Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations
Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations
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DOI：
10.1200/jco.2016.66.9218
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发表时间：
2016-09-20
影响因子：
45.3
通讯作者：
Yang, James Chih-Hsin
中科院分区：
文献类型：
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作者：
Cheng, Ying;Murakami, Haruyasu;Yang, James Chih-Hsin
目的确定与吉非替尼单药治疗相比，培美曲塞联合吉非替尼（P+G）治疗晚期非鳞状（NS）非小细胞肺癌（NSCLC）伴表皮生长因子受体（EGFR）激活突变患者是否具有临床获益。35个研究中心的晚期EGFR突变型NS NSCLC患者被随机分配（2：1;计算机生成，交互式语音应答）至开放标签培美曲塞（500 mg/m2，每21天周期的第1天）+吉非替尼（250 mg/d [n = 129]）或吉非替尼单药治疗组（n = 66）。主要终点是无进展生存期（PFS）;次要终点是疾病进展时间、总生存期、肿瘤缓解率、缓解持续时间和安全性。在意向治疗和安全性人群中评估所有终点（P+G组，n = 126;吉非替尼单药组，n = 65）。（中位数，15.8个月; 95% CI，12.6 - 18.3个月）（中位数：10.9个月; 95% CI：9.7 - 13.8个月;校正风险比[HR]：0.68; 95% CI：0.48 - 0.96;单侧P = 0.014;双侧P = 0.029）。EGFR 19号外显子缺失和EGFR 21号外显子L 858 R点突变亚组分析的结果与意向治疗结果一致。与吉非替尼单药治疗相比，P+G导致疾病进展时间显著延长（中位数分别为16.2 v10.9个月; HR，0.66; 95%CI，0.47 - 0.93），缓解持续时间在数值上延长（中位数分别为15.4 v11.3个月; HR，0.74; 95%CI，0.50 - 1.08）。肿瘤缓解率无差异。总体生存数据尚不成熟。药物相关的3级或4级不良事件与P+ G更常见，但毒性是manage.ConclusionP+G改善PFS与吉非替尼相比，单独在东亚晚期NS NSCLC患者和激活EGFR突变。与目前的标准治疗相比，这种联合治疗可能为EGFR突变阳性患者提供新的治疗选择和改善的临床结局。
PurposeTo determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations.Patients and MethodsChemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2: 1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-freesurvival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65).ResultsPFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P =.014; two-sided P =.029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+ G, but toxicities were manageable.ConclusionP+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.