Next-Generation Sequencing Reveals a Novel NSCLC ALK F1174V Mutation and Confirms ALK G1202R Mutation Confers High-Level Resistance to Alectinib (CH5424802/RO5424802) in ALK-Rearranged NSCLC Patients Who Progressed on Crizotinib

• Published in: Journal of thoracic oncology Vol. 9; no. 4; pp. 549 - 553
• Main Authors: Ou, Sai-Hong Ignatius, Azada, Michele, Hsiang, David J., Herman, June M., Kain, Tatiana S., Siwak-Tapp, Christina, Casey, Cameron, He, Jie, Ali, Siraj M., Klempner, Samuel J., Miller, Vincent A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Alectinib; ALK F1174V; ALK G1202R; ALK-rearranged NSCLC; Carbazoles - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Crizotinib resistance; Drug Resistance, Neoplasm - genetics; Female; Gene Rearrangement - genetics; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; Mutation - genetics; Neoplasm Staging; Next-generation sequencing; Piperidines - therapeutic use; Prognosis; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - genetics; ALK F1174V; ALK G1202R; Alectinib; Next-generation sequencing; ALK-rearranged NSCLC; Crizotinib resistance
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0000000000000094

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non–small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.