Gastrointestinal stromal tumor

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Last updated on 2024-09-06:12 regimens on this page
16 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ESMO/EURACAN/GENTURIS==
*2021: Casali et al. Gastrointestinal stromal tumours: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2018: Casali et al. Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2014: Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Casali & Blay. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Casali et al. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Blay & Le Cesne. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
==French Intergroup==
*2019: Landi et al. Gastrointestinal stromal tumours (GISTs): French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO) EuroPMC
==NCCN==
*NCCN Guidelines - Gastrointestinal Stromal Tumors
**2014: von Mehren et al. Gastrointestinal Stromal Tumors, Version 2.2014 EuroPMC
==SEOM-GEIS==
*2023: Serrano et al. SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022) EuroPMC
=Neoadjuvant therapy=
==Imatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Eisenberg et al. 2009 (RTOG 0132)	2002-2006 	Phase 2
====Biomarker eligibility criteria====
*Kit (CD117) positive
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
28-day cycle for 2 to 3 cycles; stopped on the day prior to surgery
====Subsequent treatment====
*Surgery, then adjuvant imatinib x 2 y, resumed as soon as possible postoperatively
===References===
#RTOG 0132: Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##Update: Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. link to original article link to PMC article EuroPMC
=Adjuvant therapy=
==Imatinib monotherapy==
===Regimen variant #1, 12 months of treatment===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Dematteo et al. 2009 (ACOSOG Z9001)	2002-2007 	Phase 3 (E-RT-esc)	Placebo 	Longer RFS (primary endpoint)RFS12: 98% vs 83%(HR 0.35, 95% CI 0.22-0.53)
Joensuu et al. 2012 (SSG XVIII/AIO)	2004-2008 	Phase 3 (C) 	Imatinib x 36 mos	Shorter OS1
1Reported efficacy for SSG XVIII/AIO is based on the 2020 update.
Treatment is started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown.
====Biomarker eligibility criteria====
*Kit (CD117) positive
====Preceding treatment====
*Surgery
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
28-day cycle for 13 cycles (1 year)
===Regimen variant #2, 2 years of treatment===
Study 	Dates of enrollment	Evidence
Eisenberg et al. 2009 (RTOG 0132)	2002-2006 	Phase 2
====Biomarker eligibility criteria====
*Kit (CD117) positive
====Preceding treatment====
*Neoadjuvant imatinib, then Surgery
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
28-day cycle for 26 cycles (2 years)
===Regimen variant #3, 3 years of treatment===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Joensuu et al. 2012 (SSG XVIII/AIO)	2004-2008 	Phase 3 (E-RT-esc)	Imatinib x 12 mos 	Longer OS1 (secondary endpoint)OS120: 79% vs 65.3%(HR 0.55, 95% CI 0.37-0.83)Longer RFS (primary endpoint)RFS60: 65.6% vs 47.9%(HR 0.46, 95% CI 0.32-0.65)
Blay et al. 2024 (IMADGIST) 	2014-12-24 to 2023-04-04	Phase 3 (C) 	Imatinib x 6 years	Shorter DFS (primary endpoint)DFS36: 57% vs 79%(HR 2.50, 95% CI 1.45-5.00)
1Reported efficacy for SSG XVIII/AIO is based on the 2020 update.
Note: Treatment is to be started within 12 weeks after surgery. While this is the FDA-recommended dose, it is noted that the optimal treatment duration is unknown. IMADGIST also allowed 300 mg/day dosing.
