Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib

Scott M. Schuetze, Vanessa Bolejack, Dafydd G. Thomas, Margaret Von Mehren, Shreyaskumar Patel, Brian Samuels, Edwin Choy, Gina D'Amato, Arthur P. Staddon, Kristen N. Ganjoo, Warren A. Chow, Daniel A. Rushing, Charles A. Forscher, Dennis A. Priebat, David M. Loeb, Rashmi Chugh, Scott Okuno, Denise K. Reinke, Laurence H. Baker

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

IMPORTANCE Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. OBJECTIVE To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. DESIGN, SETTING, AND PARTICIPANTS This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractorymetastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography ormagnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor a (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. INTERVENTIONS Dasatinib, 70mg orally twice daily. MAIN OUTCOMES AND MEASURES The primary end pointwas the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. RESULTS In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. CONCLUSIONS AND RELEVANCE Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Original languageEnglish (US)
Pages (from-to)814-820
Number of pages7
JournalJAMA oncology
Volume4
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

Fingerprint

Gastrointestinal Stromal Tumors
Disease-Free Survival
Neoplasms
Platelet-Derived Growth Factor Receptors
Sarcoma
Proto-Oncogene Proteins
Survival Rate
Dasatinib
Imatinib Mesylate
vif Genes
Mutation
Succinate Dehydrogenase
Poisons
Felidae
Therapeutics
Oncogenes
Sulfur
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Exons

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Schuetze, S. M., Bolejack, V., Thomas, D. G., Von Mehren, M., Patel, S., Samuels, B., ... Baker, L. H. (2018). Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. JAMA oncology, 4(6), 814-820. https://doi.org/10.1001/jamaoncol.2018.0601

Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. / Schuetze, Scott M.; Bolejack, Vanessa; Thomas, Dafydd G.; Von Mehren, Margaret; Patel, Shreyaskumar; Samuels, Brian; Choy, Edwin; D'Amato, Gina; Staddon, Arthur P.; Ganjoo, Kristen N.; Chow, Warren A.; Rushing, Daniel A.; Forscher, Charles A.; Priebat, Dennis A.; Loeb, David M.; Chugh, Rashmi; Okuno, Scott; Reinke, Denise K.; Baker, Laurence H.

In: JAMA oncology, Vol. 4, No. 6, 01.06.2018, p. 814-820.

Research output: Contribution to journalArticle

Schuetze, SM, Bolejack, V, Thomas, DG, Von Mehren, M, Patel, S, Samuels, B, Choy, E, D'Amato, G, Staddon, AP, Ganjoo, KN, Chow, WA, Rushing, DA, Forscher, CA, Priebat, DA, Loeb, DM, Chugh, R, Okuno, S, Reinke, DK & Baker, LH 2018, 'Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib', JAMA oncology, vol. 4, no. 6, pp. 814-820. https://doi.org/10.1001/jamaoncol.2018.0601
Schuetze, Scott M. ; Bolejack, Vanessa ; Thomas, Dafydd G. ; Von Mehren, Margaret ; Patel, Shreyaskumar ; Samuels, Brian ; Choy, Edwin ; D'Amato, Gina ; Staddon, Arthur P. ; Ganjoo, Kristen N. ; Chow, Warren A. ; Rushing, Daniel A. ; Forscher, Charles A. ; Priebat, Dennis A. ; Loeb, David M. ; Chugh, Rashmi ; Okuno, Scott ; Reinke, Denise K. ; Baker, Laurence H. / Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. In: JAMA oncology. 2018 ; Vol. 4, No. 6. pp. 814-820.
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T1 - Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib

AU - Schuetze, Scott M.

AU - Bolejack, Vanessa

AU - Thomas, Dafydd G.

AU - Von Mehren, Margaret

AU - Patel, Shreyaskumar

AU - Samuels, Brian

AU - Choy, Edwin

AU - D'Amato, Gina

AU - Staddon, Arthur P.

AU - Ganjoo, Kristen N.

AU - Chow, Warren A.

AU - Rushing, Daniel A.

AU - Forscher, Charles A.

AU - Priebat, Dennis A.

AU - Loeb, David M.

AU - Chugh, Rashmi

AU - Okuno, Scott

AU - Reinke, Denise K.

AU - Baker, Laurence H.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - IMPORTANCE Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. OBJECTIVE To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. DESIGN, SETTING, AND PARTICIPANTS This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractorymetastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography ormagnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor a (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. INTERVENTIONS Dasatinib, 70mg orally twice daily. MAIN OUTCOMES AND MEASURES The primary end pointwas the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. RESULTS In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. CONCLUSIONS AND RELEVANCE Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

AB - IMPORTANCE Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. OBJECTIVE To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. DESIGN, SETTING, AND PARTICIPANTS This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractorymetastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography ormagnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor a (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. INTERVENTIONS Dasatinib, 70mg orally twice daily. MAIN OUTCOMES AND MEASURES The primary end pointwas the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. RESULTS In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. CONCLUSIONS AND RELEVANCE Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

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