Herbst Roy S, Giaccone Giuseppe, Schiller Joan H, Natale Ronald B, Miller Vincent, Manegold Christian, Scagliotti Giorgio, Rosell Rafael, Oliff Ira, Reeves James A, Wolf Michael K, Krebs Annetta D, Averbuch Steven D, Ochs Judith S, Grous John, Fandi Abderrahim, Johnson David H
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030, USA.
J Clin Oncol. 2004 Mar 1;22(5):785-94. doi: 10.1200/JCO.2004.07.215.
Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC.
Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect.
Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.
临床前研究表明，吉非替尼（易瑞沙，ZD1839；阿斯利康公司，特拉华州威尔明顿）是一种口服活性表皮生长因子受体酪氨酸激酶抑制剂，可能增强细胞毒性药物的抗肿瘤疗效，并且在一项I期试验中，其与紫杉醇和卡铂联合使用具有可接受的耐受性。在难治性晚期非小细胞肺癌（NSCLC）的II期试验中，吉非替尼单药治疗显示出一种生物制剂无与伦比的抗肿瘤活性，毒性低于多西他赛。这项III期、随机、安慰剂对照、双盲试验评估了吉非替尼联合紫杉醇和卡铂用于未经化疗的晚期NSCLC患者。
患者接受紫杉醇225mg/m²和卡铂浓度/时间曲线下面积为6mg/（min·mL）（每3周第1天），加用吉非替尼500mg/d、吉非替尼250mg/d或安慰剂。最多六个周期后，继续每日服用吉非替尼或安慰剂直至疾病进展。终点包括总生存期、疾病进展时间（TTP）、缓解率（RR）和安全性评估。结果共招募了1037例患者。基线人口统计学特征平衡良好。各治疗组之间的总生存期（吉非替尼500mg/d组、250mg/d组和安慰剂组的中位数分别为8.
