Gefitinib With Anlotinib in Advanced Non-squamous NSCLC Patients With Uncleared Plasma ctDNA EGFRm After First-line Treatment With Gefitinib

TKIs therapy is the first-line treatment of patients with EGFR mutation advanced NSCLC.However, some patients have poor prognosis of drug resistance in the early stage. The dynamic alterations of ctDNA-based EGFR mutation after TKIs treatment is a predictor of the efficacy of TKIs treatment, which can be used to identify this part of patients in the early stage.Drug resistance can be overcome when TKIs is combined with drugs in different mechanisms of action, such as chemotherapy and anti-angiogenesis therapy.Gefitinib is the first-generation oral EGFR TKIs. Anlotinib is a domestic oral small molecule inhibitor of multireceptor tyrosine kinase, which has extensive inhibitory effect on tumor angiogenesis and growth.Gefitinib combined with anlotinib is a new option in the treatment of patients with uncleared plasma EGFRm after gefitinib treatment.

Sex

All

Minimum age

18 Years

Maximum age

80 Years

Inclusion Criteria:

* Histologically confirmed that EGFR sensitive mutation (ex19del or L858R mutation) in tumor tissue was detected by non-squamous NSCLC, and EGFR mutation (ex19del or L858R mutation) in ctDNA before treatment;
* Staging is IVB stage (AJCC 8th Edition) ;
* According to the comprehensive judgment of many disciplines, it is impossible to be treated by operation;
* PS score 0-1;
* The patient has at least one measurable tumor injury (the tumor is considered unmeasurable at the site of previous radiotherapy);
* Systemic anti-tumor therapy such as chemotherapy, immunotherapy and targeted therapy were not performed before entering the group;
* There is no history of malignant tumor and no serious medical disease;
* FEV1 ≥ 1.2L/ seconds or ≥ 50% predicted value;
* Laboratory examination: White blood cell count ≥ 4 \*10\^9/L, neutrophil count ≥ 2.0 \*10\^9, platelet count ≥ 100 \*10\^9, hemoglobin ≥ 10 g / L, liver and kidney function and ECG were normal;
* The pregnancy test was negative within 3 days before entering the group, and agreed to use medically effective contraceptive measures during the trial;
* Life expectancy is more than 12 weeks;
* Sign informed consent form; cooperate with regular follow-up.

Exclusion Criteria:

* T4 (AJCC 8th Edition) patients with severe destruction and stenosis of large vessels confirmed by imaging;
* Clinical severe infection (\> grade 2 NCI-CTC V3.0);
* Severe immunosuppressive disease;
* The patient's physical condition is life-threatening;
* A pregnant or breastfeeding patient. Female patients who are likely to become pregnant must be tested negative within 7 days of the start of treatment before continuing. Patients enrolled in the trial (both male and female) must use contraception during the trial period until two weeks after the trial is completed;
* PS score ≥ 2;
* At the same time, there are other serious diseases (congestive heart failure, transmural myocardial infarction, COPD or other respiratory diseases that affect treatment, etc.), considering that the study may aggravate or fail to control the disease;
* Those who have suffered or are currently suffering from tumors whose primary site or histology are different from those evaluated in this study. Excluding cervical carcinoma in situ, cured basal cell carcinoma, bladder surface tumor \[Ta,Tis\&T1\], or any cured tumor that has been in the study for more than 3 years;
* The patient refused to participate.

• RESULTKe EE, Zhou Q, Wu YL. Emerging paradigms in targeted treatments for Asian patients with NSCLC. Expert Opin Pharmacother. 2015 Jun;16(8):1167-76. doi: 10.1517/14656566.2015.1040391. Epub 2015 Apr 23. PMID 25907450
• RESULTBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. PMID 30207593
• RESULTDomvri K, Zarogoulidis P, Darwiche K, Browning RF, Li Q, Turner JF, Kioumis I, Spyratos D, Porpodis K, Papaiwannou A, Tsiouda T, Freitag L, Zarogoulidis K. Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy. J Cancer. 2013 Nov 23;4(9):736-54. doi: 10.7150/jca.7734. PMID 24312144
• RESULTRosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009 Sep 3;361(10):958-67. doi: 10.1056/NEJMoa0904554. Epub 2009 Aug 19. PMID 19692684
• RESULTMok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19. PMID 19692680
• RESULTSchuler M, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kolbeck K, Massey D, Marten A, Paz-Ares L, Park K. First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression. J Cancer Res Clin Oncol. 2019 Jun;145(6):1569-1579. doi: 10.1007/s00432-019-02862-x. Epub 2019 Feb 19.