Efficacy And Safety Of Apatinib Combined With First-line Chemotherapy In Extensive Stage Small Cell Lung Cancer

Part one Oral apatinib 250 mg clinical drug concentration testObjective: To investigate the plasma concentration of apatinib 250 mg orally.Methods: 36 patients were included: lung adenocarcinoma(n=6),small cell lung cancer(n=12),gastric cardia adenocarcinoma(n=4),others(n=14).Plasma specimens of 36 patients were collected.At 7:40 am,fasting blood was drawn as minimum concentration(Cmin).At 8 am,apatinib(250mg qd)was orally.At 11 am,venous blood was drawn as maximum concentration(Cmax).Each patient had Cmin and Cmax samples,and different patients had different amounts of samples.A total of 100 plasma samples were obtained.Results: Steady-state of plasma drug concentration were achieved by day4.The plasma minimum concentration ranged from 1.18ng/m L-863.3 ng/ml,and maximum concentration ranged from 71.11ng/m L-1609.4 ng/ml.The mean plasma minimum concentration was 264.4±42.5ng/ml,and the mean plasma maximum concentration was 543.6±66.1ng/ml.Conclusions:1.On the fourth day,The minimum concentration and maximum concentration reached stable state.2.The drug concentration of 250 mg was crossover with the oral concentration of 850 mg and was clinically treatable with apatinib 250 mg.Part two Efficacy and safety of apatinib combined with chemotherapy in first-line treatment of extensive small-cell lung cancerObjective: To investigate the efficacy and safety of apatinib combined with EP in the first-line treatment of extensive stage small cell lung cancer.Methods:1.According to Part I,there was a cross between apatinib 250 mg and previously studied 850 mg plasma concentrations.Using the method of apatinib 250 mg combined with EP standard chemotherapy,40 cases of extensive stage small cell lung cancer(ED-SCLC)were studied prospectively,single arm and single center.The patients were admitted to the fourth Hospital of Hebei Medical University from November 15,2017 to April 18,2019.The SCLC was diagnosed by histology or cytology,imaging staging was extensive.According to the response evaluation criteria in solid tumors(RECIST),there is at least one measurable focus,excluding patients with symptomatic brain metastasis.2.Patients in the group received apatinib(250mg oral 1/day)combined with standard first-line chemotherapy(etoposide 100mg/m2,intravenous infusion on the 1st-3rd day of each cycle,cisplatin 30mg/m2,intravenous infusion on the 1st-3rd day of each cycle),repeated every 21 days,a total of 6cycles of treatment.For patients with less than 6 cycles of treatment progression,progression-free survival(PFS)was calculated and left the group.3.Primary study endpoints were safety and secondary study endpoints were objective response rate(ORR)at 6 months,disease control rate(DCR)at6 months,progression-free survival(PFS)rate.Results:1.We enrolled 40 patients between November 15,2017 and April18,2019.Median age was 56(range 28-67),92.5% had an eastern cooperative oncology group performance status(ECOG PS)of 0.At the data cutoff(December 31,2019),27 patients were evaluated.The oral duration of apatinib was 4-26 months,with an average oral duration of 10.6 months.2.The 6-month ORR was 63%,DCR was 85% [17PR,6SD].3.9 patients(33.3%)achieved PFS,with a median PFS of 22 months(95%CI:3.643-40.357months).Log-Rank showed that age,PS score and multiple organ metastasis had significant effects on PFS(P<0.05).4.During the therapy,adverse events(AEs)were Common grade 1-2related AE,hypertension(37%),hand-foot syndrome(3.7%),and Hepatic Insufficiency(7.4%).Conclusions:Apatinib combined with first-line chemotherapy is a safe and effective treatment for extensive small-cell lung cancer.