Oncology Department, University Hospital Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, CH, Switzerland.
Oncology Department, San Luigi Hospital University of Turin, Orbassano, Turin, Italy.
Crit Rev Oncol Hematol. 2018 Feb;122:150-156. doi: 10.1016/j.critrevonc.2017.12.015. Epub 2017 Dec 30.
The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of its oral tyrosine kinase inhibitor (TKI). Crizotinib was the first ALK inhibitor approved and utilised in the treatment of ALK+ NSCLC patients in the second line setting first and subsequently in the first line one. Since then many other ALK inhibitors have been developed (ceritinib, alectinib, brigatinib, lorlatinib,etc) and the treatment paradigm of these patients has considerably drifted. The questions regarding their treatment at progression remains unanswered at the moment.
Our review clarifies what it is the state of the art in the treatment of ALK rearranged NSCLC patients, highlights the mechanisms of primary and secondary resistance mutations and suggests a treatment algorithm based on specific primary resistance or acquired mutations.
Studies that enrolled ALK+ NSCLC patients with locally advance or metastatic disease receiving treatment with ALK inhibitor, first or second line, were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library). Trials were excluded if they were phase 1, enrolled less than 10 patients.
Overall 1942 patients were included in our review. It confirms the role and the efficacy in first line of Alectinib but it highlights also that all the ALK inhibitors could play a crucial role during the patients' journey. Identifying the different mutations and utilising the most active ALK inhibitor depending on the "up-to-date" driven mutation is the way forward in the management of those patients.
the review shows the rapid drifting in the management of ALK+ NSCLC patients and the importance of fully understanding and acknowledging the role of the resistance mutation, primary or acquired. We strongly advocate a comprehensive genomic approach in the management of ALK+ NSCLC patients who develop resistance mutations that are still targetable by a different ALK inhibitor.
在 2-5%的非小细胞肺癌 (NSCLC) 患者中鉴定出间变性淋巴瘤激酶 (ALK) 重排，导致其口服酪氨酸激酶抑制剂 (TKI) 的快速临床开发。克唑替尼是第一个被批准并用于二线治疗 ALK+ NSCLC 患者的 ALK 抑制剂，随后也用于一线治疗。此后，许多其他 ALK 抑制剂已经开发出来（塞瑞替尼、阿来替尼、布加替尼、劳拉替尼等），这些患者的治疗模式发生了很大变化。目前，关于他们进展时的治疗问题仍未得到解答。
我们的综述阐明了 ALK 重排 NSCLC 患者治疗的最新进展，强调了原发性和继发性耐药突变的机制，并根据特定的原发性耐药或获得性突变提出了治疗算法。
使用电子数据库（MEDLINE、EMBASE 和 Cochrane 图书馆）确定了接受 ALK 抑制剂一线或二线治疗的局部晚期或转移性 ALK+ NSCLC 患者的研究。如果试验为 1 期、纳入的患者少于 10 人，则将其排除在外。
总共纳入了 1942 名患者。这证实了阿来替尼在一线治疗中的作用和疗效，但也强调了所有的 ALK 抑制剂在患者的治疗过程中都可能发挥关键作用。根据“最新”驱动突变，识别不同的突变并使用最有效的 ALK 抑制剂是管理这些患者的未来方向。
该综述显示了 ALK+ NSCLC 患者管理的快速变化，以及充分理解和承认原发性或获得性耐药突变作用的重要性。我们强烈主张对发生仍可被不同 ALK 抑制剂靶向的耐药突变的 ALK+ NSCLC 患者采用全面的基因组方法进行管理。
