Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure

George D. Demetri, Michael Heinrich, Jonathan A. Fletcher, Christopher D M Fletcher, Annick D. Van Den Abbeele, Christopher Corless, Cristina R. Antonescu, Suzanne George, Jeffrey A. Morgan, Ming Hui Chen, Carlo L. Bello, Xin Huang, Darrel P. Cohen, Charles M. Baum, Robert G. Maki

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/ intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.

Original languageEnglish (US)
Pages (from-to)5902-5909
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number18
DOIs
StatePublished - Sep 15 2009

Fingerprint

Gastrointestinal Stromal Tumors
Appointments and Schedules
Pharmacokinetics
Deoxyglucose
Neoplasms
Positron-Emission Tomography
Cell Proliferation
Biopsy
Research Design
Therapeutics
Tomography
Phosphorylation
Imatinib Mesylate
sunitinib
Safety
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. / Demetri, George D.; Heinrich, Michael; Fletcher, Jonathan A.; Fletcher, Christopher D M; Van Den Abbeele, Annick D.; Corless, Christopher; Antonescu, Cristina R.; George, Suzanne; Morgan, Jeffrey A.; Chen, Ming Hui; Bello, Carlo L.; Huang, Xin; Cohen, Darrel P.; Baum, Charles M.; Maki, Robert G.

In: Clinical Cancer Research, Vol. 15, No. 18, 15.09.2009, p. 5902-5909.

Research output: Contribution to journalArticle

Demetri, GD, Heinrich, M, Fletcher, JA, Fletcher, CDM, Van Den Abbeele, AD, Corless, C, Antonescu, CR, George, S, Morgan, JA, Chen, MH, Bello, CL, Huang, X, Cohen, DP, Baum, CM & Maki, RG 2009, 'Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure', Clinical Cancer Research, vol. 15, no. 18, pp. 5902-5909. https://doi.org/10.1158/1078-0432.CCR-09-0482
Demetri, George D. ; Heinrich, Michael ; Fletcher, Jonathan A. ; Fletcher, Christopher D M ; Van Den Abbeele, Annick D. ; Corless, Christopher ; Antonescu, Cristina R. ; George, Suzanne ; Morgan, Jeffrey A. ; Chen, Ming Hui ; Bello, Carlo L. ; Huang, Xin ; Cohen, Darrel P. ; Baum, Charles M. ; Maki, Robert G. / Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 18. pp. 5902-5909.
@article{587d2793f5e04240b879bce892aef0e8,
title = "Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure",
abstract = "Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/ intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54{\%}: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25{\%} in 52{\%} of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79{\%} of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.",
author = "Demetri, {George D.} and Michael Heinrich and Fletcher, {Jonathan A.} and Fletcher, {Christopher D M} and {Van Den Abbeele}, {Annick D.} and Christopher Corless and Antonescu, {Cristina R.} and Suzanne George and Morgan, {Jeffrey A.} and Chen, {Ming Hui} and Bello, {Carlo L.} and Xin Huang and Cohen, {Darrel P.} and Baum, {Charles M.} and Maki, {Robert G.}",
year = "2009",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-09-0482",
language = "English (US)",
volume = "15",
pages = "5902--5909",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure

AU - Demetri, George D.

AU - Heinrich, Michael

AU - Fletcher, Jonathan A.

AU - Fletcher, Christopher D M

AU - Van Den Abbeele, Annick D.

AU - Corless, Christopher

AU - Antonescu, Cristina R.

AU - George, Suzanne

AU - Morgan, Jeffrey A.

AU - Chen, Ming Hui

AU - Bello, Carlo L.

AU - Huang, Xin

AU - Cohen, Darrel P.

AU - Baum, Charles M.

AU - Maki, Robert G.

PY - 2009/9/15

Y1 - 2009/9/15

N2 - Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/ intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.

AB - Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/ intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.

UR - http://www.scopus.com/inward/record.url?scp=70349471245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349471245&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-09-0482

DO - 10.1158/1078-0432.CCR-09-0482

M3 - Article

C2 - 19737946

AN - SCOPUS:70349471245

VL - 15

SP - 5902

EP - 5909

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -