Cohen Martin H, Williams Grant A, Sridhara Rajeshwari, Chen Gang, Pazdur Richard
Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 20857, USA.
Oncologist. 2003;8(4):303-6. doi: 10.1634/theoncologist.8-4-303.
On May 5, 2003, gefitinib (Iressa), ZD1839) 250-mg tablets received accelerated approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence interval 6.0%-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit.
2003年5月5日，吉非替尼（易瑞沙，ZD1839）250毫克片剂获得美国食品药品监督管理局加速批准，作为铂类和多西他赛化疗失败后的局部晚期或转移性非小细胞肺癌（NSCLC）患者的单一疗法。本摘要提供的信息包括相关临床试验的疗效和安全性结果。在一项随机、双盲、II期、多中心试验中比较了两种口服剂量的吉非替尼（250毫克/天与500毫克/天），证明了其有效性。共纳入216例患者。142例对铂类和多西他赛难治或不耐受的患者组成了疗效分析的可评估人群。接受250毫克/天吉非替尼治疗的患者中有14%（66例中的9例）出现部分肿瘤缓解，接受500毫克/天吉非替尼治疗的患者中有8%（76例中的6例）出现部分肿瘤缓解。两种剂量联合的总体客观缓解率为10.6%（142例患者中的15例）（95%置信区间6.0%-16.8%）。女性和不吸烟者的缓解更常见。缓解的中位持续时间为7.0个月（范围4.6-18.6+个月）。其他提交的数据包括在未经化疗的III期和IV期NSCLC患者中进行的两项大型试验的结果。患者被随机分配接受吉非替尼（250毫克或500毫克每日）或安慰剂，联合吉西他滨加顺铂（n = 1093）或卡铂加紫杉醇（n = 1037）。这些研究的结果表明，在化疗中添加吉非替尼没有益处（缓解率、疾病进展时间或生存率）。因此，吉非替尼仅推荐作为单一疗法使用。与吉非替尼治疗相关的常见不良事件包括腹泻、皮疹、痤疮、皮肤干燥、恶心和呕吐。大多数毒性为常见毒性标准1级或2级。接受吉非替尼治疗的患者中观察到间质性肺病（ILD）。在全球范围内，ILD的发生率约为1%（日本上市后经验中为2%，美国扩大使用计划中约为0.3%）。约三分之一的病例是致命的。医生应迅速评估新出现或恶化的肺部症状。如果确诊为ILD，适当的处理包括停用吉非替尼。吉非替尼是根据替代终点缓解率在加速批准法规下获批的。迄今为止，没有对照的吉非替尼试验证明有临床益处，如改善与疾病相关的症状或提高生存率。加速批准法规要求申办者进行进一步研究，以验证吉非替尼治疗是否产生这种益处。
