Gastrointestinal stromal tumor - null regimens

The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main GIST page for regimens that include active anticancer treatment.

Adjuvant therapy

Placebo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dematteo et al. 2009 (ACOSOG Z9001)	2002-2007	Phase 3 (C)	Imatinib x 12 mos	Inferior RFS
Casali et al. 2015 (EORTC 62024)	2004-2008	Phase 3 (C)	Imatinib x 24 mos	Did not meet primary endpoint of IFFS

No active antineoplastic treatment.

Preceding treatment

• Surgery

References

1. EORTC 62024: Casali PG, Le Cesne A, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P, Fumagalli E, Judson IR, Italiano A, Gelderblom H, Adenis A, Hartmann JT, Duffaud F, Goldstein D, Broto JM, Gronchi A, Dei Tos AP, Marréaud S, van der Graaf WT, Zalcberg JR, Litière S, Blay JY. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol. 2015 Dec 20;33(36):4276-83. Epub 2015 Nov 16. link to original article PubMed NCT00103168
   1. Update: Casali PG, Le Cesne A, Velasco AP, Kotasek D, Rutkowski P, Hohenberger P, Fumagalli E, Judson IR, Italiano A, Gelderblom H, Penel N, Hartmann JT, Duffaud F, Goldstein D, Martin-Broto J, Gronchi A, Wardelmann E, Marréaud S, Zalcberg JR, Litière S, Blay JY. Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆. Ann Oncol. 2021 Apr;32(4):533-541. Epub 2021 Jan 19. link to original article PubMed
2. ACOSOG Z9001: Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. Epub 2009 Mar 18. link to original article link to PMC article PubMed NCT00041197

Metastatic or unresectable disease

Best supportive care

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Reichardt et al. 2012 (ENEST g3)	2007-03-05 to 2008-04-22	Phase 3 (C)	Nilotinib	Did not meet primary endpoint of PFS
Mir et al. 2016 (PAZOGIST)	2011-2013	Randomized Phase 2 (C)	Pazopanib	Seems to have inferior PFS

No active treatment.

References

1. ENEST g3: Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B, McArthur GA, Yazji S, Hsu Y, Galetic I, Rutkowski P. 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 Jul;23(7):1680-7. Epub 2012 Feb 21. link to original article PubMed NCT00471328
2. PAZOGIST: Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D; PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO). Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016 May;17(5):632-41. Epub 2016 Apr 5. link to original article PubMed NCT01323400

Placebo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Demetri et al. 2006 (A6181004)	2003-2005	Phase 3 (C)	Sunitinib	Inferior TTP
Kang et al. 2013 (RIGHT)	2010-2013	Phase 3 (C)	Imatinib	Inferior PFS
Demetri et al. 2012 (GRID)	2011-01 to 2011-08	Phase 3 (C)	Regorafenib	Inferior PFS
Blay et al. 2020 (INVICTUS)	2018-02-27 to 2018-11-16	Phase 3 (C)	Ripretinib	Inferior PFS
Kurokawa et al. 2022 (CHAPTER-GIST-301)	2018-2020	Phase 3 (C)	Pimitespib	Inferior OS

No active antineoplastic treatment.

Prior treatment criteria

• A6181004: Failure of imatinib
• RIGHT & GRID: Failure of imatinib & sunitinib
• INVICTUS & CHAPTER-GIST-301: Failure of imatinib, sunitinib, and regorafenib

References

1. A6181004: Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. link to original article PubMed NCT00075218
   1. Update: Demetri GD, Garrett CR, Schöffski P, Shah MH, Verweij J, Leyvraz S, Hurwitz HI, Pousa AL, Le Cesne A, Goldstein D, Paz-Ares L, Blay JY, McArthur GA, Xu QC, Huang X, Harmon CS, Tassell V, Cohen DP, Casali PG. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012 Jun 1;18(11):3170-9. link to original article link to PMC article PubMed
2. GRID: Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. 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 Jan 26;381(9863):295-302. Epub 2012 Nov 22. link to original article link to PMC article PubMed NCT01271712
3. RIGHT: Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, Nam BH, Ramaiya N, Jagannathan J, Demetri GD. 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 Nov;14(12):1175-82. Epub 2013 Oct 18. link to original article link to PMC article PubMed NCT01151852
4. INVICTUS: Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, Schöffski P, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Meade J, Shi K, Ruiz-Soto R, George S, von Mehren M. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Jul;21(7):923-934. Epub 2020 Jun 5. Erratum in: Lancet Oncol. 2020 Jul;21(7):e341. link to original article link to PMC article PubMed NCT03353753
5. CHAPTER-GIST-301: Kurokawa Y, Honma Y, Sawaki A, Naito Y, Iwagami S, Komatsu Y, Takahashi T, Nishida T, Doi T. Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2022 Sep;33(9):959-967. Epub 2022 Jun 8. link to original article PubMed JapicCTI-184094
6. ARO-012: NCT02847429