[Research Report] life saving straw for lung cancer patients

Tagrisso is an irreversible selective EGFR mutation inhibitor, which can act on the activated and resistant EGFR The drug has been approved for use in more than 40 countries and regions, such as the United States, the European Union, Japan, etc., and was approved for marketing by CFDA on March 24, 2017 It is the first approved third generation lung cancer targeting drug in China Lung cancer is the highest incidence rate and mortality rate in the world, accounting for 1/3 of all cancer deaths, of which NSCLC accounts for about 80% of all lung cancer According to statistics, about 85% of the 730000 new lung cancer patients in China are non-small cell lung cancer, and about 25% - 50% of NSCLC patients have EGFR mutations The approval of oxitinib has brought new hope for Chinese lung cancer patients with high EGFR mutation It breaks the bottleneck of no medicine for Chinese lung cancer patients after treatment with EGFR-TKI, and is a significant progress in lung cancer targeted treatment 1、 Brief introduction of basic drug information [English trade name] tagrisso [English trade name] osimertinib mesylate [Chinese trade name] Teresa [Chinese trade name] oxitinib mesylate mesylate tablets [original manufacturer name] AstraZeneca [dosage form and specification] tablets; 40mg and 80mg [chemical structure formula] On November 13, 2015, the U.S Food and Drug Administration (FDA) approved the listing application of tagrisso, with the approval specifications of 40mg and 80mg and the dosage form of tablet The drug was used as the first treatment drug for local advanced or metastatic NSCLC patients with EGFR T790M mutation positive Tagrisso has obtained FDA's accelerated approval, priority review, breakthrough treatment drug and orphan drug multiple identities It was first listed in the United States It took only two and a half years from clinical trial to marketing license It is the fastest new drug project in the history of AstraZeneca In September 2016, tagrisso was approved to be listed in China after 7 months by CFDA fast review channel, only 16 months later than that in the United States At present, AstraZeneca is studying the efficacy of oxitinib as adjuvant treatment and first-line treatment for non-small cell lung cancer (NSCLC) patients with brain metastasis or without brain metastasis, lung cancer patients with leptomeningeal metastasis, and the combination of oxitinib and other drugs 2、 EGFR-TKI is one of the first antitumor drugs successfully developed as targeted therapy EGFR is highly expressed in nearly 80% of tumor cells, which is closely related to the proliferation and metastasis of tumor cells Mutation of EGFR gene will lead to abnormal signal transduction pathway in downstream cells, resulting in excessive cell proliferation, mutation, neovascularization and even tumor cell metastasis EGFR-TKI can inhibit tumor by blocking ATP binding site of receptor in cell and blocking downstream signal transmission For patients with advanced or metastatic NSCLC and EGFR mutation, gefitinib, exetane and erlotinib are recommended as first-line treatment drugs, but long-term use will lead to acquired drug resistance About two thirds of patients will develop drug resistance due to T790M mutation, that is, EGFR The threonine at 790 site of exon 20 was replaced by methionine (T790M), which enhanced the affinity between ATP and EGFR-TKI binding domain, resulting in EGFR-TKI unable to effectively block the signal pathway and produce drug resistance 3、 Market sales situation since tagrisso went public, the global sales volume has been rising continuously, and in 2016, the global sales volume exceeded 423 million US dollars In 2017, it obtained China's listing license and successfully expanded its sales market Experts predict that the product will break through 600 million US dollars in 2017 Thomson Reuters had forecast tagrisso's potential sales of $760 million in 2019 Some experts predict that if the product is finally approved as the first-line drug for EGFR mutant non-small cell lung cancer, its peak sales is expected to reach 3 billion US dollars 4、 Patent situation AstraZeneca filed PCT international application for tagrisso compound in 2012, and successively obtained authorization in China, the United States and Japan Compared with other countries, tagrisso compound patent has a longer protection period in the United States Patent us8946235b2 has a 14 day extension period, and the protection period is until August 8, 2032 In the compound patent claim of tagrisso, in addition to protecting the compound structure, the preparation technology and indications of tagrisso are also protected by an open dependent claim, and the methanesulphonate form of API is separately