Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors

Abstract

Discovery of constitutive activation of KIT/PDGFRA tyrosine kinases in gastrointestinal stromal tumors (GISTs) leads to the development of the targeted drug imatinib. However, the inevitable development of imatinib resistance remains a major issue. Ripretinib is a novel targeted drug that inhibits the activities of a broad spectrum of drug-resistant KIT/PDGFRA mutants. It was approved in 2020 and is currently recommended by major international guidelines as the fourth-line and beyond therapy for advanced GISTs. Emerging evidence shows that ripretinib is superior to sunitinib as a second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the targeted GIST treatment.

Keywords

drug resistance / gastrointestinal stromal tumors / imatinib mesylate / ripretinib / tyrosine protein kinase inhibitors

References

[1] Blay JY,Kang YK,Nishida T,von Mehren M. Gastrointestinal stromal tumours. Nat Rev Dis Primers. 2021; 7(1):22.

[2] Søreide K,Sandvik OM,Søreide JA,Giljaca V,Jureckova A,Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 2016; 40:39-46.

[3] von Mehren M,Joensuu H. Gastrointestinal stromal tumors. J Clin Oncol. 2018; 36(2):136-143.

[4] Corless CL,Barnett CM,Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011; 11(12):865-878.

[5] Serrano C,George S. Gastrointestinal stromal tumor: challenges and opportunities for a new decade. Clin Cancer Res. 2020; 26(19):5078-5085.

[6] Joensuu H,Hohenberger P,Corless CL. Gastrointestinal stromal tumour. Lancet. 2013; 382(9896):973-983.

[7] Casali PG,Abecassis N,Aro HT, et al; ESMO Guidelines Committee and EURACAN. Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29(Suppl):iv68–iv78.

[8] von Mehren M,Randall RL,Benjamin RS, et al. Gastrointestinal stromal tumors, version 2.2014. J Natl Compr Canc Netw. 2014; 12(6):853-862.

[9] Antonescu C. Gastrointestinal stromal tumors. Curr Top Microbiol Immunol. 2012; 355:41-57.

[10] Demetri GD,van Oosterom AT,Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006; 368(9544):1329-1338.

[11] Smith BD,Kaufman MD,Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019; 35(5):738-751.e9.

[12] Blay JY,Serrano C,Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020; 21(7):923-934.

[13] Nishida T,Kanda T,Nishitani A, et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci. 2008; 99(4):799-804.

[14] Gajiwala KS,Wu JC,Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 2009; 106(5):1542-1547.

[15] Goggin C,Stansfeld A,Mahalingam P, et al. Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval. Future Oncol. 2022; 18(26):2967-2978.

[16] Heinrich MC,Corless CL,Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006; 24(49):4764-4774.

[17] Boichuk S,Galembikova A,Dunaev P, et al. Targeting of FGF-signaling re-sensitizes gastrointestinal stromal tumors (GIST) to imatinib in vitro and in vivo. Molecules. 2018; 23(10):2643.

[18] Dermawan JK,Rubin BP. Molecular pathogenesis of gastrointestinal stromal tumor: a paradigm for personalized medicine. Annu Rev Pathol. 2022; 17:323-344.

[19] Javidi-Sharifi N,Traer E,Martinez J, et al. Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance. Cancer Res. 2015; 75(5):880-891.

[20] Lee JH,Kim Y,Choi JW,Kim YS. Correlation of imatinib resistance with the mutational status of KIT and PDGFRA genes in gastrointestinal stromal tumors: a meta-analysis. J Gastrointestin Liver Dis. 2013; 22(4):413-418.

[21] Napolitano A,Thway K,Smith MJ,Huang PH,Jones RL. KIT exon 9-mutated gastrointestinal stromal tumours: biology and treatment. Chemotherapy. 2022; 67(2):81-90.

[22] Heinrich MC,Maki RG,Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008; 26(33):5352-5359.

[23] Reichardt P,Demetri GD,Gelderblom H, et al. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. BMC Cancer. 2016; 16:22.

[24] Li J,Gao J,Hong JL,Shen L. Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Future Oncol. 2012; 8(5):617-624.

[25] Janku F,Abdul Razak AR,Chi P, et al. Switch control inhibition of KIT and PDGFRA in patients with advanced gastrointestinal stromal tumor: a phase I study of ripretinib. J Clin Oncol. 2020; 38(28):3294-3303.

[26] Lostes-Bardaji MJ,García-Illescas D,Valverde C,Serrano C. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward. Ther Adv Med Oncol. 2021; 13:1758835920986498.

[27] Zhao Q,Zhang C,Qi CS, et al. Preclinical model-based evaluation of imatinib resistance induced by KIT mutations and its overcoming strategies in gastrointestinal stromal tumor (GIST). Am J Transl Res. 2021; 13(12):13608-13624.

[28] Bauer S,Heinrich MC,George S, et al. Clinical activity of ripretinib in patients with advanced gastrointestinal stromal tumor harboring heterogeneous KIT/PDGFRA mutations in the phase III INVICTUS study. Clin Cancer Res. 2021; 27(23):6333-6342.

[29] Bauer S,Jones RL,Blay JY, et al. 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; 40(34):3918-3928.

[30] von Mehren M,Heinrich MC,George S, et al. 1540P Ripretinib as ≥4th-line treatment in patients with advanced gastrointestinal stromal tumor: long-term update from the phase III INVICTUS study. Ann Oncol. 2021; 32(Suppl 5): S1120-S1121.

[31] Li J,Cai SR,Zhou YJ, et al. Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors as a fourth-or later-line therapy: a multicenter, single-arm, open-label phase II study. Clin Cancer Res. 2022; 28(16):3425-3432.

[32] Li J,Zhang J,Wu XY, et al. Abstract LB126: Population and non-compartmental pharmacokinetic analysis of ripretinib and its active metabolite in Chinese patients with gastrointestinal stromal tumor. Cancer Res. 2021; 81(13 Suppl):LB126.

[33] Heinrich MC,Jones RL,Gelderblom H, et al. INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib. J Clin Oncol. 2022; 40(36 Suppl):359881.

[34] Gelderblom H,Jones RL,Blay JY, et al. Patient reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after imatinib treatment in INTRIGUE: a phase 3 open-label study. J Clin Oncol. 2022; 40(16 Suppl):11541.

[35] Li J,Zhang J,Zhang YQ, et al. Efficacy and safety of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: a phase 2 multicenter, randomized, open-label study in China. 2023 ASCO Gastrointestinal Cancers Symposium,J Clin Oncol. 2023; 41(4 Suppl):803.

[36] Antonescu CR,Besmer P,Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005; 11(11):4182-4190.

[37] Debiec-Rychter M,Cools J,Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005; 128(2):270-279.

[38] Rubin BP,Duensing A. Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 2006; 86(10):981-986.

[39] Heinrich MC,Owzar K,Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008; 26(33):5360-5367.

[40] Huang SQ,Guo XD,Xia YZ, et al. Genotyping guided ripretinib directly after the progression of first-line imatinib therapy in advanced gastrointestinal stromal tumor: a case report. Ann Transl Med. 2022; 10(2):118.

[41] George S,Chi P,Heinrich MC, et al. Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour. Eur J Cancer. 2021; 155:236-244.

[42] Senchak J,Ahr K,von Mehren M. Gastrointestinal stromal tumors: what is the best sequence of TKIs? Curr Treat Options Oncol. 2022; 23(5):749-761.

RIGHTS & PERMISSIONS

2023 The Author(s). Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.