Clinical Investigation Of Apatinib In Third-or Subsequent-Line Treatment Of Advanced Non-Small Cell Lung Cancer

Objective:Lung cancer,which poses a great threat to public health.is the most common malignancy and the leading cause of cancer-related death worldwide.Non-small cell lung cancer is the most common subtype,accounting for 80-85%of lung cancer cases.Most patients are diagnosed at an advanced stage,with a consequently reduced five-year survival rate.Although substantial breakthroughs have been made in advanced non-small cell lung cancer and a variety of antitumor drugs have continued to emerge,third-and subsequent-line treatment options are still relatively limited.In recent years,antiangiogenic therapy has become a research hotspot,showing potential clinical benefits in tumor therapy.Apatinib mesylate,also known as YN968D1,is an antiangiogenic small molecule tyrosine kinase inhibitor independently developed in China and has been proven to be effective against a variety of malignant solid tumors.It selectively inhibits vascular endothelial growth factor receptor-2 and blocks the signaling pathway downstream of vascular endothelial growth factor binding,thus strongly inhibiting tumor angiogenesis.The aim of this study was to assess the clinical efficacy and toxicity of apatinib as a third-or subsequent-line treatment for advanced non-small cell lung cancer.In addition,by analyzing the basic characteristics,pathological characteristics and other factors,we explored the prognostic factors for the efficacy of apatinib and identified the population most likely to benefit to guide the clinical use of apatinib.Methods:We evaluated the efficacy and toxicity of apatinib in patients with previously treated advanced non-small cell lung cancer from 2016 to 2018 at Shandong Cancer Hospital and Institute.All patients were voluntarily treated with apatinib and signed the informed consent form.Apatinib treatment was initiated by the oral administration of a dosage ranging from 250 mg to 500 mg once a day,as determined by the doctor,according to the situation of each patient.One treatment cycle was 28 days long,and the dose was adjusted appropriately.Treatment was continued until disease progression,the development of an unacceptable serious toxic reaction,death,or any other reason for treatment cessation.The primary end point was progression-free survival,and the secondary end points were the objective response rate,disease control rate and adverse reactions.The main adverse events were evaluated per the Common Terminology Criteria for Adverse Events version 5.0.Kaplan-meier method was used to calculate the median progression-free survival time and its confidence interval,and the log-rank test was used to analyze the subgroup survival.Cox regression was utilized for further analyze the prognostic factors.A value of P<0.05 was considered statistically significant.Results:On the basis of inclusion and exclusion criteria,a total of seventy-one patients with advanced non-small cell lung cancer who received apatinib were included in the present study.Among them,there were 38 males(53.52%)and 33 females(46.48%).The median age was 58 years,of which 53.52%(38/71)were patients aged less than 60 years,and 46.48%(33/71)were patients aged more than 60 years.There were 55 patients(77.47%)and 16 patients(22.54%)with ECOG PS score of 0-1 and 2,respectively.A total of 73.24%(52/71)of the patients were stage Ⅳ.Patients with adenocarcinoma accounted for 73.24%(52/71)and squamous cell carcinoma patients accounted for 26.76%(1 9/71).A total of thirty-three of these patients received apatinib as a third-line therapy,and 38 patients received it as a later line of therapy.Thirty-eight patients were initially administered a dosage of 500 mg/day,seven patients were initially administered 425 mg/day,and twenty-six patients were given 250 mg/day.A total of 5 patients were dose-adjusted due to drug-related adverse reactions.All 71 patients underwent evaluations of the therapeutic response and safety.Seven patients achieved partial response,and 44 achieved stable disease,representing an objective response rate of 9.86%and a disease control rate of 71.83%.The median progression-free survival was 3.70 months(95%CI 2.899-4.501).Cox regression analysis showed that the PFS of patients with an ECOG PS of 0-1 was significantly prolonged compared to that of patients with an ECOG PS of 2(3.93 vs.1.97months.HR 2.453.95%Cl1.287-4.675.P=0.006).The ECOG PS score was an independent prognostic factor for apatinib treatment efficacy.However,age.gender,pathological type,anatomical site,EGFR driver gene mutation status,clinical stage,smoking history,history of hypertension,number of treatment lines,dosage,brain metastasis and bone metastasis were not independent prognostic factors affecting PFS.Most adverse reactions were tolerable,and the common toxicities were hand-foot syndrome(45.07%,32/71).hypertension(42.25%,30/71),proteinuria(36.62%,26/71),myelosuppression(25.53%,1 8/71),elevated transaminase levels(23.94%.1 7/71),fatigue(21.13%,15/71),elevated bilirubin levels(19.72%.14/71),anorexia(18.31%,13/71),oral mucositis(11.27%,8/71)and diarrhea(9.86%,7/71).The grade 3 adverse reactions were hand-foot syndrome(7.04%,5/71),hypertension(5.63%,4/71),proteinuria(2.82%,2/71),myelosuppression(2.82%,2/71),elevated aminotransferase levels(1.41%,1/71)and elevated bilirubin levels(1.41%,1/71).There was no grade 4 treatment-related adverse reactions or treatment-related deaths in this study.The toxicities associated with apatinib were generally controlled.Conclusion:Apatinib monotherapy can improve the objective response rate and disease control rate and prolong progression-free survival in third-or subsequent-line treatment of advanced non-small cell lung cancer.The ECOG PS is an independent prognostic factor,and patients with an ECOG PS of 0-1 have a better prognosis than those with an ECOG PS of 2.Most adverse events associated with apatinib therapy can be anticipated,tolerated,controlled,and reversed.The main adverse events are hand-foot syndrome,hypertension,proteinuria,myelosuppression,elevated transaminase levels,fatigue,elevated bilirubin levels,anorexia,oral mucositis and diarrhea.The grade 3 adverse reactions were hand-foot syndrome(7.04%),hypertension(5.63%),proteinuria(2.82%),myelosuppression(2.82%),elevated aminotransferase levels(1.41%)and elevated bilirubin levels.Because of its improved outcomes,mild toxicity,easy administration,relatively better compliance and reasonable price,apatinib could be a therapeutic option for advanced non-small cell lung cancer.