Crizotinib for the Treatment of ALK‐Rearranged Non‐Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology

• Published in: The oncologist (Dayton, Ohio) Vol. 17; no. 11; pp. 1351 - 1375
• Main Authors: Ou, Sai‐Hong Ignatius, Bartlett, Cynthia Huang, Mino‐Kenudson, Mari, Cui, Jean, Iafrate, A. John
• Format: Journal Article
• Language: English
• Published: Durham, NC, USA AlphaMed Press 01-11-2012
• Subjects: Academia-Pharma Intersect; Adult; Aged; Aged, 80 and over; ALK inhibitor; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Chromosomal rearrangements; Crizotinib; Drug Interactions; Female; Gene Rearrangement; Genetic Variation; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; MET inhibitor; Middle Aged; Molecular Targeted Therapy; Non‐small cell lung cancer (NSCLC); Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Pyrazoles - adverse effects; Pyrazoles - metabolism; Pyrazoles - therapeutic use; Pyridines - adverse effects; Pyridines - metabolism; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor tyrosine kinase fusion positive malignancies; ROS1 inhibitor; Signal Transduction - genetics; Young Adult
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2012-0311

Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK‐rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK‐rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1‐rearranged NSCLC, with potential future clinical applications in ROS1‐rearranged tumors. Here we summarize the heterogeneity within the ALK‐ and ROS1‐rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK‐rearranged NSCLC and the diagnostic assays to detect ALK‐rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular‐defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.
摘要
克唑替尼，一种ALK/MET/ROS1抑制剂，于2011年8月，即间变性淋巴瘤激酶（ALK）重排的非小细胞肺癌（NSCLC）首次公布仅4年后，由美国食品和药物管理局（FDA）批准用于治疗ALK重排的NSCLC。与此同时，还批准了作为ALK伴侣诊断的荧光原位杂交法，用于检测 ALK重排的NSCLC。随后，克唑替尼又继续被开发为用于治疗ALK和MET改变驱动的其他肿瘤类型的ALK和MET抑制剂。最近已经证实克唑替尼是治疗ROS1重排的NSCLC的一种有效的ROS1抑制剂，并且未来可能临床应用于ROS1 重组肿瘤的治疗。本文总结了NSCLC的ALK和ROS1重排的分子亚型的异质性。我们回顾和展望用于治疗ALK重排的NSCLC的克唑替尼的临床开发以及检测ALK 重排的NSCLC的诊断方法。着重介绍了克唑替尼如何成功的通过靶向作用于罕见的NSCLC的特定分子亚型，从而改变用于靶向治疗的未来药物的研发模式，以及它强调临床肿瘤学家，病理学家，和转化科学家之间的密切合作，从而影响了肿瘤的个体化给药治疗方案。
This review discusses how crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular‐defined subtype of non‐small cell lung cancer and affected the practice of personalized medicine in oncology.