Gristina Valerio, La Mantia Maria, Iacono Federica, Galvano Antonio, Russo Antonio, Bazan Viviana
Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.
Pharmaceuticals (Basel). 2020 Dec 18;13(12):474. doi: 10.3390/ph13120474.
The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.
在过去十年中，转移性非小细胞肺癌（NSCLC）的治疗发生了范式转变。对该疾病更好的分子特征分析推动了个性化医疗的迅速发展，并促使向NSCLC患者迅速提供靶向治疗。在一小部分受NSCLC影响的患者中发现EML4-ALK融合基因，以及随后在2011年克唑替尼的临床研发，是肺癌研究中一个令人瞩目的里程碑。不幸的是，获得性耐药经常出现，从而导致疾病进展。之后，现代酪氨酸激酶抑制剂（TKIs），如色瑞替尼、阿来替尼、布加替尼和劳拉替尼，已获美国食品药品监督管理局（FDA）批准用于治疗间变性淋巴瘤激酶（ALK）阳性的NSCLC。目前正在研究几种化合物以实现最佳治疗策略。此外，新一代TKI正在进行的临床试验结果将为ALK阳性NSCLC患者的最佳治疗顺序提供更多证据。在本综述中，我们全面概述了ALK阳性NSCLC中最新的靶向治疗选择。对耐药性、克服耐药性的潜在治疗策略以及该类患者的未来前景进行了批判性分析和总结。
