Efficacy And Safety Of Apatinib In The Treatment Of Progressive Iodine-refractory Differentiated Thyroid Cance

Objective:Radioactive iodine refractory differentiated thyroid cancer(RAIR-DTC)has been a global challenge due to its poor prognosis and limited treatment options.In these series of researches,we report the efficacy and safety results the phase II clinical trial of apatinib,an anti-angiogenic tyrosine kinase inhibitor,for RAIR-DTC.Methods:Twenty patients were consecutively recruited to receive apatinib(28 days per cycle,the former 10 patients starting at 750 mg once per day and the latter 10 starting at 500 mg once per day)until disease progression,unmanageable toxicity,withdrawal,or death.Efficacy and safety were recorded in each cycle at the initial two cycles and every two cycles thereafter.Structural response was assessed according to Response Evaluation Criteria in Solid Tumors,version 1.1(RECIST 1.1)and adverse events(AEs)were collected and graded according to Common Terminology Criteria for Adverse Events version 4.0(CTCAE 4.0).Treatment interruption was required for those who developed AEs of grade 3 or higher.Sequential reduction in dose(with a 250 mg tapered dose every turn to 250 mg once daily)was allowed.The primary end points were objective response rate(ORR)and disease control rate(DCR).The association between progression-free survival(PFS)and different tumor genotypes were also assessed.Results:After a median follow-up of 7.9 months of the former 10 patients(male to female ratio,5:5,750 mg once daily),rapid decrease in thyroglobulin(Tg)level(mean 60%,max 90%)and target tumor lesions(mean 40%,max 60%)have been observed after 6 and 8 weeks’treatment respectively,and there was a positive correlation between the change rate of Tg and target lesions(r=0.56,P<0.05),while all the patients have experienced treatment associated adverse events(TAAEs).Further comparison was conducted between the patients starting at 750 mg and 500 mg(n=10,male to female ratio,5:5)daily dose of apatinib.During the first 6 treatment cycles,the two dosing schedules didn’t differ regarding greatest reduction in target lesion size(750 mg-42.7%vs 500 mg-40.5%,P=0.48)and Tg level(750 mg-82.5%vs 500 mg-94.3%,P=0.14).These two dosing groups showed similar incidence in TAAEs of grade≥ 3(750 mg 100%vs 500 mg 70%,P=0.21).The frequency of TAAEs was higher in the 750 mg group than that in the 500 mg group(6.8±6.5 vs 18.1 ± 6.5 in any grades,P=0.01;5.2±3.0 vs 1.6± 1.3 in grade≥ 3,P<0.01).After a median follow-up of 48.3 months,the overall ORR was 80%(750 mg 90%,500 mg 70%),DCR was 95%(750 mg 100%,500 mg 90%).There were no differences in terms of median PFS(750 mg 34.9 months vs 500 mg 13.8 months,P=0.54)and median overall survival(OS,750 mg 51.6 months vs 500 mg 33.8 months,P=0.56)between the groups.The overall median PFS was 18.4 months(95%CI,9.2-36.8)and the overall median OS was 51.6 months(95%CI,29.2-not reached[NR]).Patients with BRAFV600E mutation(10 of 18 evaluated)had a longer median PFS compared with patients with BRAF wild-type(NR vs 9.2 months,P=0.002).The most common TAAEs included palmar-plantar erythrodysesthesia syndrome(19/20),proteinuria(18/20),and hypertension(16/20).Conclusion:In the treatment of apatinib for progressive RAIR-DTC patients,the 500 mg dose protocol might be less toxic than the 750 mg protocol,whereas the efficacy was similar between the two dosages.Apatinib displayed sustainable efficacy and tolerable safety profile,warranting it as a promising treatment option for progressive RAIR-DTC.