First-line treatment with gefitinib in patients with metastatic non–small cell lung cancer and EGFR mutations resulted in significantly longer progression-free survival, compared with standard chemotherapy with carboplatin and paclitaxel, in a randomized, phase III study of 230 patients.

At a planned interim analysis, progression-free survival reached a median of 10.4 months in the patients who were randomized to gefitinib, a tyrosine kinase inhibitor targeting EGFR (epidermal growth factor receptor), compared with 5.5 months in those who were treated with chemotherapy (hazard ratio 0.36, P less than .001), Dr. Makoto Maemondo of Miyagi (Japan) Cancer Center, and colleagues from the North-East Japan Study Group reported in the June 24 issue of the New England Journal of Medicine.

The gefitinib patients also had significantly better objective response rates (73.7% vs. 30.7%; P less than .001) in the interim analysis, which was done 4 months after the 200th patient was enrolled and 38 months after study initiation. The trial was terminated early because of the findings.

The final analysis 7 months later showed that progression-free survival remained significantly better in the gefitinib patients (10.8 months vs. 5.4 months; HR 0.30; P less than .001), but median overall survival did not differ significantly between the groups (30.5 months and 23.6 months), the investigators said (N. Engl. J. Med. 2010;362:2380-8).

“We believe that the current study ... establishes the clinical benefit of an EGFR tyrosine kinase inhibitor as first-line treatment” in patients with non–small cell lung cancer and sensitive EGFR mutations, the investigators wrote, adding that selection of patients on the basis of EGFR mutations is “strongly recommended.”

Gefitinib was shown in the group’s previous phase II studies to have a response rate of more than 70%, and a progression-free survival of 9-10 months in patients with advanced NSCLC and EGFR mutations. Subsequently, the phase III IPASS (Iressa [gefitinib] Pan-Asia Study) showed gefitinib to be superior to carboplatin and paclitaxel as first-line therapy in selected NSCLC patients, with the “most impressive” results in those with EGFR mutations, the investigators noted.

Patients in the current study were younger than age 75 years, had advanced NSCLC harboring sensitive EGFR mutations, and had received no prior chemotherapy. Those who were randomized to gefitinib received an oral dose of 250 mg per day, and those in the chemotherapy group were treated on the first day of every 3-week cycle (for at least three cycles) with 200 mg/m² of paclitaxel given intravenously over 3 hours, and a dose of carboplatin (AUC = 6), given intravenously over 1 hour.

The treatments were well tolerated, and gefitinib was associated with less hematologic toxicity and neurotoxicity than was chemotherapy, the investigators said. Adverse events in the gefitinib group included rash in 71% of patients, elevated aminotransferase levels in 55%, and three cases of severe interstitial lung disease, one of which led to death. Adverse events in the standard chemotherapy patients included neutropenia in 77%, anemia in 65%, appetite loss in 57%, and sensory neuropathy in 55%.

The best timing for treatment with an EGFR tyrosine kinase inhibitor remains undetermined in these patients, the investigators noted. They said that they believe the prolonged progression-free survival with first-line gefitinib is valuable for patients with advanced NSCLC.

“If gefitinib is administered as second-line or third-line treatment, patients may miss the opportunity to received treatment with gefitinib because of rapidly progressive disease during or after first-line treatment,” they wrote.

Availability of gefitinib is limited in the United States. It is approved only for the treatment of locally advanced or metastatic NSCLC that has not improved on chemotherapy, and it is available only through a risk-management plan called the Iressa Access Program.

This study was supported by grants-in-aid from the Japan Society for Promotion of Science and the Japanese Foundation for the Multidisciplinary Treatment of Cancer, as well as by a grant from the Tokyo Cooperative Oncology Group. Of the 23 identified authors of the study, 16 reported no other conflicts of interest. Grants, honoraria, and/or consulting fees were paid to the remaining seven investigators (Dr. Gemma, Dr. Inoue, Dr. Isobe, Dr. Kobayashi, Dr. Nukiwa, Dr. Ogura, and Dr. Saijo) from one or more of the following: AstraZeneca, Bayer, Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutical KK, Merck Serono, Nihon Kayaku, Sanofi-Aventis, Taiho Pharmaceutical Co., and Yakult Honsha Co.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一项入选230例伴EGFR突变的转移性非小细胞肺癌(NSCLC)患者的III期随机研究显示，与使用卡铂和紫杉醇的标准化疗相比，吉非替尼一线治疗可更显著延长无进展生存期。

