Gastrointestinal stromal tumor

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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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Regimen #1, 3 years of treatment

Study	Evidence	Comparator	Efficacy
Joensuu et al. 2012	Phase III	Imatinib x 12 mos	Seems to have superior OS

Treatment is to be started within 12 weeks after surgery.

Chemotherapy

• Imatinib (Gleevec) 400 mg PO once per day

36-month course

Regimen #2, 1 year of treatment

Study	Evidence	Comparator	Efficacy
Dematteo et al. 2009	Phase III	Placebo	Superior RFS
Joensuu et al. 2012	Phase III	Imatinib x 36 mos	Seems to have inferior OS

Treatment is started within 12 weeks after surgery.

Chemotherapy

• Imatinib (Gleevec) 400 mg PO once per day

1-year course

References

1. 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. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Sch?tte 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, Alveg?rd 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

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Dematteo et al. 2009	Phase III	Imatinib x 12 mos	Inferior RFS

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

References

1. 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

Imatinib monotherapy

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

Study	Evidence	Comparator	Efficacy
Demetri et al. 2002	Phase III	Higher-dose imatinib (600 mg/day)	Seems not superior
Blanke et al. 2015 (SWOG S0502)	Phase III	Bevacizumab & Imatinib	Not reported

Chemotherapy

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

Given until progression of disease or unacceptable toxicity

Regimen #2, high-dose (800 mg/day)

Study	Evidence	Comparator	Efficacy
Verweij et al. 2003	Phase II
Blanke et al. 2008 (SWOG S0033)	Phase III	Standard-dose imatinib with pre-planned dose-escalation at progression	Seems not superior
Blanke et al. 2015 (SWOG S0502)	Phase III	Bevacizumab & Imatinib	Not reported

Note: high-dose imatinib was offered to patients with KIT exon 9 mutations in SWOG S0502; all other patients received standard-dose imatinib.

Chemotherapy

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

Given until progression of disease or unacceptable toxicity

Regimen #3, standard-dose with pre-planned dose-escalation at progression

Study	Evidence	Comparator	Efficacy
Blanke et al. 2008 (SWOG S0033)	Phase III	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

Regimen #4, higher-dose (600 mg/day)

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

Chemotherapy

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

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. 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
4. 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
5. 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
6. 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	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	Phase III	Sunitinib	Inferior TTP
Demetri et al. 2012 (GRID)	Phase III	Regorafenib	Inferior PFS
Mir et al. 2016 (PAZOGIST)	Randomized Phase II	Pazopanib	Seems to have inferior PFS

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

References

1. 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. 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, Sch?ffski 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. 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
4. 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

Regorafenib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Demetri et al. 2012 (GRID)	Phase III	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, given until progression of disease or unacceptable toxicity

References

1. 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, Sch?ffski 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	Phase III	Placebo	Superior TTP

Patients in Demetri et al. 2006 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, given until progression of disease or unacceptable toxicity

References

1. 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. Prior JO, Montemurro M, Orcurto MV, Michielin O, Luthi F, Benhattar J, Guillou L, Elsig V, Stupp R, Delaloye AB, Leyvraz S. Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol. 2009 Jan 20;27(3):439-45. Epub 2008 Dec 8. link to original article contains verified protocol PubMed

Temozolomide monotherapy

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• Regimen is the same as Temozolomide (Temodar) single-agent therapy in soft tissue sarcoma, Garcia del Muro et al. 2005