Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
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DOI：
10.1056/nejmoa1006448
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发表时间：
2010-10-28
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影响因子：
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通讯作者：
Iafrate AJ
中科院分区：
文献类型：
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作者：
Kwak EL;Bang YJ;Camidge DR;Shaw AT;Solomon B;Maki RG;Ou SH;Dezube BJ;Jänne PA;Costa DB;Varella-Garcia M;Kim WH;Lynch TJ;Fidias P;Stubbs H;Engelman JA;Sequist LV;Tan W;Gandhi L;Mino-Kenudson M;Wei GC;Shreeve SM;Ratain MJ;Settleman J;Christensen JG;Haber DA;Wilner K;Salgia R;Shapiro GI;Clark JW;Iafrate AJ
由EML 4和间变性淋巴瘤激酶（ALK）组成的致癌融合基因存在于非小细胞肺癌的亚组中，占此类肿瘤的2%至7%。我们在克唑替尼（PF-02341066）的早期临床试验中探索了抑制ALK在此类肿瘤中的治疗疗效，克唑替尼是一种口服小分子ALK酪氨酸激酶抑制剂。在对约1500例非小细胞肺癌患者的肿瘤样本进行ALK重排筛查后，我们确定了82例有资格参加临床试验的晚期ALK阳性患者。大多数患者以前接受过治疗。这些患者入组了一项扩展队列研究，该研究是在I期剂量递增确立了推荐的克唑替尼剂量250 mg每日两次，28天为一个周期后开始的。评估患者的不良事件和对治疗的反应。ALK重排的患者往往比没有重排的患者更年轻，大多数患者很少或没有接触烟草，并且患有腺癌。在平均治疗持续时间为6.4个月时，总体缓解率为57%（82例患者中的47例，46例确认部分缓解，1例确认完全缓解）; 27例患者（33%）病情稳定。在数据截止日期时，82例患者中共有63例（77%）继续接受克唑替尼治疗，6个月无进展生存期的估计概率为72%，未达到研究的中位数。该药物导致1级或2级（轻度）胃肠道副作用。在大多数患者中，通过ALK重排抑制肺肿瘤中的ALK导致肿瘤缩小或疾病稳定。
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients.