What kind of surprises will be brought by upgrading 3 generations of "ALK inhibitor family" after 10 years?

Wen / Yaolung cancer, regardless of incidence rate or mortality rate, is the largest cancer in the world80-85% is NSCLC and NSCLC is targeted therapy, the most important is EGFR inhibitor; another major mutation is NSCLC, the target is anaplastic lymphoma kinase, which is ALK fusion base positive; ALK inhibitor has been developed for 10 years and has been upgraded for three generationsWhat kind of support did these three generations of alk-tkis provide for human treatment in the past 10 years? What will happen in the future? What is the momentum of imitation innovation at home and abroad? Please read this article< br / > in 1994, it was found that ALK fusion gene in anaplastic large cell lymphoma had carcinogenic characteristics; in 2007, it was found that ALK gene rearrangement was the first time in lung adenocarcinoma tumor tissueExon 1-13 of EML4 gene fused with exon 20-29 of ALK gene to form EML4-ALK fusion gene< br / > in 2006, the first listed drug of ALK, clozatinib, carried out phase I clinical trials; in 2011, FDA accelerated the approval of clozatinib for the treatment of ALK fusion positive NSCLC< br / > < br / > Fig1.1: ALK and its first inhibitor development timeline < br / >< br / >, It has been approved in the United States (August 2011), China (January 2013), Japan (March 2012), Europe (October 2012) and other countries and regions for the treatment of local advanced or metastatic NSCLC with ALK positive< br / >PS: in the domestic drug market, clozatinib has decreased from 5W yuan / bottle to nearly 1.5W yuan / bottle< br / > apart from the approval of Pfizer's original research varieties, only Zhengda Tianqing has registered and applied to copy the domestic registration and application of this variety< br / > at present, there are few studies on primary drug resistance of clozatinibGenerally speaking, patients who have progressed within 3 months are regarded as primary drug resistance, while secondary drug resistance mutations account for about 37% of the problem of clozatinib resistance, mainly including ALK kinase mutations and the expansion of ALK gene copy number, that is, the so-called ALK pathway is dominant drug resistance< br / > the mechanism of drug resistance of ALK kinase mutations is relatively clearThe mutation types include: g1269a, f1174l, l1152r, s1206y, i152tins, p1203n, v1180l, c1156y, f1164v, g1202r, g1269s, l1196m, of which g1269a and l1196m are the most common < br / > after the emergence of the drug resistance problem of clozatinib, the development strategy will naturally target the second and third generations of drugs At present, the second generation of alk-tki listed drugs include seretinib, aleutinib, bugotinib and loratinib, but it does not solve all the drug resistance problems, For example, g1202r and f1174l are the most common drug-resistant mutations of certifinib; i1171 and v1180l are the common mutations of alectinib; l1198f is the drug-resistant mutations of loratinib, etc < br / > < br / > Figure 3.1: drug resistance and sensitive mutation points (S-sensitive; r-resistant; u-uncertain) of five ALK inhibitors < br / > < br / > < br / > ceritinib, developed by Novartis, has a titer 20 times higher than that of clozatinib It is clinically used in the treatment of metastatic NSCLC patients with worsening condition or intolerance to clozatinib, And has been approved for the first-line treatment of ALK positive patients with advanced NSCLC The results of the ALK positive cell line model showed that seretinib could effectively inhibit the ALK mutations related to the acquired resistance of clozatinib, including l1196m, g1269a, i1171t and s1206y, but had no effect on g1202r and f1174c mutations PS: seretinib can pass through the blood-brain barrier, and patients with brain metastasis will benefit relatively The product has been approved by FDA (April 2014), EMA (may 2015), PMDA (March 2016) and nmpa (June 2018) < br / > in terms of global sales, the global sales of the product was less than US $100 million in the first three years before its launch As a "substitute" for clozatinib, it did not go well in the drug market < br / > in terms of domestic registration application, Zhengda Tianqing still applies for the development of varieties in this field In addition, domestic pharmaceutical enterprises such as Jichuan pharmaceutical, Nanjing Huawei, Shanxi Zhendong, Beijing kanglisheng, Jiangsu aosaikang, Jiangsu Wanbang, and Shiyao Zhongqi apply for the imitation of the varieties; however, they have not yet been mass produced < br / > < br / > The product has been approved by PMDA (July 2014), FDA (December 2015), EMA (February 2017) and nmpa (August 2018) < br / > in terms of global sales, the overall sales volume has been on the rise in the past five years In 2019, the global sales volume is nearly $900 million, which is about to grow into a heavyweight drug Among all the ALK inhibitor families on the market, the market performance is the best! < br / > domestic pharmaceutical enterprises have not yet applied for the registration of this variety, except for the approval of Roche's original research variety < br / > < br / > In April 2017, FDA approved bugotinib for the second-line treatment of alk-nsclc In addition to FDA, EMA (November 2018) also approved the listing of the product < br / > in terms of global sales, the annual sales volume has been less than US $100 million since the listing < br / > for the registration application of this variety in China, Takeda has applied for ind with class 2.4 registration, which has not been approved; other domestic pharmaceutical enterprises have not applied for registration application of this variety < br / > Compared with the existing ALK inhibitors, the potential advantage of loratinib is that it has higher permeability of blood-brain barrier and better therapeutic effect on TKI resistant ALK mutations, including crisotinib, alectinib and certinib resistant EML4-ALK mutation types (such as g1202r mutation) < br / > in terms of global sales, the time to market is relatively short, and there is no statistical reference significance < br / > Pfizer has applied for import in 2017 for the registration application of this variety in China, and has not yet approved the listing; domestic pharmaceutical companies have not yet applied for registration application for the imitation of this variety < br / > attached table 1: ALK inhibitors in the global development process, It is expected to become the first lung cancer targeted innovative drug to be listed in the global market led by Chinese enterprises In December 2018, ensatinib hydrochloride submitted a new drug listing application (NDA); in February 2019, ensatinib hydrochloride was included in the list of priority review varieties by nmpa < br / >, A total of 160 patients were enrolled By the middle of September 2018, the independent review committee's assessment results showed that the objective remission rate orr was 52%, the disease control rate (DCR) was 93%, the intracranial Orr and DCR were 70% and 98%, respectively, and the overall efficacy achieved the expected indicators < br / > at present, nsclc-alk-tki has been successfully developed for three generations, and its market performance is much worse than that of EGFR-TKI, a parallel competitor, but the valuable thing is that pharmaceutical companies have not given up on these patients, and the four generations of drugs are on the way of development For the development of drugs in this direction by domestic pharmaceutical enterprises, whether it is the layout of generic drugs or innovative drugs, Zhengda Tianqing is in place; and ensatinib of Beida pharmaceutical has entered the NDA stage, which is more worthy of attention I believe that the news of its approval will be soon! < br / > reference source: < br / > 1 < br / > 2 Critotinib: from discovery to accelerated development to front-line treatment Announcements of oncology 27 (supply 3): iii35 – iii41, 2016 doi:10.1093/annonc/mdw304 3.Targeting ALK in neuroblastoma—preclinical and clinical advancements Nat Rev Clin Oncol advance online publication 15 May 2012; doi:10.1038/nrclinonc.2012.72 4.Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology doi:10.1038/nrc3580 < br / > 5 Beida pharmaceutical official website