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Published in: Targeted Oncology 4/2018

01-08-2018 | Review Article

Growing Role of Regorafenib in the Treatment of Patients with Sarcoma

Authors: Mark Agulnik, Steven Attia

Published in: Targeted Oncology | Issue 4/2018

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Abstract

Sarcomas encompass a group of rare solid tumors responsible for approximately 1% of all cancer-related deaths in the United States each year. Subtypes include, but are not limited to, soft tissue sarcomas (STS) such as leiomyosarcoma, liposarcoma, pleomorphic sarcoma, and gastrointestinal stromal tumor (GIST). Treatment options for patients with STS vary depending on, among other factors, histological subtype. Data from a mix of phase 2 and phase 3 trials have suggested that the orally available multikinase inhibitor regorafenib may have efficacy in patients with STS who have progressed on previous lines of systemic therapy. Some clinical benefit of regorafenib has been shown in patients with leiomyosarcoma, synovial sarcoma, GIST, Ewing’s sarcoma, and other sarcoma subtypes, suggesting a broad spectrum of potential activity in this population. Studies have also shown that the safety profile of regorafenib is acceptable in these patients, with adverse events that can be managed through dose reductions and/or interruptions as well as other supportive measures.
Literature
1.
2.
go back to reference Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchere D, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91(10):1914–26.CrossRefPubMed Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchere D, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91(10):1914–26.CrossRefPubMed
3.
go back to reference Demetri GD, von Mehren M, Antonescu CR, Dematteo RP, Ganjoo KN, Maki RG, et al. NCCN task force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Cancer Netw. 2010;8(Suppl 2):S1–S41.CrossRef Demetri GD, von Mehren M, Antonescu CR, Dematteo RP, Ganjoo KN, Maki RG, et al. NCCN task force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Cancer Netw. 2010;8(Suppl 2):S1–S41.CrossRef
5.
go back to reference Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–8.CrossRefPubMedPubMedCentral Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–8.CrossRefPubMedPubMedCentral
6.
go back to reference Attia S, Bolejack V, Ganjoo KN, George S, Agulnik M, Rushing DA, et al. A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results. J Clin Oncol. 2017;35(15 suppl; abstr 11005). Attia S, Bolejack V, Ganjoo KN, George S, Agulnik M, Rushing DA, et al. A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results. J Clin Oncol. 2017;35(15 suppl; abstr 11005).
7.
go back to reference Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1732–42.CrossRefPubMed Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1732–42.CrossRefPubMed
8.
go back to reference Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, 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):626–32.CrossRefPubMed Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, 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):626–32.CrossRefPubMed
9.
go back to reference Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127–34.CrossRefPubMed Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127–34.CrossRefPubMed
10.
go back to reference Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, 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):1329–38.CrossRefPubMed Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, 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):1329–38.CrossRefPubMed
11.
go back to reference Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. 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;381(3863):295–302.CrossRefPubMed Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. 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;381(3863):295–302.CrossRefPubMed
12.
go back to reference Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.CrossRefPubMed Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.CrossRefPubMed
13.
go back to reference van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.CrossRefPubMed van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.CrossRefPubMed
14.
go back to reference Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005;35(11):3332–42.CrossRefPubMed Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005;35(11):3332–42.CrossRefPubMed
15.
go back to reference Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.CrossRefPubMed Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.CrossRefPubMed
16.
go back to reference Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29.CrossRefPubMed Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29.CrossRefPubMed
17.
go back to reference Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.CrossRefPubMed Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.CrossRefPubMed
