AbstractBackgroundImatinib is the standard first‐line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance, leading to considerable clinical challenges. Few direct comparisons have been made between different post‐first‐line therapies on clinical efficacy in advanced GIST following imatinib failure.MethodsDatabases including PubMed, Embase, Scopus, Google Scholars, and Cochrane Library from inception to February 2023 were retrieved for randomized controlled trials evaluating the clinical efficacy of different post‐first‐line agents for advanced GIST following imatinib failure. Network and conventional meta‐analysis were carried out using Stata/MP 16.0.ResultsRipretinib showed significant improvement in progression‐free survival (PFS) rates from the 2nd to the 12th month compared to placebo, while there was virtually no evidence that the rest active agents had a significant benefit at the 12th month. Masitinib, ripretinib, sunitinib, regorafenib, and pimitespib exhibited significantly longer median PFS than placebo, and pairwise comparisons indicated there were no significant differences among masitinib, ripretinib, and sunitinib. These post‐first‐line agents decreased the risk of disease progression or death by 65% (HR = 0.35, 95% CI: 0.26–0.47) compared to placebo. Ripretinib and sunitinib came into effect earlier and exhibited more consistent overall survival (OS) rate improvements than masitinib and pimitespib, while pairwise comparisons revealed no significant differences in these four active agents concerning the improvement in OS rate. These post‐first‐line agents decreased the risk of death by 39% (HR = 0.61, 95% CI: 0.44–0.83) over placebo for advanced GIST following imatinib failure.ConclusionThe active agents in our analysis as post‐first‐line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post‐first‐line treatment for advanced GIST following imatinib failure.