7.1.3 Application of Tyrosine Kinase Inhibitors in...
Tyrosine kinase inhibitor（TKI）drugs are small molecule chemicals that block intracellular tyrosine kinase and atp binding sites，thereby blocking mitotic signaling to cells，competitively inhibiting atp and egfr's tyrosine Kinase kinase binds，thereby inhibiting autophosphorylation of egfr to block downstream signaling.The difference is that TKI can enter the cell and bind to the intracellular domain of the tyrosine kinase receptor，completely blocking downstream signal transduction..
（1）neratinib（HKI-272）
The aniline quinoline compound is also a small molecule tyrosine kinase inhibitor，but unlike lapatinib，it is for EGFR/HER-1，ErbB-2/HER-2 and ErbB-4/HER-2.The inhibition of these three signal transduction pathways is irreversible.Preclinical studies and clinical studies have shown that neratinib has antitumor activity against HER-2 positive breast tumors，either as a monotherapy or in combination with chemotherapy.
In the phase Ⅰ/Ⅱ clinical trial，after treatment with trastuzumab after multi-course chemotherapy，the effective rate of single-agent neratinib was 24%to 32%，and the median PFS was 22.3 to 39.6 weeks.The main adverse reaction to natalini is diarrhea，followed by nausea and rash.Although the phase Ⅱ non-inferiority clinical study reported in 2011 by Sabbs showed that neratinib monotherapy for HER-2 positive recurrent metastatic breast cancer is not better than lapatinib+capecitabine，but with the results of natalin combined with taxane，vinorelbine，capecitabine in the treatment of recurrent metastatic breast cancer，and future large-scale phase Ⅲ study.The development of neratinib may still be the second approved HER-1/HER-2 tki after lapatinib.
Although neratinib did not have outstanding findings in advanced HER-2 positive breast cancer，the 5-year results of the ExteNET study were published，consistent with the 3-year results published in 2015.The study enrolled 2840 patients with early HER2-positive breast cancer chemotherapy，randomized 1∶1 to the natalinib group and placebo group，and explored no infiltration sexual disease survival rate and safety.after 1 year of treatment with standard trastuzumab for 1 year after natalinib treatment.The 3-year follow-up results significantly improved the rate of non-invasive disease survival（IFFS）（90.5%vs 88.6%，P=0.023）；the 5-year follow-up results were consistent with the 3-year follow-up results，respectively increase of 90.2%，87.7%（P=0.083）.At the same time，the study mentioned that theincidence of diarrhea in 3-4 years is 40%，so the need for prophylactic use of loperamide is needed.Given that neratinib is a treatment after surgery，chemotherapy，or radiotherapy，whether all patients receive extended neratinib treatment and how to determine the best treatment population remains to be explored.Linatinib is currently the only TKI drug for HER-1/HER-2 that can be used for postoperative adjuvant therapy in HER-2 positive breast cancer.(https://www.daowen.com)
（2）Lapatinib
Lapatinib is a small molecule tyrosine kinase receptor inhibitor that inhibits both HER2 and epidermal growth factor receptor（EGFR）.Its inhibitory function is mainly through inhibition of the autophosphorylation of the intracellular adenosine triphosphate domain of HER2 and EGFR，which further prevents the activation of MAPK and PI3K/AKT signaling pathways，and ultimately affects cell proliferation and leads to apoptosis.
In a randomized phase Ⅲ clinical trial of trastuzumab-resistant HER2 metastatic breast cancer，lapatinib and trastuzumab have been shown to be effective：lapatinib PFS and CBR were significantly improved in patients treated with trastuzumab，and the risk of death was reduced by 26%.Studies have found that lapatinib combined with capecitabine can significantly prolong the median time to progression（TTP）and PFS compared with capecitabine alone.However，lapatinib did not achieve a positive result in the first-line treatment and adjuvant treatment of advanced breast cancer compared with the trastuzumab head-to-head comparison.Lapatinib is also highly effective in phase I clinical trials of HER2 overexpressing advanced breast cancer and is not cross-resistant to trastuzumab.Because it is a quinazoline derivative，and it is a novel small molecule inhibitor that acts on both EGFR and HER-2 receptors.Unlike trastuzumab，and it is able to cross the blood-brain barrier for breast cancer.Brain metastasis has a certain therapeutic effect.There is increasing evidence that multi-receptor targeted therapy with antibodies or small molecule inhibitors may be a more effective therapeutic strategy compared to single-receptor target therapy.
（3）pyrrolidine
Pyrrolidine is a new anti-HER-2 drug developed in China.Its mechanism of action is similar to that of neratinib.Phase I clinical trial results show that pyrrolidine maleate combined with capecitabine in the treatment of HER-2 positive advanced breast cancer.The PFS was 35.4 weeks，and the clinical data published in early lapatinib was 27 weeks.It can be seen that pyrrolidine can be superior to lapatinib.A pyrrolidinib center，randomized phase Ⅱ clinical trial.The study found that compared with lapatinib+capecitabine，the international standard program，pyrrolidine+capecitabine increased efficiency from 57.1%to 78.5%，patients'PFS from 7 months Significantly extended to 18.1 months，OS has not yet reached.Subgroup analysis found that whether or not trastuzumab was used in the past did not affect the advantages of the new TKI pyrrozine compared to lapatinib，the median of patients PFS have been significantly improved.Pyrrolidine may replace lapatinib as the standard treatment after failure of trastuzumab treatment.