Advertisement

New Agents for Gastrointestinal Stromal Tumors

  • Yoichi NaitoEmail author
  • Toshihiko Doi
Chapter

Abstract

Gastrointestinal stromal tumors (GISTs) are rare soft tissue sarcomas arising from gastrointestinal tract. Standard of care for metastatic GIST is molecular targeted therapy (imatinib, sunitinib, and regorafenib). Developmental therapeutics for GIST is focused on primary or acquired resistance to these agents. In this section, we discuss new agents for the treatment of GIST.

Keywords

Developmental therapeutics Gastrointestinal stromal tumor Imatinib resistance 

References

  1. 1.
    Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, Zhu XJ, Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Gebreyohannes YK, Schöffski P, Heinrich MC, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med. 2017;9(414):eaao1690.CrossRefGoogle Scholar
  2. 2.
    Heinrich MC, Jones RL, von Mehren M, Schoffski P, Bauer S, Mir O, Cassier PA, Eskens F, Shi H, Alvarez-Diez T, Schmidt-Kittler O, Healy ME, Wolf BB, George S. Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2017;35(15_suppl):11011.CrossRefGoogle Scholar
  3. 3.
    (VOYAGER) Study of avapritinib vs regorafenib in patients with locally advanced unresectable or metastatic GIST. Available from https://clinicaltrials.gov/ct2/show/NCT03465722.
  4. 4.
    Janku F, et al. Encouraging activity of novel pan-KIT and PDGFRα inhibitor DCC-2618 in patients (pts) with gastrointestinal stromal tumor (GIST). Ann Oncol. 2017;28(5):v521–38.Google Scholar
  5. 5.
    Phase 3 study of DCC-2618 vs placebo in advanced GIST patients who have been treated with prior anticancer therapies (invictus). Available from https://clinicaltrials.gov/ct2/show/NCT03353753.
  6. 6.
    Le Cesne A, Blay JY, Bui BN, Bouché O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, Moussy A, Kinet JP, Hermine O. Phase II study of oral masitinib mesylate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). Eur J Cancer. 2010;46(8):1344–51.CrossRefGoogle Scholar
  7. 7.
    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;25(9):1762–9.CrossRefGoogle Scholar
  8. 8.
    A phase 3 study to evaluate efficacy and safety of masitinib in comparison to sunitinib in patients with gastrointestinal stromal tumour after progression with imatinib. Available from https://clinicaltrials.gov/ct2/show/NCT01694277.
  9. 9.
    A phase 3 study to evaluate efficacy and safety of masitinib in comparison to imatinib in patients with gastro-intestinal stromal tumour in first line medical treatment. Available from https://clinicaltrials.gov/ct2/show/NCT00812240.
  10. 10.
    Masitinib vs placebo - phase iii study to compare the efficacy and safety of masitinib to placebo in patients with localized, primary gist after complete surgery and with high risk of recurrence. Available from https://clinicaltrials.gov/ct2/show/NCT02009423.
  11. 11.
    Wagner AJ, Chugh R, Rosen LS, Morgan JA, George S, Gordon M, Dunbar J, Normant E, Grayzel D, Demetri GD. A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas. Clin Cancer Res. 2013;19(21):6020–9.CrossRefGoogle Scholar
  12. 12.
    Demetri G, Le Cesne A, Von Mehren M, Chmielowski B, Bauer S, Chow W, et al. Final results from a phase III study of IPI-504 (retaspimycin hydrochloride) versus placebo in patients (pts) with gastrointestinal stromal tumors (GIST) following failure of kinase inhibitor therapies. 2010 ASCO Gastrointestinal Cancers Symposium. Abstract No. 64.Google Scholar
  13. 13.
    Bendell JC, Bauer TM, Lamar R, Joseph M, Penley W, Thompson DS, Spigel DR, Owera R, Lane CM, Earwood C, Burris HA 3rd. A phase 2 study of the Hsp90 inhibitor AUY922 as treatment for patients with refractory gastrointestinal stromal tumors. Cancer Investig. 2016;34(6):265–70.CrossRefGoogle Scholar
  14. 14.
    Kurokawa Y, Doi T, Sawaki A, Komatsu Y, Ozaka M, Takahashi T, Naito Y, Okubo S, Nishida T. Phase II study of TAS-116, an oral inhibitor of heat shock protein 90 (HSP90) in metastatic or unresectable gastrointestinal stromal tumor refractory to imatinib, sunitinib and regorafenib. Ann Oncol. 2017;28(Suppl 5):Abstr 1479PD.Google Scholar
  15. 15.
    Kampa-Schittenhelm KM, Frey J, Haeusser LA, Illing B, Pavlovsky AA, Blumenstock G, Schittenhelm MM. Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia. Oncotarget. 2017;8(47):82897–909.CrossRefGoogle Scholar
  16. 16.
    von Mehren M, Tetzlaff ED, Macaraeg M, Davis J, Agarwal V, Ramachandran A, et al. Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations. J Clin Oncol. 2016;34(suppl 5):11010.CrossRefGoogle Scholar
  17. 17.
    Randomized trial of crenolanib in subjects with D842V mutated GIST. Available from https://clinicaltrials.gov/ct2/show/NCT02847429.
  18. 18.
    Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865–78.CrossRefGoogle Scholar
  19. 19.
    Shi E, Chmielecki J, Tang CM, Wang K, Heinrich MC, Kang G, Corless CL, Hong D, Fero KE, Murphy JD, Fanta PT, Ali SM, De Siena M, Burgoyne AM, Movva S, Madlensky L, Heestand GM, Trent JC, Kurzrock R, Morosini D, Ross JS, Harismendy O, Sicklick JK. FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors. J Transl Med. 2016;14(1):339.CrossRefGoogle Scholar
  20. 20.
    Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35(11):1712–21.CrossRefGoogle Scholar
  21. 21.
    Study of the glutaminase inhibitor CB-839 in solid tumors. Available from https://clinicaltrials.gov/ct2/show/NCT02071862.
  22. 22.
    A phase II trial of the DNA methyl transferase inhibitor, guadecitabine (SGI-110), in children and adults with wild type GIST, pheochromocytoma and paraganglioma associated with succinate dehydrogenase deficiency and HLRCC-associated kidney cancer. Available from https://clinicaltrials.gov/ct2/show/NCT03165721.
  23. 23.
    Mitogen activated protein kinase kinase (MEK1/2) inhibitor selumetinib (AZD6244 Hydrogen Sulfate) in people with neurofibromatosis type 1 (NF1) mutated gastrointestinal stromal tumors (GIST). Available from https://clinicaltrials.gov/ct2/show/NCT03109301.
  24. 24.
    Falchook GS, Trent JC, Heinrich MC, Beadling C, Patterson J, Bastida CC, et al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget. 2013;4(2):310–5.CrossRefGoogle Scholar
  25. 25.
    Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–9.CrossRefGoogle Scholar
  26. 26.
    Liu D, Offin M, Harnicar S, Li BT, Drilon A. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018;14:1247–52.CrossRefGoogle Scholar
  27. 27.
    Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.CrossRefGoogle Scholar
  28. 28.
    Singh AS, Chmielowski B, Randolph Hecht J, Rosen LS, Wang X, Brackert S, Adame CR, Linares PJ, Schink E, Marubio LM, Eilber FC. A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST). J Clin Oncol. 2018;36(suppl 4S):abstr 55.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Experimental TherapeuticsNational Cancer Center Hospital EastKashiwaJapan

Personalised recommendations