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

Suzanne George, Qian Wang, Michael Heinrich, Christopher Corless, Meijun Zhu, James E. Butrynski, Jeffrey A. Morgan, Andrew J. Wagner, Edwin Choy, William D. Tap, Jeffrey T. Yap, Annick D. Van Den Abbeele, Judith B. Manola, Sarah M. Solomon, Jonathan A. Fletcher, Margaret Von Mehren, George D. Demetri

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Abstract

Purpose: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients and Methods: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. Results: From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Conclusion: Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

Original languageEnglish (US)
Pages (from-to)2401-2407
Number of pages7
JournalJournal of Clinical Oncology
Volume30
Issue number19
DOIs
StatePublished - Jul 1 2012

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Safety
Neoplasms
Platelet-Derived Growth Factor Receptors
regorafenib
Imatinib Mesylate
sunitinib
Disease-Free Survival
Foot
Phosphotransferases
Hand
Placebos
Hypertension
Biopsy
Skin
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / George, Suzanne; Wang, Qian; Heinrich, Michael; Corless, Christopher; Zhu, Meijun; Butrynski, James E.; Morgan, Jeffrey A.; Wagner, Andrew J.; Choy, Edwin; Tap, William D.; Yap, Jeffrey T.; Van Den Abbeele, Annick D.; Manola, Judith B.; Solomon, Sarah M.; Fletcher, Jonathan A.; Von Mehren, Margaret; Demetri, George D.

In: Journal of Clinical Oncology, Vol. 30, No. 19, 01.07.2012, p. 2401-2407.

Research output: Contribution to journalArticle

George, S, Wang, Q, Heinrich, M, Corless, C, Zhu, M, Butrynski, JE, Morgan, JA, Wagner, AJ, Choy, E, Tap, WD, Yap, JT, Van Den Abbeele, AD, Manola, JB, Solomon, SM, Fletcher, JA, Von Mehren, M & Demetri, GD 2012, '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', Journal of Clinical Oncology, vol. 30, no. 19, pp. 2401-2407. https://doi.org/10.1200/JCO.2011.39.9394
George, Suzanne ; Wang, Qian ; Heinrich, Michael ; Corless, Christopher ; Zhu, Meijun ; Butrynski, James E. ; Morgan, Jeffrey A. ; Wagner, Andrew J. ; Choy, Edwin ; Tap, William D. ; Yap, Jeffrey T. ; Van Den Abbeele, Annick D. ; Manola, Judith B. ; Solomon, Sarah M. ; Fletcher, Jonathan A. ; Von Mehren, Margaret ; Demetri, George D. / 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. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 19. pp. 2401-2407.
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abstract = "Purpose: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients and Methods: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. Results: From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79{\%} (95{\%} CI, 61{\%} to 91{\%}). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Conclusion: Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.",
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T1 - Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib

T2 - A multicenter phase II trial

AU - George, Suzanne

AU - Wang, Qian

AU - Heinrich, Michael

AU - Corless, Christopher

AU - Zhu, Meijun

AU - Butrynski, James E.

AU - Morgan, Jeffrey A.

AU - Wagner, Andrew J.

AU - Choy, Edwin

AU - Tap, William D.

AU - Yap, Jeffrey T.

AU - Van Den Abbeele, Annick D.

AU - Manola, Judith B.

AU - Solomon, Sarah M.

AU - Fletcher, Jonathan A.

AU - Von Mehren, Margaret

AU - Demetri, George D.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Purpose: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients and Methods: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. Results: From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Conclusion: Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

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