Introduction: 1st generation EGFR-TKI has better efficacy than chemotherapy in advanced non-cellular lung cancer (NSCLC) with EGFR gene mutation, however, most patients develop acquired drug resistance around 10 months, and 60-70% of the resistance is related to T790M. The advent of 3rd generation EGFR-TKIs has brought light to T790M mutated NSCLC. Yang Xiaobing, Department of Oncology, Guangdong Province Hospital of Traditional Chinese Medicine Compiled by Yang Xiaobing, Department of Oncology, Guangdong Province Hospital of Traditional Chinese Medicine Source: Medical Oncology Channel It is well known that 60-70% of TKI resistance is associated with T790M mutation. Third-generation EGFR-TKI can inhibit both EGFR and T790M. The representative drugs are AZD9291 and Rociletinib (C01686), both of which are effective in advanced non-small cell lung cancer (NSCLC) with EGFR mutation and/or T790M mutation. Two articles published in the New England Journal in April of this year reported the role of third-generation EGFR-TKI in advanced NSCLC after resistance to first- and second-generation TKI. The designs of the two studies were essentially identical, and the results are interpreted below: 1. AZD9291 Pasi A. Janne et al. from the Dana-Farber Cancer Institute, USA [1] enrolled 253 imaging-diagnosed, The overall objective response rate (ORR) was found to be 51%. Subgroup analysis revealed an ORR of 61% in the T790M mutation-positive group compared to 21% in the T790M mutation-negative group, and a progression-free survival time (PFS) of 9.6 months (some not yet achieved) in the T790M mutation-positive group and 2.8 months in the T790M mutation-negative group. No dose-limiting toxic reactions were observed in the dose-escalation group as the treatment dose was increased. Common adverse events in the dose escalation group were diarrhea (47%), rash (40%, 1st and 2nd degree), nausea, and loss of appetite. This study confirmed the efficacy of AZD9291 in the treatment of TKI-resistant NSCLC, and the optimal drug dose for follow-up studies is 80 mg/day. The FDA has authorized AZD9291 as a breakthrough drug, and the phase III AURA trial will be compared with platinum-based two-drug chemotherapy. 2. Rociletinib (CO1686) Also from the United States, Lecia V. Sequist et al [2] enrolled 130 cases of EGFR-mutated NSCLC receiving TKI progression in a phase I/II study to simultaneously validate the efficacy of two different forms of the drug’s formulation, 57 cases receiving the free-radical form of Rociletinib (dose 150mg~ 900 mg bid) and 73 cases received the brominated salt form of Rociletinib (dose 500 mg to 1000 mg bid). The ORR was found to be 59% in T790M-positive patients and 29% in T790M-negative patients. the PFS was 13.1 months in the T790M-positive group and 5.6 months in the T790M-negative group. The most common dose-limiting adverse event was hyperglycemia (22%, grade 3), the mechanism of which may be related to Rociletinib interference with the insulin-like growth factor 1 receptor (IGF-1R); asymptomatic long QT syndrome on ECG at increasing doses, and other adverse reactions included diarrhea, malaise, and no skin toxicity such as rash was seen.Rociletinib for EGFR mutations T790M-positive NSCLC patients resulted in sustained remission and was well tolerated. Third-generation EGFR-TKIs have been shown to be more effective in first- and second-generation TKI-treated post-resistance NSCLC (especially in T790M-positive individuals), and the next step will be to compare their efficacy with platinum-based two-drug regimens. In addition, studies are currently underway to compare the efficacy of third-generation versus first-generation TKI for the first-line treatment of EGFR-mutated NSCLC, the results of which will be awaited; the sequential order of third- versus first-generation TKI treatment will also be further explored in future studies. The success of third-generation TKI suggests that inhibition of specific targets of resistance (e.g., T790M) can help overcome resistance, and the development of other drugs targeting resistance mechanisms (MET amplification, HER amplification, PI3CA, EMT, and BRAF mutations) will continue in the future. The T790M mutation detection by peripheral circulating tumor cell (CTC) DNA can help to screen for the superiority of third-generation TKI, and the plasma detection of T790M has good sensitivity and specificity, which helps to avoid re-biopsy, the results of which still need to be confirmed by prospective studies. The current data suggest that Rociletinib has a slightly longer PFS, but since PFS has not yet been achieved in some patients with AZD9291, the verdict is still inconclusive and needs to be compared and validated in a head-to-head multicenter study. References: 1. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015;372(18):1689-1699.2. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700-1729.