The anaplasticlymphomareceptortyrosinekinase (ALK) gene is located on the short arm of chromosome 2 (223) and encodes a transmembrane receptor tyrosine kinase. This kinase, consisting of 1620 amino acids, belongs to the insulin receptor superfamily and plays an important role in the development of the central nervous system. the ALK gene is found in a range of malignancies including non-small cell lung cancer, mesenchymal large cell lymphoma and neuroblastoma, with rearrangements, point mutations or amplifications. Of these, chromosomal rearrangements resulting in fusions with other genes to produce ALK fusion mutations are most common. the incidence of ALK fusion genes in the total population is 3-7%. In non-small cell lung cancer, ALK genes can fuse with EML4 genes, but also with other genes including TFG, KIF5B, KLC1, DCTNI, SQSTM1, BIRC6, HIP1, TPR and PTPN3, and each fusion gene has different forms of fusion. The incidence of ALK fusion mutations is relatively low, and the use of the corresponding targeted drugs can achieve better efficacy and longer survival, so ALK fusion mutations are called “diamond mutations”. ALK inhibitors from the first generation of crizotinib 2011 market, after 10 years of development, is now the third generation of lauratinib marketed, including: a generation: ① crizotinib; second generation: ② aletinib (also known as erlotinib), ③ ceritinib (also known as: ceritinib), ④ enzatinib (domestic), ⑤ brigatinib; third generation: ⑥ lauratinib. Now we introduce the development history of the above targeted drugs with you. ①Crizotinib: Applicable to ALK fusion gene or ROS1 fusion gene positive locally advanced or metastatic non-small cell lung cancer. Crizotinib, a first-generation targeted agent developed by Pfizer, is the world’s first ALK kinase inhibitor and a targeted agent for ROS1 fusion gene-positive non-small cell lung cancer. Crizotinib has been shown to be more effective and less toxic than chemotherapy in the Profile1007, Profile1014 and PROFILE1029 studies. In the Profile1007 study, 173 patients were treated with crizotinib and 174 patients were treated with chemotherapy, comparing progression-free survival and objective remission rates between the two groups. All patients were treated with platinum-based drugs. The trial results showed that the median progression-free survival (PFS) was 7.7 months in the crizotinib group and 3 months in the chemotherapy group; the objective remission rate (ORR) was 65% in the crizotinib and 20% in the chemotherapy group. In the Profile1014 study, the median progression-free survival (PFS) for 172 patients treated with crizotinib was 10.9 months, with an objective remission rate (ORR) of 74%; the median progression-free survival (PFS) for 171 patients treated with pemetrexed plus platinum (cisplatin or carboplatin) was 7 months, with an objective remission rate (ORR) of 45%. The PROFILE1029 trial is a randomized, open, two-arm phase III clinical study of crizotinib in patients with ALK-positive advanced NSCLC, and this study has essentially the same design as the previous phase III clinical study, PROFILE1014. The difference is that the population enrolled in PROFILE1029 is all East Asian (with the majority of the Chinese population), thus providing more guidance for the treatment of disease in the East Asian population. The study showed significant efficacy of crizotinib first-line therapy compared to standard platinum-containing chemotherapy in terms of progression-free survival (PFS) and objective remission rate (ORR) in ALK+ advanced NSCLC patients (median PFS 11.1 months vs. 6.8 months, P<0.0001; objective remission rate (ORR) 88% vs. 46%, P<0.0001), and that Asian population had more benefit for first-line treatment with crizotinib, suggesting that crizotinib is more preferable for first-line treatment in ALK-positive NSCLC advanced Asian patients. The most common adverse events in the crizotinib group included visual disturbances, diarrhea, nausea, and edema. The most common adverse events in the chemotherapy group were nausea, malaise, vomiting, and decreased appetite. Compared with chemotherapy, crizotinib significantly reduced symptoms associated with lung cancer and substantially improved quality of life. ②Aletinib: Indicated for the treatment of ALK-positive patients with locally advanced or metastatic NSCLC. The ALEX study is a large, global, multicenter, phase III clinical