Skip to main content

Comparative Efficacy and Safety of Different Regimens of Advanced Gastrointestinal Stromal Tumors After Failure Prior Tyrosine Kinase Inhibitors: A Network Meta-Analysis



The prospect of targeted therapies for advanced gastrointestinal stromal tumors (GISTs) has been dramatically transformed after encouraging results achieved in recent clinical trials. At present, the number of second- and third-line treatments are increasing, although the challenge is to take into account the differences between these interventions. Therefore, our goal is to evaluate the investigation of different regimens currently used in GISTs based on findings from phase II or phase III randomized controlled trials (RCTs), and then indirectly compare the effectiveness and safety of the available therapies.


The qualified literatures in relevant sources were searched systematically. Studies to identify RCTs of which main endpoints were progression-free survival (PFS), overall survival (OS), and grade 3 or more adverse events (AEs) in patients with GISTs were considered for inclusion.


Eight RCTs met our inclusion criteria, which involved 2351 patients. For PFS, compared with placebo, imatinib, and sunitinib, regorafenib (HR = 0.12, 95% CI 0.07–0.23; HR = 0.27, 95% CI 0.19–0.39; HR = 0.36, 95% CI 0.19–0.72, respectively) and ripretinib (HR = 0.15, 95% CI 0.09–0.25; HR = 0.33, 95% CI 0.16–0.68; HR = 0.44, 95% CI 0.25–0.78, respectively) were significantly correlated with the improvement of PFS, and regorafenib may be the preferred option according to the analysis of treatment rankings. For OS, compared with placebo, imatinib, and sunitinib, masitinib (HR = 0.13, 95% CI 0.04–0.44; HR = 0.13, 95% CI 0.04–0.51; HR = 0.27, 95%CI 0.09–0.84) and ripretinib (HR = 0.36, 95% CI 0.21–0.62; HR = 0.36, 95% CI 0.16–0.80; HR = 0.18, 95% CI 0.09–0.36, respectively) were significantly more effective, and masitinib may be the best choice according to treatment ranking analysis. Statistically, regorafenib can be considered to be the highest in high-grade AEs, while the rate of severe AEs of ripretinib and masitinib was likely the lowest.


Our results show that ripretinib has the most favorable balance between effectiveness and tolerability among the different treatment regimens for GISTs.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer. 2007;7:230.

    Article  Google Scholar 

  2. Mei L, Du W, Idowu M, et al. Advances and challenges on management of gastrointestinal stromal tumors. Front Oncol. 2018;8:135.

    Article  Google Scholar 

  3. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865–78.

    CAS  Article  Google Scholar 

  4. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731–41.

    CAS  Article  Google Scholar 

  5. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumours. Ann Chir Gynaecol. 1998;87:278–81.

    CAS  PubMed  Google Scholar 

  6. Martin J, Poveda A, Llombart-Bosch A, et al. Deletions affecting codons 557–558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol. 2005;23:6190–8.

    CAS  Article  Google Scholar 

  7. Kato N, Kato S, Ueno H. Hemangiopericytoma: characteristic features observed by magnetic resonance imaging and angiography. J Dermatol. 1990;17:701–6.

    CAS  Article  Google Scholar 

  8. Lasota J, Wozniak A, Sarlomo-Rikala M, et al. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. Am J Pathol. 2000;157:1091–5.

    CAS  Article  Google Scholar 

  9. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–64.

    CAS  Article  Google Scholar 

  10. Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:58.

    Article  Google Scholar 

  11. Nemunaitis J, Bauer S, Blay JY, et al. Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020;16:4251–64.

    CAS  Article  Google Scholar 

  12. Avapritinib DS. First approval. Drugs. 2020;80:433–9.

    Article  Google Scholar 

  13. Demetri GD, Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–38.

    CAS  Article  Google Scholar 

  14. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.

    CAS  Article  Google Scholar 

  15. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. 2012;23:1680–7.

    CAS  Article  Google Scholar 

  16. Adenis A, Blay JY, Bui-Nguyen B, et al. Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol. 2014;25:1762–9.

    CAS  Article  Google Scholar 

  17. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–32.

    CAS  Article  Google Scholar 

  18. Kang YK, Ryu MH, Yoo C, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14:1175–82.

    CAS  Article  Google Scholar 

  19. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:923–34.

    CAS  Article  Google Scholar 

  20. Blay JY, Shen L, Kang YK, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol. 2015;16:550–60.

    CAS  Article  Google Scholar 

  21. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article  Google Scholar 

  22. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–55.

    CAS  Article  Google Scholar 

  23. Serrano C, George S. Gastrointestinal stromal tumor: challenges and opportunities for a new decade. Clin Cancer Res. 2020;26:5078–85.

    CAS  Article  Google Scholar 

  24. Shah K, Chan KKW, Ko YJ. A systematic review and network meta-analysis of post-imatinib therapy in advanced gastrointestinal stromal tumour. Curr Oncol. 2017;24:e531–9.

    CAS  Article  Google Scholar 

  25. Mazzocca A, Napolitano A, Silletta M, et al. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019;11:1758835919841946.

    Article  Google Scholar 

  26. Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(738–751):e9.

    Google Scholar 

  27. Roskoski RJ. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016;103:26–48.

    CAS  Article  Google Scholar 

  28. Farag S, Smith MJ, Fotiadis N, et al. Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates. Curr Treat Options Oncol. 2020;21:55.

    Article  Google Scholar 

  29. Khoshnood A. Gastrointestinal stromal tumor a review of clinical studies. J Oncol Pharm Pract. 2019;25:1473–85.

    CAS  Article  Google Scholar 

  30. Uhlmann L, Jensen K, Kieser M. Hypothesis testing in Bayesian network meta-analysis. BMC Med Res Methodol. 2018;18:128.

    Article  Google Scholar 

Download references


All the researchers involved in the study made equal contributions and approved the final manuscript.


The research or publication of this article has received no funding or sponsorship. The processing charges of the article shall be funded by the author.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.


Xue Zhang, Yueqin Liang, Yanhua Li, Jiafu Yin have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previous studies and does not include any experiments with human participants or animals performed by any of the authors.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jiafu Yin.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Liang, Y., Li, Y. et al. Comparative Efficacy and Safety of Different Regimens of Advanced Gastrointestinal Stromal Tumors After Failure Prior Tyrosine Kinase Inhibitors: A Network Meta-Analysis. Adv Ther 38, 399–412 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Different regimens
  • Efficacy and safety
  • Gastrointestinal stromal tumors
  • Network meta-analysis