“…A series of clinical response data, including PROFILE 1001 (phase I, 2008), PROFILE 1005 (phase I/II, 2011), PROFILE 1007 (phase III, 2012), and PROFILE 1014 (phase III, 2014), confirmed that 1 is superior to the standard chemotherapy (pemetrexed or docetaxel) in the treatment of advanced or metastatic EML4-ALK NSCLCs, − which led to the approval of 1 for the treatment of ALK-positive NSCLC in 2011. In addition, compound 1 also shows excellent efficacy in ALK-positive IMTs and Kelly neuroblastomas induced by gene amplification and/or mutations. , Unfortunately, the success of 1 was overshadowed by the rapid emergence of drug resistance. , The most frequently acquired mutations are L1196M, C1156Y, G1202, and G1269A/S (Figure B). Moreover, the 1151Tins, L1152R, I1171T/N/S, F1174 V/L/C, G1202R, D1203N, S1206Y, and V1180L mutations were also reported to be able to confer resistance to 1 (Figure A).…”