Throughout the process from ALK fusion gene discovery to ALK inhibitor application in the clinic, the years from 2005 to 2015 give the impression of being very short, but how much time and work we actually accumulated. Moreover, studies on ALK were published in very heavyweight journals, four of which were published in the New England Journal. 2011 saw the FDA approval of crizotinib for ALK-positive non-small cell lung cancer, and two years later it entered the Chinese market in 2013, and the reason why the speed is so fast is that it draws on the clinical application process of EGFR TKIs. There are many ongoing studies on ALK inhibitors, such as Profile 10011, Profile 10052 and 8 others, as well as the China-focused study PROFILE 1029, and we look forward to the results. The following questions need to be answered in clinical practice: first-line or second-line use? There are two large clinical trials on first-line use or second-line use, Profile 10073 and Profile 10144, with crizotinib in second line in the former and crizotinib in first line in the latter; the former with 65% efficiency and the latter with 74% efficiency; the former with a median survival time of 7.7 months and the latter with a median survival time of 10.9 months. Although it was not a head-to-head clinical trial, numerically it was a little better to use it in first line. We summarized the data from our hospital from participation in clinical trials to clinical practice, and analyzed them to conclude that ALK is slightly different from EGFR, and that first-line treatment with ALK inhibitors is better than second-line treatment. Therefore, we recommend that in clinical practice, if a patient is ALK positive, we first consider using ALK inhibitors rather than chemotherapy and other treatments. Do different variants of ALK have different efficacy? Several EML4-ALK fusion variants have been identified and shown to be functionally active in non-small cell lung cancer. In our study, we analyzed the frequency of ALK variant distribution in 61 positive patients and found that the V1 variant accounted for 36%, V3a/b variant for 30%, V2 variant for 11%, V7 for 13%, and other variants for a total of 6%. There are three commonly used methods to detect ALK: FISH, IHC and RT-PCR, but only by RT-PCR can the different variants be distinguished. The analysis revealed that there was little difference between the variants in terms of the efficiency of each variant on crizotinib treatment; there was no significant difference between the variants that accounted for a larger proportion of the PFS of patients treated with crizotinib. Does the efficacy of ALK differ by ALK abundance? ALK abundance is receiving increasing attention, and we currently believe that differences in the abundance of targeted therapies can lead to differences in treatment sensitivity. We look at ALK-positive cells, which are defined by the FISH assay as 13% positive, but we believe that the percentage distribution of ALK-positive cells is likely to be measured by abundance in the future. In another way, we plotted the percentage of ALK-positive cells against crizotinib and found that the higher the abundance, the better the treatment effect, and the lower the abundance, the worse the treatment effect. Although 13% was selected by the FISH assay as a criterion to determine positivity, we had two patients with positive cell counts of 11% and 12% who had a median survival time of one or two months less after crizotinib treatment than the other patients, but there was no statistical difference. Do ALK inhibitors treat brain metastases? Brain metastases have become a very difficult problem for targeted therapy, and statistics tell us that 50% of patients develop brain metastases over the course of their disease as they live longer. So how effective are ALK inhibitors for brain metastases? This year our 1014 study at WCLC reported the efficacy of crizotinib after first-line treatment for brain metastases: median PFS was 10.9 months and 7.0 months for the total population studied, first-line crizotinib compared to chemotherapy; median PFS was 9.0 months and 4.0 months for patients with brain metastases studied, first-line crizotinib compared to chemotherapy; patients without brain metastases In patients without brain metastases, the median PFS was 11.1 months and 7.2 months for first-line crizotinib versus chemotherapy. When we put the three groups together we find that if a patient starts with brain metastases, it is a very bad situation to apply chemotherapy and the first thing we should do is apply crizotinib. This trial tells us that crizotinib has the same effect as the first generation EGFR TKIs, that is, it has a better effect on brain metastases. This year’s ASCO reported the efficacy of another ALK inhibitor, alectinib, on brain metastases, and from this trial we see that this drug has a better effect on brain metastases, and we also see that the efficacy of different ALK inhibitors on brain metastases is different. Therefore, we can conclude that crizotinib can be used in patients with brain metastases. Can ALK inhibitors continue to be used after imaging progression? In a trial published in WCLC in 2013 on the continued use of crizotinib after PD in patients, one group of patients continued to use it after progression and the other group stopped using it after progression. The results suggest that we should not easily stop crizotinib just because the tumor markers are higher or the mass is larger, but we can still continue to use it. What else can be done with ALK in the future? Can crizotinib be used for postoperative adjuvant therapy? The NCCN is leading an ALCHMIST clinical trial to explore the feasibility of two-year targeted adjuvant therapy with erlotinib or crizotinib in EGFR or ALK-positive patients, respectively, after surgery, to screen 6,000 to 8,000 patients, and we look forward to the results. A new generation of overcoming drug-resistant ALK inhibitors is currently under development and is developing very rapidly. ALKoma can be understood as crizotinib is effective no matter which tumor is positive for ALK and is the driver gene. The characteristics are: multiple tumors are present; all are driver genes; and uniform drug is effective. So far we have found ALK gene fusions in 13 tumors including lymphoma, leukemia, neurological tumors, sarcoma, etc. And ALK mutations or amplifications have been found in 8 tumors. So can crizotinib be applied to treat all tumors? The answer is that multiple tumors share the same driver gene and the relevant inhibitor treatment is effective. Tumor driver gene commonality: tumor growth is closely related to gene variants; gene variant pattern (tyrosine kinase abnormally active): mutation, fusion gene, amplification, overexpression; the same inhibitor is effective in treating the same gene variant in different tumors. As an example, let’s look at BRAF mutations. We find BRAF mutations present in many tumors, such as lung cancer, melanoma, colon cancer, thyroid cancer, hairy cell leukemia, etc. So is it possible that BRAF inhibitors are effective against them? just published in the journal New Ingra answers this question and the answer is yes. The future outlook is that tumors will be classified according to driver genes: ALK-positive tumors; EGFR-positive tumors; HER2-positive tumors; BRAF-positive tumors, etc. Conclusion First-line or second-line use? The answer is first-line; do different variants of ALK have different efficacy? The answer is the same; does the efficacy of ALK variants differ by abundance? The answer is that it may be different; do ALK inhibitors treat brain metastases? The answer is yes; can ALK inhibitors be continued after imaging progression? The answer is yes. The mechanism of progression is more complex. akloma becomes the paradigm.