Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Ther Adv Med Oncol. 2011 May;3(3):113-25. doi: 10.1177/1758834010397569.
Non-small cell lung cancers (NSCLCs) are heterogeneous cancers. In 2004, the identification of epidermal growth factor receptor (EGFR) somatic mutations provided the first glimpse of a clinically relevant NSCLC oncogene. Approximately 70% of NSCLCs with EGFR mutations (exon 19 deletions or the exon 21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, with improved response rate (RR), progression-free survival (PFS) and in some reports overall survival (OS) when compared with EGFR wildtype (WT) cases. Three randomized trials of gefitinib versus chemotherapy (IPASS, WJTOG3405, NEJ002) in stage IV NSCLC have consistently demonstrated better RR and PFS (hazard ratios of 0.48 [IPASS], 0.49 [WJTOG3405] and 0.30 [NEJ002]) for EGFR-mutated NSCLCs treated with gefitinib. Novel irreversible EGFR TKIs (afatinib, XL647, PF00299804) show similar activity in EGFR-mutated patients. A translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4, identified in 2007, is the most recent oncogene found in NSCLC. Crizotinib (PF02341066), an ALK TKI, has shown impressive activity against ALK translocated NSCLC in an expanded cohort of a phase I trial (NCT00585195). Over 80 patients have been treated and the RR is ∼60% with the 6-month PFS rate exceeding 70%. A registration phase III trial of crizotinib versus second-line chemotherapy (pemetrexed/docetaxel) is underway (PROFILE 1007, NCT00932893). KRAS, EGFR mutations and ALK translocations are mutually exclusive and few EGFR WT NSCLCs respond to EGFR TKIs. The promising results of EGFR and ALK TKIs in molecular subgroups of NSCLCs herald a new age of drug and clinical trial development for patients with NSCLC.
非小细胞肺癌（NSCLC）是一种异质性癌症。2004 年，表皮生长因子受体（EGFR）体细胞突变的鉴定首次揭示了一种具有临床相关性的 NSCLC 致癌基因。大约 70%的 EGFR 突变（外显子 19 缺失或外显子 21 L858R）的 NSCLC 对 EGFR 酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼有反应，与 EGFR 野生型（WT）病例相比，反应率（RR）、无进展生存期（PFS）以及在一些报告中的总生存期（OS）得到改善。三项吉非替尼对比化疗（IPASS、WJTOG3405、NEJ002）的 IV 期 NSCLC 随机试验一致表明，EGFR 突变的 NSCLC 患者接受吉非替尼治疗时，RR 和 PFS（IPASS 为 0.48、WJTOG3405 为 0.49、NEJ002 为 0.30）更好。新型不可逆的 EGFR TKI（阿法替尼、XL647、PF00299804）在 EGFR 突变患者中显示出相似的活性。2007 年鉴定出的涉及间变性淋巴瘤激酶（ALK）基因与 EML4 的易位，是 NSCLC 中最近发现的致癌基因。ALK TKI 克唑替尼（PF02341066）在一项 I 期试验的扩展队列中对 ALK 转位 NSCLC 显示出令人印象深刻的活性（NCT00585195）。已有超过 80 名患者接受治疗，RR 约为 60%，6 个月 PFS 率超过 70%。一项克唑替尼对比二线化疗（培美曲塞/多西他赛）的注册 III 期试验正在进行中（PROFILE 1007，NCT00932893）。KRAS、EGFR 突变和 ALK 易位是相互排斥的，很少有 EGFR WT NSCLC 对 EGFR TKI 有反应。EGFR 和 ALK TKI 在 NSCLC 分子亚群中的有前途的结果预示着 NSCLC 患者的药物和临床试验开发的新时代的到来。