====Biomarker eligibility criteria====
*Kit (CD117) positive
====Preceding treatment====
*Surgery
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
28-day cycle for 39 cycles (3 years)
===Regimen variant #4, 6 years of treatment===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Blay et al. 2024 (IMADGIST)	2014-12-24 to 2023-04-04	Phase 3 (C)	Imatinib x 3 years	Longer DFS (primary endpoint)DFS36: 79% vs 57%(HR 0.40, 95% CI 0.20-0.69)
====Biomarker eligibility criteria====
*Kit (CD117) positive
====Preceding treatment====
*Surgery
====Targeted therapy====
*Imatinib (Gleevec) 300 or 400 mg PO once per day
28-day cycle for 78 cycles (6 years)
===References===
#RTOG 0132: Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##Update: Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M, Eisenberg BL. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol. 2012 Apr;19(4):1074-80. Epub 2011 Dec 28. Erratum in: Ann Surg Oncol. 2012 Jul;19(7):2420. link to original article link to PMC article EuroPMC
#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. 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00041197
#SSG XVIII/AIO: Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28;307(12):1265-72. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00116935
##Update: Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D, Ramadori G, Hohenberger P, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Nilsson B, Sihto H, Bono P, Kallio R, Junnila J, Alvegård T, Reichardt P. Adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol. 2016 Jan 20;34(3):244-50. Epub 2015 Nov 2. link to original article EuroPMC
## Update: Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hermes B, Schütte J, Cameron S, Hohenberger P, Jost PJ, Al-Batran SE, Lindner LH, Bauer S, Wardelmann E, Nilsson B, Kallio R, Jaakkola P, Junnila J, Alvegård T, Reichardt P. Survival Outcomes Associated With 3 Years vs 1 Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors: An Analysis of a Randomized Clinical Trial After 10-Year Follow-up. JAMA Oncol. 2020 Aug 1;6(8):1241-1246. link to original article link to PMC article EuroPMC
#IMADGIST: Blay JY, Schiffler C, Bouché O, Brahmi M, Duffaud F, Toulmonde M, Landi B, Lahlou W, Pannier D, Bompas E, Bertucci F, Chaigneau L, Collard O, Pracht M, Henon C, Ray-Coquard I, Armoun K, Salas S, Spalato-Ceruso M, Adenis A, Verret B, Penel N, Moreau-Bachelard C, Italiano A, Dufresne A, Metzger S, Chabaud S, Perol D, Le Cesne A. A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. Ann Oncol. 2024 Dec;35(12):1157-1168. Epub 2024 Sep 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02260505
=Metastatic or unresectable disease, all lines of therapy=
==Imatinib monotherapy==
===Regimen variant #1, standard-dose (400 mg/day)===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Demetri et al. 2002 	2000-07 to 2001-04 	Phase 3 (C) 	Imatinib; higher-dose (600 mg/day)	Did not meet primary endpoint of ORR
Blanke et al. 2008 (SWOG S0033) 	2000-12-15 to 2001-09-01	Phase 3 (C) 	Imatinib; high-dose (800 mg/day) 	Did not meet co-primary endpoints of PFS/OS
Verweij et al. 2004 (EORTC 62005)	2001-02 to 2002-02 	Phase 3 (C) 	Imatinib; high-dose 	Did not meet primary endpoint of PFS1
Blay et al. 2007 (BFR14) 	2002-2004 	Phase 3 (C) 	1. Imatinib x 1 y2. Imatinib x 3 y	Longer PFS
Blanke et al. 2015 (SWOG S0502) 	2008-04-15 to 2009-10-01	Phase 3 (C) 	Imatinib & Bevacizumab 	Not reported
Blay et al. 2015 (ENESTg1) 	2009-2011 	Phase 3 (C) 	Nilotinib 	Longer PFS (primary endpoint)PFS24: 59.2% vs 51.6%(HR 0.68, 95% CI 0.51-0.91)
Kang et al. 2013 (RIGHT) 	2010-2013 	Phase 3 (E-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 1.8 vs 0.9 mo(HR 0.46, 95% CI 0.27-0.76)
1Reported efficacy for EORTC 62005 is based on the 2017 update.
Note: This arm of SWOG S0033 had pre-planned dose escalation to 800 mg/day at the time of progression. BFR14 had two separate comparisons, to one year and to three years of imatinib versus continuous (this arm); the efficacy outcome was the same in both reports.
====Prior treatment criteria====
*Demetri et al. 2002 & SWOG S0033: Any number of prior chemotherapy regimens
*BFR14: None specified
*SWOG S0502 & ENESTg1: None allowed (untreated)
*RIGHT: Failure of imatinib & sunitinib
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
Continued indefinitely (see note)
===Regimen variant #2, higher-dose (600 mg/day)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Demetri et al. 2002	2000-07 to 2001-04 	Phase 3 (E-esc)	Imatinib; standard-dose (400 mg/day)	Did not meet primary endpoint of ORR
====Prior treatment criteria====
*Demetri et al. 2002: Any number of prior chemotherapy regimens
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
Continued indefinitely
===Regimen variant #3, high-dose (800 mg/day)===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Van Oosterom et al. 2001 	2000 	Phase 1, fewer than 20 pts in this cohort	 	
Verweij et al. 2003 	Not reported 	Phase 2 	 	
Blanke et al. 2008 (SWOG S0033) 	2000-12-15 to 2001-09-01	Phase 3 (E-RT-esc) 	Imatinib; standard-dose with pre-planned dose-escalation at progression	Did not meet co-primary endpoints of PFS/OS
Verweij et al. 2004 (EORTC 62005)	2001-02 to 2002-02 	Phase 3 (E-RT-esc) 	Imatinib; standard-dose 	Did not meet primary endpoint of PFS1
Blanke et al. 2015 (SWOG S0502) 	2008-04-15 to 2009-10-01	Phase 3 (C) 	Imatinib & Bevacizumab 	Not reported
Blay et al. 2015 (ENESTg1) 	2009-2011 	Phase 3 (C) 	Nilotinib 	Longer PFS (primary endpoint)PFS24: 59.2% vs 51.6%(HR 0.68, 95% CI 0.51-0.91)
1Reported efficacy for EORTC 62005 is based on the 2017 update.
