Santarpia Mariacarmela, Altavilla Giuseppe, Rosell Rafael
Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy.
Expert Rev Respir Med. 2015 Jun;9(3):255-68. doi: 10.1586/17476348.2015.1009040. Epub 2015 Feb 5.
Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. In a Phase I/II study from Japan, alectinib was found to be highly active and safe in crizotinib-naïve, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.
克唑替尼是首个可用于临床的间变性淋巴瘤激酶（ALK）抑制剂，对ALK重排的非小细胞肺癌（NSCLC）显示出显著活性。尽管初始反应良好，但对克唑替尼不可避免地会产生获得性耐药，脑是常见的复发部位。阿来替尼是一种高度选择性的新一代ALK抑制剂，对赋予克唑替尼耐药性的ALK突变也具有强效抑制活性，包括守门人L1196M替代突变。在日本的一项I/II期研究中，发现阿来替尼在未接受过克唑替尼治疗、ALK重排的NSCLC患者中具有高活性且安全性良好。阿来替尼在克唑替尼耐药患者中也显示出有前景的抗肿瘤活性，包括那些有中枢神经系统转移的患者。基于这些数据，该药物获得了美国食品药品监督管理局（FDA）的突破性疗法认定，并且最近在日本被批准用于治疗ALK阳性的晚期NSCLC患者。然而，患者最终可能会对阿来替尼产生耐药，这凸显了需要新的治疗策略来进一步改善ALK重排NSCLC的治疗管理。