study, a hard-bar head-to-head clinical study to compare the efficacy and safety of aletinib and crizotinib in the first-line treatment of patients with advanced ALK-positive non-small cell lung cancer. The study enrolled 303 patients in 161 centers in 31 countries worldwide, randomized 1:1 to receive either alectinib 600 mg BID (n=152) or crizotinib 250 mg BID (n=151). The final PFS in the aletinib group was 34.8 months, 3-fold higher than that of crizotinib at 10.9 months. The 5-year survival rate in both groups was better in the alaitinib group than the crizotinib group data (62.5% vs. 45.5%). OS in the crizotinib group was 57.4 months, and median OS in the alaitinib group remained immature, suggesting that it would be substantially better than crizotinib. For patients with brain metastases at baseline, the aletinib treatment group showed a survival benefit with a 42% reduction in the risk of death compared to the crizotinib group. In patients with measurable lesions, the proven intracranial remission rates were 81% versus 50%, respectively. The incidence of grade 3 to 5 adverse events was lower in the aletinib group (41% in the aletinib group versus 50% in the crizotinib group). On April 8, 2019, the results of the ALESIA study for Asian patients with ALK-positive NSCLC, led by Professors Cai-Cun Zhou and Tension in China and published in The LancetRespiratoryMedicine, a subjournal of The Lancet, also replicated the results of the ALEX study. Based on these findings, guidelines including NCCN/ESMO/CSCO have made aletinib a priority recommendation for ALK-positive patients with locally advanced or metastatic NSCLC. ③Ceretinib: It is indicated for the treatment of ALK-positive, ROS1-positive patients with locally advanced or metastatic NSCLC. In the ASCEND series, of which the results of the ASCEND-4 and ASCEND-8 studies established ceritinib's status in the first-line treatment of ALK-positive advanced non-small cell lung cancer, the ASCEND-4 clinical was a clinical phase III trial involving a total of 376 patients with advanced ALK-positive NSCLC in 28 countries (including China), with patients randomly assigned 1:1 to receive cretinoin or platinum-based chemotherapy. The results showed that in the population used, progression-free survival (PFS) was 16.6 months in the cretinoin group compared to 8.1 months in the chemotherapy group. In the subgroup, the PFS in the cretinoin group was 26.3 months, which was much higher than the 10.6 months in the chemotherapy group. However, in the ASCEND-4 clinical study, ceritinib was administered at 750 mg on an empty stomach, and its highly effective antitumor effect was accompanied by significant gastrointestinal (GI) adverse effects. How to achieve high efficiency and low toxicity is the focus of research on ceritinib. To address this issue, the ASCEND-8 clinical study was conducted to compare the efficacy and side effects of ceritinib at low doses and to verify whether the efficacy of ceritinib would be affected after dose reduction. The study enrolled 306 advanced ALK-positive patients in three groups treated with cretinoin 450 mg with meals, 600 mg with meals and 750 mg on an empty stomach to observe the efficacy and safety of the different groups. Clinical results: As a first-line drug, the objective remission rate (ORR) was comparable in the three groups of patients with 450 mg with meals, 600 mg with meals and 750 mg on an empty stomach, 78.1%, 72.5% and 75.7%, respectively. After dose reduction, cretinib PFS was, respectively, not achieved, 17.0 months and 12.2 months in the three groups of patients, with an improvement in efficacy seen instead after dose reduction, which may be related to fewer side effects in the 450 mg with meals group. After cretinoin was adjusted to 450 mg/day with meals, only one patient experienced dose adjustment due to gastrointestinal adverse effects (vomiting), and no patient discontinued the drug due to gastrointestinal toxicity. ④Ensatinib: indicated for the treatment of ALK-positive patients with locally advanced or metastatic NSCLC. The eXalt3 study is a global open multicenter randomized controlled phase III first-line clinical study. The experimental arm was an enzatinib 225 mg QD regimen until disease progression; the control arm was a crizotinib 250 mg BID regimen until disease progression, with no crossover allowed between the two arms. The progression-free survival (PFS) data