Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy.
Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Orbassano, Turin, Italy.
Lancet Oncol. 2014 Jun;15(7):713-21. doi: 10.1016/S1470-2045(14)70162-7. Epub 2014 May 13.
An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer.
From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m(2), intravenously, every 21 days, or docetaxel 75 mg/m(2), intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690.
142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8-10·9) in the chemotherapy group and 7·7 months (5·9-10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08-2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77-1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group.
Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib.
Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.
一种已确立的多变量血清蛋白检测可用于根据患者接受表皮生长因子受体酪氨酸激酶抑制剂治疗后是否可能获得良好或不良结局对其进行分类。我们评估了该检测在厄洛替尼与化疗比较中对非小细胞肺癌患者的预测能力。
从 2008 年 2 月 26 日至 2012 年 4 月 11 日，意大利 14 个中心招募了组织学或细胞学证实的二线、局部晚期 IIIB 或 IV 期非小细胞肺癌患者（年龄≥18 岁）。根据东部合作肿瘤组表现状态、吸烟史、中心和掩蔽预处理血清蛋白检测分类的最小化算法对患者进行分层，并以 1:1 的比例随机分配接受厄洛替尼（150 mg/天，口服）或化疗（培美曲塞 500 mg/m²，静脉注射，每 21 天一次，或多西他赛 75 mg/m²，静脉注射，每 21 天一次）。蛋白组检测分类对接受治疗的患者和研究者是掩蔽的，而治疗分配对生成蛋白组分类的研究者是掩蔽的。主要终点是总生存期，主要假设是血清蛋白检测分类与治疗之间存在显著交互作用。按方案人群进行分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT00989690。
142 例患者随机分配至化疗组，143 例患者随机分配至厄洛替尼组，分别有 129（91%）和 134（94%）例患者纳入方案人群分析。化疗组中 88（68%）例患者和厄洛替尼组中 96（72%）例患者的蛋白组检测分类为良好。化疗组的中位总生存期为 9.0 个月（95%CI 6.8-10.9），厄洛替尼组为 7.7 个月（5.9-10.4）。我们注意到治疗与蛋白组分类之间存在显著交互作用（调整分层因素后，pinteraction=0.017；未调整分层因素时，pinteraction=0.031）。蛋白组检测分类为不良的患者接受厄洛替尼治疗的生存结局比接受化疗差（危险比 1.72[95%CI 1.08-2.74]，p=0.022）。蛋白组检测分类良好的患者接受两种治疗的总生存期无显著差异（调整后的 HR 1.06[0.77-1.46]，p=0.714）。在接受化疗的患者中，最常见的 3 级或 4 级毒性反应是中性粒细胞减少症（19[15%]例，厄洛替尼组为 1[＜1%]例），而皮肤毒性（1[＜1%]例 vs 22[16%]例）是厄洛替尼组最常见的毒性反应。
我们的研究结果表明，血清蛋白检测状态是预测厄洛替尼与化疗二线治疗中总生存期差异获益的指标。蛋白组检测分类为不良结局的患者在化疗中的结局比在厄洛替尼中更好。
意大利卫生部、意大利癌症研究协会和 Biodesix。
