Gastrointestinal stromal tumor

Comparator

Dematteo et al. 2009 (ACOSOG Z9001)

ESMO-MCBS (A)

2002-2007

Phase 3 (E-RT-esc)

Joensuu et al. 2012 (SSG XVIII/AIO)

Superior RFS (primary endpoint)
RFS12: 98% vs 83%
(HR 0.35, 95% CI 0.22-0.53)

2004-2008

Phase 3 (C)

Imatinib x 36 mos

Inferior 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

12-month course

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

2-year course

Regimen variant #3, 3 years of treatment

FDA-recommended dose

Study

Dates of enrollment

Comparator

Joensuu et al. 2012 (SSG XVIII/AIO)

ESMO-MCBS (A)

2004-2008

Phase 3 (E-RT-esc)

Imatinib x 12 mos

Superior OS¹ (secondary endpoint)
OS120: 79% vs 65.3%
(HR 0.55, 95% CI 0.37-0.83)

¹Reported efficacy is based on the 2020 update.
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.

Biomarker eligibility criteria

Kit (CD117) positive

Preceding treatment

Surgery

Targeted therapy

Imatinib (Gleevec) 400 mg PO once per day

36-month course

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 contains dosing details in manuscript 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 original article link to PMC article PubMed
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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in manuscript PubMed NCT00116935
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
2. 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 PubMed

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	2000-2001	Phase 3 (C)	Imatinib; higher-dose (600 mg/day)	Did not meet primary endpoint of ORR
Verweij et al. 2004 (EORTC 62005)	2001-2002	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 y 2. Imatinib x 3 y	Superior PFS
Blanke et al. 2015 (SWOG S0502)	2008-2009	Phase 3 (C)	Imatinib & Bevacizumab	Not reported
Blay et al. 2015 (ENESTg1)	2009-2011	Phase 3 (C)	Nilotinib	Superior PFS
Kang et al. 2013 (RIGHT)	2010-2013	Phase 3 (E-esc)	Placebo	Superior PFS 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.
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: 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

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Demetri et al. 2002	2000-2001	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, <20 pts in this cohort
Verweij et al. 2003	NR	Phase 2
Verweij et al. 2004 (EORTC 62005)	2001-2002	Phase 3 (E-RT-esc)	Imatinib; standard-dose	Did not meet primary endpoint of PFS¹
Blanke et al. 2008 (SWOG S0033)	2001-2002	Phase 3 (E-RT-esc)	Imatinib; standard-dose with pre-planned dose-escalation at progression	Did not meet primary endpoints of PFS/OS
Blanke et al. 2015 (SWOG S0502)	2008-2009	Phase 3 (C)	Imatinib & Bevacizumab	Not reported
Blay et al. 2015 (ENESTg1)	2009-2011	Phase 3 (C)	Nilotinib	Superior PFS

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

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Blanke et al. 2008 (SWOG S0033)	2001-2002	Phase 3 (C)	Imatinib; high-dose (800 mg/day)	Did not meet primary endpoints of PFS/OS

Prior treatment criteria

SWOG S0033: Any number of prior chemotherapy regimens

Targeted therapy

Imatinib (Gleevec) 400 mg PO once per day

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

Targeted therapy

Imatinib (Gleevec) 400 mg PO twice per 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 contains dosing details in abstract PubMed
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 dosing details in manuscript PubMed
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 contains dosing details in manuscript PubMed
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 dosing details in abstract PubMed NCT00685828
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in abstract PubMed NCT00367861
1. 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 contains dosing details in abstract PubMed
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 dosing details in manuscript PubMed NCT00009906
1. 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 PubMed
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
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 dosing details in manuscript PubMed 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 contains dosing details in manuscript PubMed 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 contains dosing details in manuscript link to PMC article PubMed 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

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 contains dosing details in manuscript PubMed NCT01560260

Sunitinib monotherapy

Regimen

Study

Dates of enrollment

Comparator

Demetri et al. 2006 (A6181004)

ESMO-MCBS (3)

2003-2005

Phase 3 (E-RT-esc)

Adenis et al. 2014 (AB07001)

Superior TTP (primary endpoint)
Median TTP: 27.3 vs 6.4 weeks
(HR 0.33)

2009-2011

Randomized Phase 2 (C)

Masitinib

Seems to have inferior OS

Bauer et al. 2022 (INTRIGUE)

2019-NR

Phase 3 (C)

Ripretinib

Did not meet primary endpoint of PFS

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 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 contains dosing details in manuscript 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
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 PubMed 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 contains dosing details in abstract PubMed NCT03673501
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

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 contains dosing details in abstract PubMed 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 superior PFS 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

Continued indefinitely

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 contains dosing details in abstract PubMed NCT01323400

Regorafenib monotherapy

Regimen

Study

Dates of enrollment

Comparator

Demetri et al. 2012 (GRID)

ESMO-MCBS (3)

2011

Phase 3 (E-RT-esc)

Kang et al. 2021 (VOYAGER)

Superior PFS (primary endpoint)
Median PFS: 4.8 vs 0.9 mo
(HR 0.27, 95% CI 0.19-0.39)

2018-2019

Phase 3 (C)

Avapritinib

Might have superior PFS
Median 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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in abstract link to PMC article PubMed 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 contains dosing details in abstract PubMed 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

Heinrich et al. 2020 (NAVIGATOR)

ESMO-MCBS (3)

2015-2018

Phase 1 (RT)

Note: Patients in this study either had the PDGFRA D842V mutation or already had treatment failure with imatinib and ≥1 additional tyrosine kinase inhibitor. This is the recommended phase II dose.

Biomarker eligibility criteria

Gene: PDGFRA
Alteration: D842V

Targeted therapy

Avapritinib (Ayvakit) 300 mg PO once per day 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 contains dosing details in abstract PubMed NCT02508532
1. 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 PubMed

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	Superior OS 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 contains dosing details in manuscript PubMed JapicCTI-184094

Ripretinib monotherapy

Regimen

FDA-recommended dose

Study

Dates of enrollment

Comparator

Blay et al. 2020 (INVICTUS)

ESMO-MCBS (3)

2018

Phase 3 (E-RT-esc)