However, it is important to note that, although clinical studies have shown that AZD9291 and other third-generation EGFR-TKI first-line treatment is more effective, but this does not mean three generations of EGFR-TKI first-line use will bring absolute benefits to patients. For the first generation of EGFR-TKI-sensitive people, Iressa, Tarceva or Kamehner were used first, and third-generation EGFR-TKI was used after drug resistance. Theoretically, these patients could obtain longer OS, perhaps a more reasonable choice . Medical treatment of the tumor to establish a holistic view, from the whole to consider the dynamic, the development of vision, at the right time window using the appropriate drugs.
1.2 ALK fusion gene-positive NSCLC first-line treatment
The human short arm of chromosome 2 inverses and rearranges to the EML4-ALK fusion gene, resulting in the fusion of the N-terminal part of the echinodermal microtubule-associated protein-4 (EML4) -encoding protein to the intracellular cytokine of the anaplastic lymphoma kinase (ALK) (10). The presence of ALK mutations in NSCLC patients is usually mutually exclusive with mutations in the EGFR / KRAS gene (in rare cases, dual-driven mutations are present in the NSCLC patients) ALK fusion gene-positive patients usually have a clinicopathological character- istic of younger patients, past / mild smoking, adenocarcinoma (signet-ring cell type, or acinar type) .11 Basic studies have demonstrated that ALK kinase inhibitors Tumor cells stagnate in the G1 – S phase, and induce apoptosis [12].
For ALK mutations in patients with NSCLC first choice for first-line treatment of ketoconazole. Phase III clinical study PROFILE1014 demonstrated a first-line use of kazostatin compared with chemotherapy, ALK gene mutation-positive patients to obtain significant survival benefit and quality of life improved.13 Another phase of clinical study PROFILE1007 contrast analysis of tazobactam and Pemetrexed or second-line treatment of patients with ALK-positive advanced NSCLC efficacy and safety, the results show that ketoconazole can improve the efficiency and prolong PFS [14].
1.3 The first-line treatment of NSCLC with unknown gene status
Existing clinical studies have shown that the first-line chemotherapy regimen with platinum (cisplatin or carboplatin) in the dual-drug regimen is preferred for advanced NSCLC patients with unknown genetic status; pemetrexed plus platinum is preferred for adenocarcinoma and gemcitabine for squamous cell carcinoma Combined platinum class. For the tumor load is large, rapid progress in patients with chemotherapy can be considered based on the addition of anti-angiogenic drugs such as bevacizumab, or with EGFR monoclonal antibody such as cetuximab, necitumumab and so on.
Stage Ⅲ-stage ISCAN (CTONG-1102) study of patients with stage ⅢB or Ⅳ Chinese lung adenocarcinoma who were non-smokers and unknown status of EGFR mutations. After receiving 2 cycles of gemcitabine plus carboplatin (GC) for the first time Were randomized to receive one cycle of 4 weeks, GC treatment of gefitinib or one cycle of GC monotherapy for 4 weeks on days 15-25. In the absence of progression of the disease, chemotherapy can be continued for up to 4 cycles, after which the patient continues to receive gefitinib or undergo observation until disease progression or unacceptable therapeutic toxicity occurs. Median PFS was significantly prolonged (10.0 vs. 4.4 months; hazard ratio 0.475, 95% CI 0.349-0.646; P <0.000 1) in the gefitinib-treated and placebo groups, The patients were well tolerated. The results of this subgroup analysis are currently unknown and the rate of EGFR mutations in patients receiving chemotherapy and EGFR-TKI is not known, so the results should be treated with caution. However, the study also suggests that sequential EGFR-TKI / EGFR-TKI chemotherapy followed by sequential treatment with chemotherapy and EGFR-TKI alternation in patients with EGFR-sensitive mutations should be further explored in patients with EGFR-sensitive mutations. Resistant, giving patients a longer survival benefit.
2 Maintenance therapy
A number of clinical studies have shown that survival in patients with PR / SD after 4 to 6 cycles of first-line chemotherapy is associated with survival benefits.15-17 Maintenance therapy is supported by four options: (1) single-agent maintenance chemotherapy (4) EGFR-TKI maintenance (4) EGFR-TKI maintenance therapy; (4) EGFR-TKI maintenance of the same drug or dressing maintenance); 2) first-line addition of bevacizumab patients, maintenance treatment of bevacizumab monotherapy to maintain; 3) single drug chemotherapy with bevacizumab maintenance therapy; treatment.
For the first line chemotherapy after the discovery of EGFR-sensitive mutations or ALK fusion gene-positive patients, most scholars believe that tolerance in patients with acceptable circumstances, chemotherapy 4-6 cycles, the beginning of EGFR kinase inhibitors or ALK kinase inhibitors Of the maintenance treatment.
For patients with unknown genetic status, prior clinical studies have shown that maintenance of the same drug or maintenance of dressing in a first-line chemotherapy regimen can benefit. For patients undergoing first-line chemotherapy combined with cetuximab, the FLEX study shows that cetuximab can be used for maintenance therapy until disease progression [18]. For patients receiving first-line chemotherapy combined with bevacizumab, Maintenance therapy is the choice of chemotherapy drugs single drug, bevacizumab monotherapy, or the combination of the two is still controversial. Two Phase III studies (PointBreak study and AVAPERL study) in 2013 suggest that maintenance therapy with a combination of bevacizumab and bevacizumab alone may yield a modest benefit from PFS, but OS is not statistically significant Differences [19-20]. The ongoing ECOG 5508 study may shed further light on the best model of maintenance therapy in patients receiving carboplatin, paclitaxel and bevacizumab after first-line therapy, Drug bevacizumab, paclitaxel and bevacizumab in combination with maintenance therapy.
3 After the line treatment
3.1 EGFR-TKI drug resistance after treatment options
Patients treated with EGFR-TKI will eventually develop drug resistance [21], and their mechanisms of resistance fall into the following categories: 1) Secondary mutations in the EGFR gene itself, such as exon 20 T790M mutation. 2) EGFR downstream signal pathway targets secondary mutations, such as BRAF, PIK3CA gene mutation. 3) Bypass activation, such as MET amplification, HER-2 amplification, IGFR overexpression, AXL overexpression, and the like. 4) Loss of PTEN gene expression. 5) In addition, resistance to re-histological biopsy, pathological morphology found in cell morphology from NSCLC into small cell lung cancer [22-24].
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