Echinoderm microtubule-associated protein-like 4 (EML4)-encoded protein N-terminally partially fused to the intracellular tyrosine kinase structural domain of mesenchymal lymphoma kinase (ALK) rearranges to EML4-ALK, resulting in aberrant tyrosine kinase expression.EML4-ALK rearrangement fusion was first detected by Soda in 2007 in postoperative specimens from patients with non-small cell lung cancer. In unselected NSCLC, EML4-ALK positive detection rate is low, about 1.5-6.7%. Shaw et al. showed that the proportion of EML4-ALK fusions increased in populations with limited screening conditions, such as non-smokers or those with only a small amount of smoking and no EGFR mutations, with an EML4-ALK positivity rate as high as 33%, which is the highest EML4-ALK detection rate reported to date. The results of this study suggest that these aforementioned EGFR-TKIs treatment-advantaged but insensitive populations substantially harbor novel molecular events. The results of the phase I clinical study reported at the 2010 ASCO meeting showed that 82 patients with NSCLC with EML4-ALK fusion treated with Crizotinib (250 mg, bid) showed tumor shrinkage in 90% and objective remission in 57% of patients. patients who received Crizotinib had a 1-year survival rate of 77% and a 2-year survival rate of 64%, with a median OS not yet reached. Given this unimpressive efficacy and mild side effects, the discovery and therapeutic breakthrough of EML4-ALK fusion was named one of the top 10 advances in clinical oncology in 2011, and the FDA approved Crizotinib for the treatment of NSCLC patients with ALK fusion on August 26, 2011. One of the 2012 NCCN updates is that for non-squamous NSCLC patients, EML4-ALK testing is recommended for first-line treatment and if positive, Crizotinib is recommended for treatment. cases, with a positive rate of 20.8% (818/3927). Updated efficacy and safety data were reported at this year’s ASCO annual meeting: median treatment period of 25 weeks, ORR of 53%, DCR of 85% at 12 weeks, and median PFS of 8.5 months. Common adverse reactions were visual abnormalities (50%), nausea (46%), vomiting (39%), and diarrhea (35%, mostly grade 1-2). Crizotinib treatment was continued after PD in 146 patients patients, mostly with progression of single organ lesions. 53% of patients were treated with crizotinib for more than 2 weeks after PD, with a median post-PD treatment duration of 10 weeks, and most patients had good physical status. Targeted agents and intensified localized lesion treatment after progression is a sign of “individualized therapy” from which patients can still benefit. Ryohei Katayama et al. analyzed the mechanisms of resistance to ALK inhibitors: this study examined molecularly 18 specimens from patients with crizotinib resistance and found that resistance was associated with mutations in a number of different kinase regions, including: ALK fusions copy number gain (CNG), reappearance of proto-oncogene expression in the same cell, or detection of proto-oncogene in different cells. Overcoming or reversing resistance requires distinguishing whether resistance is associated with secondary mutations or copy number gain in the ALK region or with primary or secondary proto-oncogene driver expression. Researchers are actively searching for new drugs that can reverse resistance to ALK inhibitors, and LDK378 is expected to be one of them. ranee Mehra reported a phase I clinical study: 56 patients (ALK-positive patients with various types of solid tumors, including lung cancer) were given LDK-378 after previous treatment failure to assess its safety, tolerability and initial efficacy. The results were encouraging: the dose of LDK-378 was escalated from 50 mg/d to 750 mg/d, and the majority of patients were able to tolerate 750 mg/d. The major adverse events were mild nausea (59%), vomiting (54%), diarrhea (48%), malaise (21%), and dyspnea (12%). Serious adverse events included elevated transaminases, vomiting, dehydration, and interstitial lung disease, one case each, which resolved after discontinuation of the drug. The median age of this subset of patients was 53 years (22-78), 66% were female, 89% had NSCLC, 7% had breast cancer, and 4% had other types of tumors. Cycles of treatment ranged from 1-53 weeks, with 64% of patients still on treatment. Sixty-six percent of the patients had received prior treatment with Crizotinib. Of note, 26 patients with NSCLC previously treated with Crizotinib were given LDK378 (400 mg/d or higher) with an overall efficacy rate of 81%. A total of 33 NSCLC patients treated with at least 400 mg/d of LDK378 had an objective remission rate of 67% and was also effective in brain metastases at the maximum tolerated dose of 750 mg/d, but this significant efficacy was not observed in other tumor types. The results of this study are expected to partially resolve the treatment dilemma in ALK-positive patients after the emergence of drug resistance, and larger clinical studies are expected.