Gastrointestinal stromal tumor

Section editors
	Neeta K. Venepalli, MD, MBA Chicago, IL		James L. Chen, MD, MS Columbus, OH LinkedIn

11 regimens on this page 15 variants on this page

Guidelines

ESMO

• Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2014) PubMed

NCCN

• NCCN Guidelines - Soft Tissue Sarcoma

Neoadjuvant therapy

Imatinib monotherapy

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Regimen

Study	Evidence
Eisenberg et al. 2009 (RTOG 0132)	Phase II

Chemotherapy

• Imatinib (Gleevec) 600 mg PO once per day

Given for 8 to 12 weeks prior to surgery, stopped on the day prior to surgery, resumed as soon as possible postoperatively, and continued for 2 years as postoperative adjuvant therapy

References

1. 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. contains verified protocol link to PMC article PubMed
   1. 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 PMC article PubMed

Adjuvant therapy

Imatinib monotherapy

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Variant #1, 12 months of treatment

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Dematteo et al. 2009 (ACOSOG Z9001)	Phase III (E)	Placebo	Superior RFS
Joensuu et al. 2012 (SSG XVIII/AIO)	Phase III (C)	Imatinib x 36 mos	Seems to have inferior OS

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.

Preceding treatment

• Surgery

Chemotherapy

• Imatinib (Gleevec) 400 mg PO once per day

12-month course

Variant #2, 3 years of treatment

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Joensuu et al. 2012 (SSG XVIII/AIO)	Phase III (E)	Imatinib x 12 mos	Seems to have superior OS

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.

Preceding treatment

• Surgery

Chemotherapy

• Imatinib (Gleevec) 400 mg PO once per day

36-month course

References

1. 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. link to original article contains verified protocol link to PMC article PubMed
2. 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 contains verified protocol PubMed
   1. 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 PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Dematteo et al. 2009 (ACOSOG Z9001)	Phase III (C)	Imatinib x 12 mos	Inferior RFS

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.

Preceding treatment

• Surgery

References

1. 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. contains verified protocol link to PMC article PubMed

Metastatic or unresectable disease

Best supportive care

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Regimen

Study	Evidence	Comparator	Efficacy
Mir et al. 2016 (PAZOGIST)	Randomized Phase II (C)	Pazopanib	Seems to have inferior PFS

No active treatment. Used as a comparator arm and here for reference purposes only.

References

1. 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 contains protocol PubMed

Imatinib monotherapy

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Variant #1, standard-dose (400 mg/day)

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Demetri et al. 2002	Phase III (C)	Higher-dose imatinib (600 mg/day)	Seems not superior
Verweij et al. 2004 (EORTC 62005)	Phase III (C)	High-dose imatinib	Seems not superior (*)
Kang et al. 2013 (RIGHT)	Phase III (E)	Placebo	Superior PFS
Blay et al. 2015 (ENESTg1)	Phase III (C)	Nilotinib	Superior PFS
Blanke et al. 2015 (SWOG S0502)	Phase III (C)	Bevacizumab & Imatinib	Not reported

Note: Efficacy reported for EORTC 62005 is based on the 2017 update.

Chemotherapy

• Imatinib (Gleevec) 400 mg PO once per day, taken with food

Given until progression of disease or unacceptable toxicity

Variant #2, higher-dose (600 mg/day)

Study	Evidence	Comparator	Efficacy
Demetri et al. 2002	Phase III (E)	Standard-dose imatinib (400 mg/day)	Seems not superior

Chemotherapy

• Imatinib (Gleevec) 600 mg PO once per day, taken with food

Given until progression of disease or unacceptable toxicity

Variant #3, high-dose (800 mg/day)

Study	Evidence	Comparator	Efficacy
Verweij et al. 2004 (EORTC 62005)	Phase III (E)	Standard-dose imatinib	Seems not superior (*)
Blanke et al. 2008 (SWOG S0033)	Phase III (E)	Standard-dose imatinib with pre-planned dose-escalation at progression	Seems not superior
Blay et al. 2015 (ENESTg1)	Phase III (C)	Nilotinib	Superior PFS
Blanke et al. 2015 (SWOG S0502)	Phase III (C)	Bevacizumab & Imatinib	Not reported

Note: high-dose imatinib was offered to patients with KIT exon 9 mutations in ENESTg1 and SWOG S0502; all other patients received standard-dose imatinib. Efficacy reported for EORTC 62005 is based on the 2017 update.

Chemotherapy

• Imatinib (Gleevec) 400 mg PO twice a day, taken after a meal

Given until progression of disease or unacceptable toxicity

Variant #4, standard-dose with pre-planned dose-escalation at progression

Study	Evidence	Comparator	Efficacy
Blanke et al. 2008 (SWOG S0033)	Phase III (C)	High-dose imatinib (800 mg/day)	Seems not superior

Standard dose therapy

• Imatinib (Gleevec) 400 mg PO once per day

Given until progression of disease or unacceptable toxicity

Patients who progressed could receive high-dose therapy, as follows:

High-dose therapy

• Imatinib (Gleevec) 400 mg PO twice per day

Given until progression of disease or unacceptable toxicity

References

1. 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 contains verified protocol PubMed
2. 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. 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 contains verified protocol PubMed
3. 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 contains protocol PubMed
   1. 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; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, and 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 PubMed
4. 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 contains verified protocol PubMed
5. 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 PubMed
6. 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 contains verified protocol PubMed
7. 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 contains verified protocol PubMed
8. 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. contains verified protocol link to PMC article PubMed

Pazopanib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Mir et al. 2016 (PAZOGIST)	Randomized Phase II (E)	Best supportive care	Seems to have superior PFS

Chemotherapy

• Pazopanib (Votrient) 800 mg PO once per day

Given until progression of disease, unacceptable toxicity, withdrawal of consent, or death

References

1. 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 contains protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Demetri et al. 2006 (A6181004)	Phase III (C)	Sunitinib	Inferior TTP
Demetri et al. 2012 (GRID)	Phase III (C)	Regorafenib	Inferior PFS
Kang et al. 2013 (RIGHT)	Phase III (C)	Imatinib	Inferior PFS

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.

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 contains verified protocol 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. contains verified protocol link to PMC article PubMed
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 contains verified protocol PubMed

Regorafenib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Demetri et al. 2012 (GRID)	Phase III (E)	Placebo	Superior PFS

Patients in this study already had treatment failure with imatinib and sunitinib.

Chemotherapy

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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. contains verified protocol link to PMC article PubMed

Sunitinib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Demetri et al. 2006 (A6181004)	Phase III (E)	Placebo	Superior TTP

Patients in A6181004 had treatment failure with imatinib.

Chemotherapy

• Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
  • Dose may be decreased to 37.5 mg or 25 mg depending on tolerability

42-day cycles

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 contains verified protocol PubMed