protected in another independent claim Tagrisso protection of main market of original research patents tagrisso protection of domestic non original research patents v overview of similar listed varieties 1 First generation EGFR-TKI inhibitor 1.1 gefitinib [English trade name] Iressa [Chinese trade name] yiruisha [Chinese drug name] gefitinib [original manufacturer name] AstraZeneca On May 5, 2003, the U.S FDA approved the listing application of Iressa, the specification of which was 250mg, and the dosage form was tablet The drug was used for the treatment of locally advanced or metastatic non-small cell lung cancer that had previously received chemotherapy In January 2017, CFDA approved the listing of gefitinib generic drugs produced by Qilu Pharmaceutical (Hainan) Co., Ltd It is reported that compared with the original research products, the first domestic gefitinib products produced by Qilu pharmaceutical are not only high-quality and equivalent, but also cheaper 1.2 erlotinib [English trade name] Tarceva [Chinese trade name] trokai [Chinese drug name] erlotinib [original manufacturer name] Roche On November 18, 2004, the U.S FDA approved the listing application of Tarceva, with the approval specifications of 25mg, 100mg and 150mg, and the dosage form is tablet The drug was used for local advanced or metastatic non-small cell lung cancer after the failure of at least one chemotherapy program in the past 1.3 exinib [Chinese trade name] Kemena [Chinese drug name] exinib [original manufacturer name] Zhejiang Beida Pharmaceutical Co., Ltd In 2011, the EGFR targeting drug Kemena (exetane) developed by Zhejiang Beida Pharmaceutical Co., Ltd was listed in China The indication is the first-line treatment for local advanced or metastatic non-small cell lung cancer patients with sensitive mutations of epidermal growth factor receptor gene It is known as the first small molecule targeting anti-cancer drug developed by China But from a scientific point of view, Kemena is not 100% original It is similar to Troika's chemical structure In fact, Kemena's listing is based on a loophole in the original research patent protection Although the efficacy of the first generation of targeted drugs is significant, most patients will develop drug resistance after 1-2 years of drug use, whether it is Iressa, trocaine or Kemena, so scientists developed the second generation of EGFR inhibitors 2 Second generation EGFR-TKI inhibitor [English trade name] gilotif [Chinese trade name] jitari [Chinese drug name] avastini [original manufacturer name] bringer ingelham On July 12, 2013, the U.S FDA approved the listing application of gilotif, with the approval specifications of 20mg, 30mg and 40mg, and the dosage form is tablet The drug is used for the first-line treatment of advanced non-small cell lung cancer and the patients with HER2 positive advanced breast cancer On February 27, 2017, gilotif obtained the import drug registration certificate issued by CFDA, which is the first second generation of lung cancer targeted drugs approved by China, and the first time that new lung cancer drugs listed in the United States have been approved in China in the past five years About 1 / 4 of NSCLC patients are resistant to the first generation EGFR inhibitors from the beginning of treatment Even if the patients respond during the treatment, the efficacy is often extremely short-lived Patients turn to the second-generation EGFR inhibitor gilotif, but almost all tumors eventually develop resistance within 10-12 months 6、 It is expected that EGFR-TKI is the most widely used targeted drug for NSCLC, but the emergence of its primary and acquired drug resistance problems make targeted therapy face new challenges Not all the first generation EGFR-TKI resistance is due to T790M The treatment strategy after drug resistance should be determined by gene detection, reasonable arrangement of target and chemotherapy Although the third generation EGFR-TKIs can target T790M mutation, it has been found that it can produce drug resistance through c797s mutation Therefore, it is of great significance to further clarify the mechanism of resistance of the third generation EGFR-TKIs and develop a new generation of targeted drugs With the increasingly clear regulatory mechanism of lung cancer occurrence and development, more and more targets will be found, and the combination of multiple targets will be a development direction of NSCLC treatment in the future Reference sources: 1 Https://www.fda.gov/drugs/informationondrugs/default.htm 2 Https://www.astrazeneca.com/3 Http://www.roche.com/4 Https://www.boehringer-ingelheim.com/5 Https://www.pharmacodia.com/cn original statement: This is the original manuscript of yaozhi.com, please indicate the source and author, thank you!