 

日本宫城县立癌症中心的Makoto Maemondo博士与来自日本东北大学研究小组的同事在6月24日出版的《新英格兰医学杂志》(New England Journal of Medicine)上发文指出，按计划进行的中期分析显示，吉非替尼组和化疗组的无进展生存期分别为10.4个月和5.5个月 [危险比(HR)0.36，P<0.001]。吉非替尼是一种靶向表皮生长因子受体(EGFR)的酪氨酸激酶抑制剂。

 

在第200例患者入组后4个月和研究开始后38个月进行的中期分析还显示，吉非替尼组的客观有效率明显更高(73.7%对30.7%；P<0.001)。 该试验由于上述结果而提前终止。

 

研究者表示，7个月后进行的最终分析显示，吉非替尼组的无进展生存期仍明显更长(10.8个月对 5.4个月；HR 0.30；P <0.001)，但中位总生存期的组间差异不显著(30.5个月对23.6个月) (N. Engl. J. Med. 2010;362:2380-8)。

 

研究者写道：“我们认为，当前研究……明确了作为一线治疗药物的EGFR酪氨酸激酶抑制剂对伴敏感EGFR突变NSCLC的临床收益”，并“强烈建议”基于EGFR突变来选择患者。

 

该研究小组此前进行的II期研究显示，吉非替尼在伴EGFR突变的晚期NSCLC患者中的有效率为70%以上，无进展生存期为9~10个月。研究者指出，随后的III期IPASS[易瑞沙(吉非替尼)泛亚研究]显示，吉非替尼一线治疗对所选择的NSCLC患者的疗效优于卡铂和紫杉醇，其中那些伴EGFR突变的患者获益“最显著”。

 

当前研究入选的是年龄低于75岁且此前未接受过化疗的携带敏感EGFR突变的晚期NSCLC患者。给药方案如下：吉非替尼组患者每日口服吉非替尼250 mg。化疗组患者每个周期(3周为1周期)的第1天接受紫杉醇200 mg/m²静滴3 h和卡铂(AUC = 6)静滴1 h，至少治疗3个周期。

 

研究者表示，这些治疗方案的耐受性均较好，并且吉非替尼引起的血液学毒性和神经毒性小于化疗。吉非替尼组的不良事件包括皮疹(71%)、转氨酶水平升高(55%)以及3例严重间质性肺病(其中1例死亡)。标准化疗组的不良事件包括中性粒细胞减少(77%)、贫血(65%)、食欲下降(57%)和感觉神经病变(55%)。

 

研究者指出，对这些患者实施EGFR酪氨酸激酶抑制剂治疗的最佳时间点尚未明确。他们认为，一线吉非替尼延长无进展生存期的作用对晚期NSCLC患者而言具有重要意义。

 

他们写道：“如果将吉非替尼用于二线或三线治疗，则患者可能会因一线治疗期间或之后出现的迅速疾病进展而错过接受吉非替尼治疗的机会。”

 

吉非替尼目前仅在美国可以获取。该药仅获准用于治疗化疗未能改善的局部晚期或转移性NSCLC，并且其仅可通过一项名为易瑞沙获取计划的风险管理计划获取。

 

本研究获得日本学术振兴协会和日本癌症多学科治疗基金会的补助金支持，并获得东京肿瘤协作组的资金支持。在本研究23位作者中，16位声明无其他经济利益冲突。其他7位研究者(Gemma博士、Inoue博士、Isobe博士、Kobayashi博士、Nukiwa博士、Ogura博士和Saijo博士)从以下一家或多家公司获得资金、酬金和(或)顾问费：阿斯利康、拜耳、百时美施贵宝、中外制药株式会社、第一三共株式会社、礼来、葛兰素史克、扬森制药株式会社、默克雪兰诺、Nihon Kayaku、赛诺菲-安万特、大鹏药品工业株式会社和日本国株式会社Yakult本社。

 

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