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

E. Ben-Ami, C. M. Barysauskas, M. von Mehren, Michael Heinrich, Christopher Corless, J. E. Butrynski, J. A. Morgan, A. J. Wagner, E. Choy, J. T. Yap, A. D. Van den Abbeele, S. M. Solomon, J. A. Fletcher, G. D. Demetri, Suzanne George

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Abstract

Background: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. Patients and methods: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. Results: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. Conclusions: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. Clinical trial number: NCT01068769.

Original languageEnglish (US)
Article numbermdw228
Pages (from-to)1794-1799
Number of pages6
JournalAnnals of Oncology
Volume27
Issue number9
DOIs
StatePublished - Sep 1 2016

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Protein-Tyrosine Kinases
Gastrointestinal Stromal Tumors
Neoplasms
Disease-Free Survival
Therapeutics
Confidence Intervals
Safety
Exons
regorafenib
Mutation
Survival
Foot
Hand
Genotype
Research Personnel
Clinical Trials
Hypertension
Skin

Keywords

  • GIST
  • KIT mutation
  • Regorafenib
  • SDH-deficient GIST

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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. / Ben-Ami, E.; Barysauskas, C. M.; von Mehren, M.; Heinrich, Michael; Corless, Christopher; Butrynski, J. E.; Morgan, J. A.; Wagner, A. J.; Choy, E.; Yap, J. T.; Van den Abbeele, A. D.; Solomon, S. M.; Fletcher, J. A.; Demetri, G. D.; George, Suzanne.

In: Annals of Oncology, Vol. 27, No. 9, mdw228, 01.09.2016, p. 1794-1799.

Research output: Contribution to journalArticle

Ben-Ami, E, Barysauskas, CM, von Mehren, M, Heinrich, M, Corless, C, Butrynski, JE, Morgan, JA, Wagner, AJ, Choy, E, Yap, JT, Van den Abbeele, AD, Solomon, SM, Fletcher, JA, Demetri, GD & George, S 2016, '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', Annals of Oncology, vol. 27, no. 9, mdw228, pp. 1794-1799. https://doi.org/10.1093/annonc/mdw228
Ben-Ami, E. ; Barysauskas, C. M. ; von Mehren, M. ; Heinrich, Michael ; Corless, Christopher ; Butrynski, J. E. ; Morgan, J. A. ; Wagner, A. J. ; Choy, E. ; Yap, J. T. ; Van den Abbeele, A. D. ; Solomon, S. M. ; Fletcher, J. A. ; Demetri, G. D. ; George, Suzanne. / 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. In: Annals of Oncology. 2016 ; Vol. 27, No. 9. pp. 1794-1799.
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abstract = "Background: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. Patients and methods: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. Results: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76{\%}; 95{\%} confidence interval (CI) 58{\%} to 89{\%}], including six PRs. The median PFS was 13.2 months (95{\%} CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95{\%} CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. Conclusions: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. Clinical trial number: NCT01068769.",
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T1 - 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

AU - Ben-Ami, E.

AU - Barysauskas, C. M.

AU - von Mehren, M.

AU - Heinrich, Michael

AU - Corless, Christopher

AU - Butrynski, J. E.

AU - Morgan, J. A.

AU - Wagner, A. J.

AU - Choy, E.

AU - Yap, J. T.

AU - Van den Abbeele, A. D.

AU - Solomon, S. M.

AU - Fletcher, J. A.

AU - Demetri, G. D.

AU - George, Suzanne

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Background: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. Patients and methods: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. Results: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. Conclusions: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. Clinical trial number: NCT01068769.

AB - Background: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. Patients and methods: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. Results: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. Conclusions: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. Clinical trial number: NCT01068769.

KW - GIST

KW - KIT mutation

KW - Regorafenib

KW - SDH-deficient GIST

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