Note: this was the MTD in Van Oosterom et al. 2001. In some studies, high-dose imatinib was offered to patients with KIT exon 9 mutations in ENESTg1 and SWOG S0502; all other patients received standard-dose imatinib.
====Prior treatment criteria====
*SWOG S0033: Any number of prior chemotherapy regimens
*SWOG S0502 & ENESTg1: None allowed (untreated)
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO twice a day
Continued indefinitely
===References===
#Phase 1: van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS; EORTC Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001 Oct 27;358(9291):1421-3. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, Radford J, Le Cesne A, Hogendoorn PC, di Paola ED, Brown M, Nielsen OS; EORTC Soft Tissue and Bone Sarcoma Group. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003 Sep;39(14):2006-11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 62005: Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00685828
##Update: Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR; EORTC Soft Tissue and Bone Sarcoma Group; Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005 Aug;41(12):1751-7. link to original article EuroPMC
##Update: Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schöffski P, Leyvraz S, Italiano A, Grünwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litière S, Marreaud S, van der Graaf W, Gronchi A, Verweij J; EORTC Soft Tissue and Bone Sarcoma Group; Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017 May 20;35(15):1713-1720. Epub 2017 Mar 31. link to original article EuroPMC
#BFR14: Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, Adenis A, Viens P, Rios M, Bompas E, Cupissol D, Guillemet C, Kerbrat P, Fayette J, Chabaud S, Berthaud P, Perol D; French Sarcoma Group. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007 Mar 20;25(9):1107-13. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00367861
##Update: Le Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F, Duffaud F, Chevreau C, Cupissol D, Cioffi A, Emile JF, Chabaud S, Pérol D, Blay JY; French Sarcoma Group. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010 Oct;11(10):942-9. Epub 2010 Sep 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
##Update: Blay JY, Devin Q, Duffaud F, Toulmonde M, Firmin N, Collard O, Bompas E, Verret B, Ray-Coquard I, Salas S, Henon C, Honoré C, Brahmi M, Dufresne A, Pracht M, Hervieu A, Penel N, Bertucci F, Rios M, Saada-Bouzid E, Soibinet P, Perol D, Chabaud S, Italiano A, Cesne AL. Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2024 Sep;25(9):1163-1175. Epub 2024 Aug 7. link to original article EuroPMC
#SWOG S0033: Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. 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 Feb 1;26(4):626-32. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00009906
##Update: Heinrich MC, Rankin C, Blanke CD, Demetri GD, Borden EC, Ryan CW, von Mehren M, Blackstein ME, Priebat DA, Tap WD, Maki RG, Corless CL, Fletcher JA, Owzar K, Crowley JJ, Benjamin RS, Baker LH. Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol. 2017 Jul 1;3(7):944-952. Erratum in: JAMA Oncol. 2017 Jul 1;3(7):1002. link to original article link to PMC article EuroPMC
#Meta-analysis: Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-53. Epub 2010 Feb 1. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01151852
#ENESTg1: Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D, Wan D, Trent J, Srimuninnimit V, Pápai Z, Le Cesne A, Novick S, Taningco L, Mo S, Green S, Reichardt P, Demetri GD. 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 May;16(5):550-60. Epub 2015 Apr 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00785785
#SWOG S0502: Blanke CD, Rankin C, Corless C, Eary JF, Mulder K, Okuno SH, George S, Heinrich M. S0502: A SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist. 2015 Dec;20(12):1353-4. Epub 2015 Nov 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00324987
=Metastatic or unresectable disease, second-line=
Most trials define this context as imatinib-resistant.
==Linsitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Von Mehren et al. 2019 (SARC 022)	2012-2013 	Phase 2
Patients in this study had wild-type GIST and had previously failed treatment with at least one prior TKI 
====Targeted therapy====
*Linsitinib (OSI-906) 150 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#SARC 022: Von Mehren M, George S, Heinrich M, Schuetze S, Yap J, Yu J, Abbott A, Litwin S, Crowley J, Belinsky M, Janeway K, Hornick J, Flieder D, Chugh R, Rink L, Van den Abbeele A. Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors: a SARC Phase II Study. Clin Cancer Res. 2020 April; 15;26(8):1837-1845. Epub 2019 Dec 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01560260
==Sunitinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Demetri et al. 2006 (A6181004)	2003-2005 	Phase 3 (E-RT-esc) 	Placebo 	Longer TTP (primary endpoint)Median TTP: 27.3 vs 6.4 weeks(HR 0.33)
Adenis et al. 2014 (AB07001) 	2009-2011 	Randomized Phase 2 (C)	Masitinib 	Seems to have shorter OS (secondary endpoint)Median OS: 17.4 vs 29.8 mo(HR 2.50, 95% CI 1.04-6.25)
Bauer et al. 2022 (INTRIGUE) 	2019 to not reported	Phase 3 (C) 	Ripretinib	Did not meet primary endpoint of PFSMedian PFS: 8.3 vs 8 mo(HR 0.95, 95% CI 0.75-1.22)
====Prior treatment criteria====
*A6181004, AB07001, INTRIGUE: Failure of imatinib
====Targeted therapy====
*Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
42-day cycles
====Dose and schedule modifications====
*Sunitinib (Sutent) dose may be decreased to 37.5 mg once per day or 25 mg once per day depending on tolerability
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00075218
##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 EuroPMC
#AB07001: Adenis A, Blay JY, Bui-Nguyen B, Bouché O, Bertucci F, Isambert N, Bompas E, Chaigneau L, Domont J, Ray-Coquard I, Blésius A, Van Tine BA, Bulusu VR, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Le Cesne A. Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol. 2014 Sep;25(9):1762-9. Epub 2014 Jul 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01506336
#INTRIGUE: Bauer S, Jones RL, Blay JY, Gelderblom H, George S, Schöffski P, von Mehren M, Zalcberg JR, Kang YK, Razak AA, Trent J, Attia S, Le Cesne A, Su Y, Meade J, Wang T, Sherman ML, Ruiz-Soto R, Heinrich MC. Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2022 Dec 1;40(34):3918-3928. Epub 2022 Aug 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03673501
##HRQoL analysis: Gelderblom H, Jones RL, Blay JY, George S, von Mehren M, Zalcberg JR, Kang YK, Razak AA, Trent J, Attia S, Le Cesne A, Siontis BL, Goldstein D, Boye K, Sanchez C, Steeghs N, Rutkowski P, Druta M, Serrano C, Somaiah N, Chi P, Harrow B, Becker C, Reichmann W, Sherman ML, Ruiz-Soto R, Heinrich MC, Bauer S; INTRIGUE investigators. Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study. Eur J Cancer. 2023 Oct;192:113245. Epub 2023 Jul 20. link to original article EuroPMC
#AB11002: NCT01694277
=Metastatic or unresectable disease, third-line=
==Cabozantinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Schöffski et al. 2020 (CaboGIST)	2017-2018 	Phase 2
====Prior treatment criteria====
*CaboGIST: Failure of imatinib and sunitinib
====Targeted therapy====
*Cabozantinib (Cometriq) 60 mg PO once per day on days 1 to 28
28-day cycles
===References===
#CaboGIST: Schöffski P, Mir O, Kasper B, Papai Z, Blay JY, Italiano A, Benson C, Kopeckova K, Ali N, Dileo P, LeCesne A, Menge F, Cousin S, Wardelmann E, Wozniak A, Marreaud S, Litiere S, Zaffaroni F, Nzokirantevye A, Vanden Bempt I, Gelderblom H. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 'CaboGIST'. Eur J Cancer. 2020 Jul;134:62-74. Epub 2020 May 26. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02216578
==Pazopanib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mir et al. 2016 (PAZOGIST)	2011-2013 	Randomized Phase 2 (E-esc)	Best supportive care	Seems to have longer PFS (primary endpoint)Median PFS: 3.4 vs 2.3 mo(HR 0.59, 95% CI 0.37-0.96)
====Prior treatment criteria====
*PAZOGIST: Failure of imatinib and sunitinib
====Targeted therapy====
*Pazopanib (Votrient) 800 mg PO once per day on days 1 to 28
28-day cycles
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01323400
==Regorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Demetri et al. 2012 (GRID)	2011-01 to 2011-08 	Phase 3 (E-RT-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 4.8 vs 0.9 mo(HR 0.27, 95% CI 0.19-0.39)
