受单药化疗的患者中有30.0%发生了与药物相关的3/4级不良事件。治疗相关不良事件与之前每种药物报告的情况一致。
结论
与单药化疗相比，阿法替尼加紫杉醇在对厄洛替尼/吉非替尼产生耐药性且在最初获益后使用阿法替尼病情仍进展的患者中改善了PFS和ORR。LUX-Lung 5是首个前瞻性试验，证明了病情进展后继续靶向ErbB比换用单药化疗更有益。
试验注册号
NCT01085136（clinicaltrials.gov）。
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