Bevacizumab Plus EGFR-TKI Combination After Acquired Resistance To Tkis In T790M(-)EGFR-sensitive Mutations NSCLC Patients: A Single Arm Observational Study

1.BackgroundIn worldwide,lung cancer is the malignant tumor with the highest morbidity and mortality,among which non-small-cell lung cancer(NSCLC)accounts for about 85% of lung cancer.Because the early symptoms of lung cancer are not easy to be detected,early diagnosis is relatively difficult,about 70% of patients have entered the advanced stage when they are found,and they have lost the best surgical opportunity.Therefore,systemic chemotherapy has become the main treatment for this part of patients.At present,the efficacy of standard chemotherapy regimen for NSCLC has reached a stable level with poor efficacy and obvious adverse events.With the emergence of various new targeted drugs,anti-angiogenic drugs and immunotherapy drugs,the survival time of patients has been further extended,but it is still limited.For epidermal growth factor receptor(EGFR)sensitive mutations in patients with NSCLC,tyrosine kinase inhibitors(TKIs)targeted therapy is an effective treatment method,because of its effectiveness by the patient and the doctor,but the specific mechanism of action,adverse events and drug resistance is still not allow to ignore.To explore the treatment after TKIs resistance and how to make full use of TKIs is still a research focus.Patients with EGFR-mutant NSCLC usually develop acquired resistance to EGFR-TKIs after a median of 10-16 months.First-generation EGFR drug resistance usually results from EGFR T790 M mutation.Third generation TKIs are therefore recommended for patients with a T790 M mutation;however,the recommended treatment for patients without T790 M mutation and the efficacy of EGFR-TKIs combined with bevacizumab in this patient population remains unclear.Therefore,we explored a single arm observational study to evaluate the efficacy and safety of this combination therapy.Bevacizumab,as a humanized anti-vascular endothelial growth factor(VEGF)drug,has demonstrated its controllability and safety in the treatment of advanced NSCLC.However,the efficacy of TKIs combined with bevacizumab in the treatment of patients with T790M(-)is still unclear.The purpose of this study was to evaluate the efficacy of continued use of TKIs combined with bevacizumab for treatment of TKIs resistance in patients with NSCLC with T790M(-).2.MethodsPatients with T790M(-)EGFR-mutant adenocarcinoma resistant to TKIs and showing gradual progression were administered bevacizumab in combination with continuous TKI therapy until disease progression or intolerable adverse events.The primary endpoint was progression-free survival(PFS),and the secondary endpoints were overall survival(OS)and adverse events(AEs).Kaplan-Meier curves were used to evaluate PFS and OS.3.ResultsBetween January 2016 and April 2018,16 patients were enrolled,among whom 9 received erlotinib,5geftinib,and 2icotinib.The median PFS of the combination therapy was 6.47 months(95%CI 3.98-12.22)and the median OS was 14.95 months(95%CI 12.22-18.92).Overall,the objective response rate(ORR)of the bevacizumab combined with TKIs was 25.00% and the disease control rate(DCR)was 93.75%,respectively.No clinically relevant grade 4 or 5 AEs were reported and there were no treatment-related deaths.4.ConclusionFirst-line treatment of EGFR-TKIs is recommended for patients with EGFR mutant NSCLC,but resistance is common.Retesting is recommended after drug resistance,and treatment options are selected according to gene status.For NSCLC patients with EGFR-sensitive mutations,after drug resistance,in patients with T790M(-),the continued application of original TKI combined with bevacizumab may be an effective method to treat TKIs resistance in patients with T790M(-)NSCLC.In terms of drug toxicity,no clinically relevant grade 4 or above adverse reactions occurred,and the most common ones were rash,nausea and hypertension.