Kang et al. 2021 (VOYAGER)	2018-03-26 to 2019-11-15	Phase 3 (C) 	Avapritinib	Might have longer PFSMedian PFS: 5.6 vs 4.2 mo(HR 0.80, 95% CI 0.64-1.01)
====Prior treatment criteria====
*GRID: Failure of imatinib & sunitinib
*VOYAGER: Failure of imatinib and one or two additional TKIs
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01271712
#VOYAGER: Kang YK, George S, Jones RL, Rutkowski P, Shen L, Mir O, Patel S, Zhou Y, von Mehren M, Hohenberger P, Villalobos V, Brahmi M, Tap WD, Trent J, Pantaleo MA, Schöffski P, He K, Hew P, Newberry K, Roche M, Heinrich MC, Bauer S. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol. 2021 Oct 1;39(28):3128-3139. Epub 2021 Aug 3. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT03465722
==Sorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Park et al. 2012 (SMC 2009-08-102)	2009-2010 	Phase 2
====Prior treatment criteria====
*SMC 2009-08-102: Failure of 2 or more TKIs
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day
Continued indefinitely
===References===
#Abstract: Kindler HL, Campbell NP, Wroblewski K, Maki RG, D’Adamo DR, Chow WA, Gandara DR, Antonescu C, Stadler WM, Vokes EE. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial. 2011. 29 (15_suppl) 10009-10009. link to original article (abstract only)
#SMC 2009-08-102: Park SH, Ryu MH, Ryoo BY, Im SA, Kwon HC, Lee SS, Park SR, Kang BY, Kang YK; Korean gastrointestinal stromal tumors study group. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012 Dec; 30(6) 2377-83. Epub 2012 Jan 25. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01091207
=Metastatic or unresectable disease, fourth-line=
Many trials define this context as imatinib-, sunitinib-, and regorafenib-resistant.
==Avapritinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Heinrich et al. 2020 (NAVIGATOR)	2015-10-26 to 2018-11-16	Phase 1 (RT)
Note: Patients enrolled in this study met either the biomarker eligibility OR the prior treatment criteria. This is the recommended phase 2 dose. 
====Prior treatment criteria====
*Treatment failure with imatinib and at least 1 additional tyrosine kinase inhibitor
====Biomarker eligibility criteria====
*Gene: PDGFRA
*Alteration: D842V
====Targeted therapy====
*Avapritinib (Ayvakit) 300 mg PO once per day, taken on an empty stomach (at least 1 hour before and 2 hours after a meal)
Continued indefinitely
===References===
#NAVIGATOR: Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P, Chawla SP, Trent J, Tugnait M, Evans EK, Lauz T, Zhou T, Roche M, Wolf BB, Bauer S, George S. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. Erratum in: Lancet Oncol. 2020 Sep;21(9):e418. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02508532
##Update: Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142. Epub 2021 Jan 16. link to original article link to PMC article EuroPMC
==Pimitespib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kurokawa et al. 2022 (CHAPTER-GIST-301)	2018-2020 	Phase 3 (E-esc)	Placebo 	Longer OS (secondary endpoint)Median OS: 13.8 vs 7.6 mo(HR 0.42, 95% CI 0.21-0.85)
====Prior treatment criteria====
*CHAPTER-GIST-301: Failure of imatinib, sunitinib, and regorafenib
====Targeted therapy====
*Pimitespib (Jeselhy) 160 mg PO once per day on days 1 to 5, 8 to 12, 15 to 19
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-184094
==Ripretinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Blay et al. 2020 (INVICTUS)	2018-02-27 to 2018-11-16	Phase 3 (E-RT-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: 6.3 vs 1 mo(HR 0.15, 95% CI 0.09-0.25)
====Prior treatment criteria====
*Failure of imatinib, sunitinib, and regorafenib
====Targeted therapy====
*Ripretinib (Qinlock) 150 mg PO once per day
Continued indefinitely
===References===
#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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT03353753
##PRO analysis: Schöffski P, George S, Heinrich MC, Zalcberg JR, Bauer S, Gelderblom H, Serrano C, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Becker C, Shi K, Meade J, Ruiz-Soto R, Blay JY, von Mehren M. Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial. BMC Cancer. 2022 Dec 13;22(1):1302. link to original article link to PMC article EuroPMC
Category:Gastrointestinal stromal tumor regimens
Category:Disease-specific pages
Category:Soft tissue sarcomas
Category:Gastrointestinal cancers