Clinical Efficacy Of Third-line Tyrosine Kinase Inhibitors In Advanced Gastrointestinal Stromal Tumors After Failure Of Imatinib And Sunitinib: A Meta-analysis Of Recent Clinical Trials

Background:Gastrointestinal stromal tumors(GISTs),proposed in 1983,is one of the most common gastrointestinal tumors originated from Cajal stromal cells(ICCs).In recent years,tyrosine kinase inhibitors(TKIs)have developed rapidly.With imatinib and sunitinib as the first and second-line drugs,the survival rate of GISTs patients significantly increased.However,the primary and secondary drug resistance of the two drugs has been a major challenge in clinical work,which also promotes the continuous research and development of new TKIs represented by regorafenib as third-line drugs.Pazopanib and Nilotinib also gradually entered clinical trials.MethodsRandomized controlled trials(RCTS)were determined to evaluate the clinical efficacy of third-line TKIs according to the established inclusion criteria and literature quality assessment by searching PubMed and EMBASE from 2010 to December 2018.Outcomes subjected to analysis were progression-free survival and overall survival.Statistical analyses were performed using Review Manager 5.3.Weighted hazard ratios(HR)with 95% confidence intervals(CIs)were calculated for the outcomes.Fixed-effects or random-effects models were used,depending on the degree of heterogeneity across the selected studies.Results528 patients after failure of imatinib and sunitinib were included in 3 randomized controlled studies.338 of them received third-line TKIs(regorafenib,pazopanib,or nilotinib),and 190 in the control group were treated with placebo and best supportive care(BSC).The analysis data showed that progression-free survival was significantly improved in the TKI-treated group compared with the control group(HR 0.58,95%Cis 0.45-0.76,p<0.0001).No statistically significant difference was detected in overall survival between the treatment group and the control group(HR 0.85,95%Cis 0.66-1.08,p=0.18).Conclusion:Third-line TKIs(regorafenib,pazopanib,and nilotinib)are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib and sunitinib.