IRC assessment update was 31.3 months for the ITT population in the enzatinib group and 12.7 months for the ITT population in the control crizotinib group, with an HR of 0.50 (95% CI 0.36-0.71; P<0.0001). mITT population PFS data IRC assessment results have not been reached. Study results were published in JAMAOncology. ⑤ Bugatinib: indicated for the treatment of patients with disease progression or intolerance to its toxicity after treatment with crizotinib and intermittent lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). ALTA-1L study: 275 patients with advanced, untreated ALK-positive NSCLC treated with targeted agents, distinguishing between patients with baseline brain metastases and prior chemotherapy. Randomized by proportion, 137 patients received once-daily 180 mg brigatinib (starting at 90 mg and reaching 180 mg within 7 days) and 138 patients received twice-daily 250 mg crizotinib. -BIRC assessment: progression-free survival PFSHR of 0.48 (95% CI: 0.35-0.66, P<0.0001); median progression-free survival (mPFS) of 24.0 months (95% Cl: 18.4-43.2) for bucatinib versus 11.1 months (95% Cl: 9.1- 13.0); 3-year survival (bucatinib/ crizotinib) 43%/19%. (vi) Lauratinib: for the treatment of patients with ALK-positive metastatic non-small cell lung cancer whose disease has progressed after treatment with crizotinib and at least one other ALK inhibitor, or who have received aletinib or ceritinib as the first ALK inhibitor but whose disease has progressed. CROWN study: This study included patients aged ≥18 or 20 years (depending on region) with histopathologically or cytopathologically confirmed locally advanced/metastatic non-small cell lung cancer and carrying an ALK fusion.ALK fusion was based on immunohistochemical detection (D5F3 antibody) and patients with asymptomatic brain metastases or stable brain metastases were allowed to be enrolled. Patients meeting the enrollment criteria were randomized in a 1:1 ratio to treatment with either loratinib 100 mg orally once daily or crizotinib 250 mg orally twice daily. The primary study endpoint was median PFS as assessed by an independent review committee. Data from the CROWN study were updated at this year's AACR annual meeting, and the median follow-up for the entire group was 36.7 months, which is more than 3 years. The objective remission rates (ORR) assessed by the independent review committee were 77.2% and 58.5%, respectively, with a median progression-free survival (PFS) of 9.3 months in the crizotinib group, while still not achieved in the loratanib group, with PFS rates of 63.5% and 18.9% at 36 months in the two groups (HR=0.27), respectively. For patients with brain metastases at baseline, the median PFS was 7.2 months and not reached in the two groups, HR=0.21, respectively; for patients without brain metastases, the median PFS was 11.0 months and not reached in the two groups, HR=0.29. It also means that the median PFS with first-line use of loratinib is well over 36 months, which is the longest PFS to date for lung cancer treated with a single drug. Although ALK inhibitors can be switched to second-generation after the emergence of resistance in the first generation, and to third-generation inhibitors after the emergence of resistance in the second generation. However, overall, first-line treatment with ALK inhibitors results in longer progression-free survival, which is why this presentation focuses on first-line treatment. ALK inhibitors, especially second-generation drugs, are already blossoming, and the efficacy of the national light, enzatinib, is no less than that of aletinib. At present, the approved ALK-targeted drugs in China are: crizotinib, ceritinib, aletinib, and enzatinib, which can meet the needs of most patients with ALK gene fusion mutations. In the case that the third generation ALK inhibitors have not been approved in China, the second generation ALK inhibitors will be the preferred choice for patients with ALK fusion mutations. The research on the first-line treatment of ALK inhibitors described above truly reflects the fact that the wave after the Yangtze River pushes the wave before it, and the wave before it is stronger than the wave before it, and only Crizotinib knows whether the wave before it has been slapped on the beach. It is the happiness of doctors and the well-being of patients to see the continuous progress of medicine and the continuous development of drugs.