Email this article Ripretinib (DCC-2618): a new tyrosine kinase inhibitor for the treatment of metastatic gastrointestinal stromal tumors
- Authors: Filonenko D.A1, Tikhomirova T.E.1, Meshcheryakov A.A.1
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Affiliations:
- N.N. Blokhin Cancer Research Center
- Issue: Vol 25, No 1 (2020)
- Pages: 4-8
- Section: Original Study Articles
- URL: https://rjonco.com/1028-9984/article/view/35003
- DOI: https://doi.org/10.18821/1028-9984-2020-25-1-4-8
- ID: 35003
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Abstract
Ripretinib (DCC-2618) is a novel tyrosine kinase inhibitor designed to broadly inhibit primary and secondary mutations in KIT (exons 9,11, 13, 14,17,18) and PDGFRA (exon 18). Here in our article we describe clinical trials of ripretinib for patient with advanced gastrointestinal stromal tumors (GIST).
The clinical trial INVICTUS-randomized phase III study of ripretinib for patient with advanced GIST in ≥4 lines therapy; it is the most important results, because there are currently no approved drugs for such patients. Median PFS was significantly improved with ripretinib compared with placebo 6,3 и 1 months (p<0,0001) and median OS was significantly improved with ripretinib compared with placebo 15,1 и 6,6 months (p<0,004).
High efficacy of ripretinib was accompanied with favorable profile of toxicity, only 8,2% patients experienced treatment discontinuations due to adverse events.
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About the authors
D.. A Filonenko
N.N. Blokhin Cancer Research Center
Author for correspondence.
Email: shubina_d@mail.ru
ORCID iD: 0000-0002-7224-3111
Russian Federation, Moscow, 115478
T. E. Tikhomirova
N.N. Blokhin Cancer Research Center
Email: shubina_d@mail.ru
ORCID iD: 0000-0002-7313-4013
Russian Federation, Moscow, 115478
A. A. Meshcheryakov
N.N. Blokhin Cancer Research Center
Email: shubina_d@mail.ru
ORCID iD: 0000-0002-6009-653X
Russian Federation, Moscow, 115478
References
- Paolo G. Casali, John Zalcberg, Axel Le Cesne et al. 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. Clin. Oncol. 2017; 35: 1713–20.
- Demetri G.D., von Mehren M., Blanke C.D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 2002; 347 (7): 472.
- Verweij J., Casali P.G., Zalcberg J. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364 (9440): 1127.
- Blanke C.D., Rankin C., Demetri G.D. et al. 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; 26 (4): 626.
- Desai J. et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin. Cancer Res. 2007; 13 (18 Pt 1), 5398–405.
- Heinrich M. C. et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J. Clin. Oncol. 2006; 24, 4764–74.
- Liegl B. et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J. Pathol. 2008; 216: 64–74.
- Wardelmann E. et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin. Cancer Res. 2006; 12: 1743–9.
- Demetri G.D., van Oosterom A.T., Garrett C.R. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006; 368: 1329–38.
- Demetri G.D., Reichardt P., Kang Y.-K. et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebocontrolled phase 3 trial (GRID). Lancet. 2013; January 26; 381 (9863): 1–14.
- Heinrich M.C., Maki R.G. Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor. JCO. 2006; 23: 5352–9.
- Reichardt P., Demetri G.D., Gelderblom H., Rutkowski P., Seock-Ah Im. 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.
- Napolitano A., Vincenzi B.. Secondary KIT mutations: the GIST of drug resistance and sensitivity. Journal of Cancer. 2019; 120: 577–8.
- Hsueh Y. S. et al. Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations. PLoS One. 2013; 8, e65762.
- Serrano C. et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br. J. Cancer. 2019; 120.
- Yeh C.N. et al. A phase II trial of regorafenib in patients with metastatic and/or an unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17. Oncotarget. 2017; 8: 44121–30.
- Smith B.D., KaufmanM.D., Lu W.-P. 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: 738–51.
- George S., Rodon Ahnert J., Wolf J. et al. Initial results of Phase I study of DCC-2618, a broad-spectrum KIT and PDGFRa inhibitor, in patients (pts) with gastrointestinal stromal tumor (GIST) by number of prior regimens. Ann. Oncol. 2018; 29(Suppl. 8), viii576–viii577.
- Von Mehren M., Serrano C., Bauer S. et al. INVICTUS: a Phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Presented at: European Society of Medical Oncology. Barcelona, Spain, 27September–1 October 2019.
- Nemunaitis J., Bauer S. et al. Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020; 16 (1): 4251–64.
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