Clinic for the generation of EGFR-TKI resistance has the following treatment options: 1) in patients with general condition is acceptable, the choice of platinum-containing double drug chemotherapy. It should be noted that after second-line chemoresistance, EGFR-TKI response to first-line patients can re-use first-line EGFR-TKI, some patients will still be effective. Sequist et al [25] reported EGFR T790M mutations in EGFR-TKI-resistant tumors and EGFR T790M mutations in some patients, and EGFR-sensitive mutations in some patients after radiotherapy and chemotherapy, and re-use EGFR-TKI. It is also important to note the results of the IMPRESS study. The study attempted to add TKI chemotherapy to patients with EGFR-TKI after chemotherapy, and the results showed that EGFR-TKI combined with chemotherapy shortened the OS of patients with chemotherapy alone. This study indicated that after the second course of chemotherapy, TKI should be stopped EGFR-TKI continued to be treated.26 At the same time, it should be noted that another Phase III study (ASPIRATION) showed that the continuation of erlotinib after RECIST assessment of progress could extend PFS for another 3.1 months, Increased adverse reactions, suggesting that resistance to EGFR-TKI appeared after the slow progress, well tolerated patients can continue to use EGFR-TKI maintenance treatment for some time. Try to use three generations of EGFR-TKI inhibitors, such as AZD9291, CO-1686 etc. [27-28]. A phase I / II study of plasma or tumor tissue confirmed EGFR T790M mutations in NSCLC patients receiving different dose groups CO-1686 (Rociletinib), the results showed that the tumor tissue T790M positive test of patients with objective response rate of 60%, disease control rate of 90%, PFS of 8.0 months, no history of brain metastases PFS up to 10.3 Month, the incidence of> 10% of the 3/4 treatment-related adverse reactions for hyperglycemia, but the symptomatic treatment of oral medication control; for plasma T790M mutation-positive patients, Roc Rocininib acceptable rate of objective response can reach 50% ; The T790M mutation in plasma was positive and the T790M mutation was negative in the tissue, with a response rate of 32% to 39%. [27] Although three generations of EGFR-TKI inhibitors overcome one generation of TKI resistance, Generally acceptable, a generation of TKI resistance after chemotherapy, in order to maximize the recovery of tumor cells on EGFR-TKI sensitivity. 3) re-biopsy, looking for secondary mutagenic targets, combined with other targeted drugs, the downstream mutations or bypass mutations horizontal or vertical strike [29] .4) immunotherapy.
3.2 Crizotinib resistance after treatment options
Resistance to Crizotinib is also present in patients with persistent use of Crizotinib. The current mechanism of drug resistance in Crizotinib includes: 1) Secondary mutations in the ALK protein kinase domain, including L1196M and G1269A [30-31], notably Is a G1202R mutation that makes the tumor resistant to second-generation ALK inhibitors.32) Activation of cell signaling pathways such as EGFR, KIT, IGF1R (32) Insulin-like growth factor-1 receptor pathway [30,34-35] .Therefore, for Crizotinib resistance after treatment strategies are: 1) chemotherapy. It is reported that some patients in the chemotherapy progression after the re-application of Crizotinib will be effective, which is similar to EGFR-TKI [36] .2) selection of second-generation ALK inhibitors, such as ceritinib, alectinib and so on. Clinical studies have reported that ALK-TKI is effective in ALK gene rearrangement in NSCLC patients and can overcome Crizotinib resistance.37-38 ALK inhibitors are used in combination with other signaling pathway inhibitors. 4) immunotherapy.
3.3 Find rare mutations in the drive gene target
At present, there are some rare mutations in NSCLC, such as ROS-1 fusion gene, C-met gene amplification, HER-2 gene amplification or mutation, BRAF gene mutations and RET gene mutations, in addition to EGFR and ALK.
3.3.1 ROS1 chromosome translocation ROS1 is a transmembrane receptor tyrosine kinase. The translocation of the chromosome encoding the c-ros of the oncogene, ROS1, activates ROSl kinase activity. The positive rate of ROS-1 fusion in patients with NSCLC was low (1% to 2%). [39] The patients with ROS-1 fusion gene have similar clinicopathological features as those with ALK fusion: no history of smoking, Cancer [40]. Clinical studies have shown that Crizotinib on ROS1-positive NSCLC is effective, the ORR of about 56% [41].
3.3.2 MET over-expression MET is a tyrosine kinase receptor, its over-activation and tumorigenesis, development, prognosis and prognosis are closely related to tyrosine kinase over-activation, leading to its downstream signaling pathway activation, and ultimately Leading to cell transformation, proliferation and resistance to apoptosis, promote cell survival, causing tumor metastasis, angiogenesis and epithelial-mesenchymal transition (EMT). Approximately 7% of patients with NSCLC may exhibit overexpression of MET.42 Data from studies have shown that Crizotinib has a 33% response rate for MET over-expressing non-small cell lung cancer. For patients with high overexpression of MET, the response rate was 67% [43].
3.3.3 HER-2 gene mutations HER-2 gene abnormalities in the NSCLC showed mutations, amplification and protein overexpression in three forms. The incidence of HER2 mutations in NSCLC is about 2% to 4%, and most of mutations are exon 20 insertions.44 Over-expression of HER2 protein in NSCLC occurs in approximately 59% of cases, with immunohistochemistry ( 2 + / 3 +) ratio of about 5% – 20% (in lung adenocarcinoma up to 30%). The clinicopathological features of HER2 protein in NSCLC were not related to HER2 gene amplification, and many immunohistochemical positive (2+) immunoreactivities were found in patients with non-smokers and non-smokers.44 In contrast to breast cancer, NSCLC patients, HER2 FISH detection without amplification. In addition, HER2 mutations were not associated with HER2 amplification or protein overexpression. A clinical study of 103 cases of HER2 gene amplification or protein overexpression suggests that patients with partial HER2 IHC2, 3 + / FISH- may benefit from treatment with trastuzumab / lapatinib [45] Another study of 65 patients with HER2 mutant lung cancer showed a 96% (n = 15) and 100% (n = 4) DCR for trastuzumab combined with chemotherapy and monotherapy. However, lapatinib (n = 2) and masatinib (n = 1) were ineffective [46].
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