18.
go back to reference Dressel A, Vogelgesang A, Brinkmeier H, Mader M, Weber F. Glatiramer acetate-specific human CD8(+) T cells: increased IL-4 production in multiple sclerosis is reduced by glatiramer acetate treatment. J Neuroimmunol. 2006;181(1–2):133–40.CrossRefPubMed Dressel A, Vogelgesang A, Brinkmeier H, Mader M, Weber F. Glatiramer acetate-specific human CD8(+) T cells: increased IL-4 production in multiple sclerosis is reduced by glatiramer acetate treatment. J Neuroimmunol. 2006;181(1–2):133–40.CrossRefPubMed
19.
go back to reference Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–9.CrossRefPubMed Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–9.CrossRefPubMed
20.
go back to reference George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012;30(19):2401–7.CrossRefPubMedPubMedCentral George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012;30(19):2401–7.CrossRefPubMedPubMedCentral
21.
go back to reference Ben-Ami E, Barysauskas CM, von Mehren M, Heinrich MC, Corless CL, Butrynski JE, et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol. 2016;27(9):1794–9.CrossRefPubMedPubMedCentral Ben-Ami E, Barysauskas CM, von Mehren M, Heinrich MC, Corless CL, Butrynski JE, et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol. 2016;27(9):1794–9.CrossRefPubMedPubMedCentral
22.
go back to reference Demetri GD, Reichardt P, Kang YK, Blay JY, Joensuu H, Schafer H, et al. An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID). J Clin Oncol. 2015;33(3 suppl; abstr 110). Demetri GD, Reichardt P, Kang YK, Blay JY, Joensuu H, Schafer H, et al. An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID). J Clin Oncol. 2015;33(3 suppl; abstr 110).
23.
go back to reference Schvartsman G, Wagner MJ, Amini B, Zobniw CM, Trinh VA, Barbo AG, et al. Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients. Sci Rep. 2017;7(1):9519.CrossRefPubMedPubMedCentral Schvartsman G, Wagner MJ, Amini B, Zobniw CM, Trinh VA, Barbo AG, et al. Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients. Sci Rep. 2017;7(1):9519.CrossRefPubMedPubMedCentral
24.
go back to reference Son MK, Ryu MH, Park JO, Im SA, Kim TY, Lee SJ, et al. Efficacy and safety of Regorafenib in Korean patients with advanced gastrointestinal Stromal tumor after failure of Imatinib and Sunitinib: a multicenter study based on the management access program. Cancer Res Treat. 2017;49(2):350–7.CrossRefPubMed Son MK, Ryu MH, Park JO, Im SA, Kim TY, Lee SJ, et al. Efficacy and safety of Regorafenib in Korean patients with advanced gastrointestinal Stromal tumor after failure of Imatinib and Sunitinib: a multicenter study based on the management access program. Cancer Res Treat. 2017;49(2):350–7.CrossRefPubMed
25.
go back to reference Heinrich MC, Jones RL, Von Mehren M, Schoffski P, Bauer S, Mir O. Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2017;35(15 suppl; abstr 11011). Heinrich MC, Jones RL, Von Mehren M, Schoffski P, Bauer S, Mir O. Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2017;35(15 suppl; abstr 11011).
26.
go back to reference Janku F, Abdul Razak A, Gordon M, Brooks D, Flynn D, Kaufmann M. Pharmacokinetic-driven phase I study of DCC-2618, a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors. J Clin Oncol. 2017;35(15 suppl; abstr 2515). Janku F, Abdul Razak A, Gordon M, Brooks D, Flynn D, Kaufmann M. Pharmacokinetic-driven phase I study of DCC-2618, a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors. J Clin Oncol. 2017;35(15 suppl; abstr 2515).
27.
go back to reference Burgess MA, Bolejack V, Van Tine BA, Schuetze S, Hu J, D’Angelo SP. Multicenter phase II study of pembrolizumab (P) in advanced soft tissue sarcoma (STS) and bone sarcomas (BS): final results of SARC028 and biomarker analyses. J Clin Oncol. 2017;35(15 suppl; abstr 11008). Burgess MA, Bolejack V, Van Tine BA, Schuetze S, Hu J, D’Angelo SP. Multicenter phase II study of pembrolizumab (P) in advanced soft tissue sarcoma (STS) and bone sarcomas (BS): final results of SARC028 and biomarker analyses. J Clin Oncol. 2017;35(15 suppl; abstr 11008).
28.
go back to reference D’Angelo SP, Mahoney MR, Van Tine BA, Atkins JN, Milhem MM, Tap WD, et al. A multi-center phase II study of nivolumab +/− ipilimumab for patients with metastatic sarcoma (Alliance A091401). J Clin Oncol. 2017;35(15 suppl; abstr 11007). D’Angelo SP, Mahoney MR, Van Tine BA, Atkins JN, Milhem MM, Tap WD, et al. A multi-center phase II study of nivolumab +/− ipilimumab for patients with metastatic sarcoma (Alliance A091401). J Clin Oncol. 2017;35(15 suppl; abstr 11007).
Metadata
Title
Growing Role of Regorafenib in the Treatment of Patients with Sarcoma
Authors
Mark Agulnik
Steven Attia
Publication date
01-08-2018
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 4/2018
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-018-0575-0

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