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Figure 1.
Study Flow Diagram
Study Flow Diagram

Fifty patients enrolled in the study and started treatment. Treatment was stopped in 34 patients because of objective disease progression; 6, patient decision; 4, clinical disease progression; 1, medical need for prohibited medication; 1, adverse event; 1, physician decision; and 3, other reasons.

Figure 2.
Kaplan-Meier Curves for Overall Survival (OS) and Progression-Free Survival (PFS)
Kaplan-Meier Curves for Overall Survival (OS) and Progression-Free Survival (PFS)
Table 1.  
Patient Characteristicsa
Patient Characteristicsa
Table 2.  
Tumor Characteristicsa
Tumor Characteristicsa
1.
Heinrich  MC, Corless  CL, Demetri  GD,  et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.  J Clin Oncol. 2003;21(23):4342-4349.PubMedGoogle ScholarCrossref
2.
Heinrich  MC, Owzar  K, Corless  CL,  et al.  Correlation of kinase genotype and clinical outcome in the North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.  J Clin Oncol. 2008;26(33):5360-5367.PubMedGoogle ScholarCrossref
3.
Boikos  SA, Pappo  AS, Killian  JK,  et al.  Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.  JAMA Oncol. 2016;2(7):922-928.PubMedGoogle ScholarCrossref
4.
Blanke  CD, Rankin  C, Demetri  GD,  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):626-632.PubMedGoogle ScholarCrossref
5.
Verweij  J, Casali  PG, Zalcberg  J,  et al.  Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.  Lancet. 2004;364(9440):1127-1134.PubMedGoogle ScholarCrossref
6.
Heinrich  MC, Rankin  C, Blanke  CD,  et al.  Correlation of long-term results of imatinib in advanced gastrointestinal stromal tumors with next-generation sequencing results: analysis of phase 3 SWOG Intergroup Trial S0033.  JAMA Oncol. 2017;3(7):944-952.PubMedGoogle ScholarCrossref
7.
Heinrich  MC, Corless  CL, Blanke  CD,  et al.  Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.  J Clin Oncol. 2006;24(29):4764-4774.PubMedGoogle ScholarCrossref
8.
Demetri  GD, van Oosterom  AT, Garrett  CR,  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):1329-1338.PubMedGoogle ScholarCrossref
9.
Heinrich  MC, Maki  RG, Corless  CL,  et al.  Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.  J Clin Oncol. 2008;26(33):5352-5359.PubMedGoogle ScholarCrossref
10.
Demetri  GD, Reichardt  P, Kang  YK,  et al; GRID study investigators.  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(9863):295-302.PubMedGoogle ScholarCrossref
11.
Hsueh  YS, Lin  CL, Chiang  NJ,  et al.  Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations.  PLoS One. 2013;8(6):e65762.PubMedGoogle ScholarCrossref
12.
Dewaele  B, Wasag  B, Cools  J,  et al.  Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation.  Clin Cancer Res. 2008;14(18):5749-5758.PubMedGoogle ScholarCrossref
13.
Schittenhelm  MM, Shiraga  S, Schroeder  A,  et al.  Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.  Cancer Res. 2006;66(1):473-481.PubMedGoogle ScholarCrossref
14.
Sako  H, Fukuda  K, Saikawa  Y,  et al.  Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells.  PLoS One. 2014;9(9):e107613.PubMedGoogle ScholarCrossref
15.
Sawaki  A, Nishida  T, Doi  T,  et al.  Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor.  Cancer. 2011;117(20):4633-4641.PubMedGoogle ScholarCrossref
16.
Cauchi  C, Somaiah  N, Engstrom  PF,  et al.  Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib.  Cancer Chemother Pharmacol. 2012;69(4):977-982.PubMedGoogle ScholarCrossref
17.
Lombardo  LJ, Lee  FY, Chen  P,  et al.  Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.  J Med Chem. 2004;47(27):6658-6661.PubMedGoogle ScholarCrossref
18.
Rotert  JV, Leupold  J, Hohenberger  P, Nowak  K, Allgayer  H.  Src activity is increased in gastrointestinal stromal tumors—analysis of associations with clinical and other molecular tumor characteristics.  J Surg Oncol. 2014;109(6):597-605.PubMedGoogle ScholarCrossref
19.
Choi  H, Charnsangavej  C, Faria  SC,  et al.  Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.  J Clin Oncol. 2007;25(13):1753-1759.PubMedGoogle ScholarCrossref
20.
Schuetze  SM, Bolejack  V, Choy  E,  et al.  Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.  Cancer. 2017;123(1):90-97.PubMedGoogle ScholarCrossref
21.
Schuetze  SM, Wathen  JK, Lucas  DR,  et al.  SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma.  Cancer. 2016;122(6):868-874.PubMedGoogle ScholarCrossref
22.
Cox  DR.  Regression models and life-tables.  J R Stat Soc B. 1972;34(2):187.Google Scholar
23.
Kaplan  EL, Meier  P.  Nonparametric-Estimation from Incomplete Observations.  J Am Stat Assoc. 1958;53(282):457-481.Google ScholarCrossref
24.
Demetri  GD, Lo Russo  P, MacPherson  IR,  et al.  Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors.  Clin Cancer Res. 2009;15(19):6232-6240.PubMedGoogle ScholarCrossref
25.
Wang  X, Roy  A, Hochhaus  A, Kantarjian  HM, Chen  TT, Shah  NP.  Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.  Clin Pharmacol. 2013;5:85-97.PubMedGoogle Scholar
26.
Antonescu  CR, Besmer  P, Guo  T,  et al.  Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation.  Clin Cancer Res. 2005;11(11):4182-4190.PubMedGoogle ScholarCrossref
27.
Reichardt  P, Blay  JY, Gelderblom  H,  et al.  Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib.  Ann Oncol. 2012;23(7):1680-1687.PubMedGoogle ScholarCrossref
28.
Italiano  A, Cioffi  A, Coco  P,  et al.  Patterns of care, prognosis, and survival in patients with metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-line sunitinib.  Ann Surg Oncol. 2012;19(5):1551-1559.PubMedGoogle ScholarCrossref
Original Investigation
June 2018

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib

Author Affiliations
  • 1Department of Internal Medicine, University of Michigan, Ann Arbor
  • 2Cancer Research and Biostatistics, Seattle, Washington
  • 3Department of Pathology, University of Michigan, Ann Arbor
  • 4Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 5Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
  • 6Summit Cancer Centers, Post Falls, Idaho
  • 7Department of Medicine, Massachusetts General Hospital, Boston
  • 8Georgia Cancer Specialists, Sandy Springs
  • 9Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia
  • 10Department of Medicine, Stanford Cancer Institute, Stanford, California
  • 11Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, Duarte, California
  • 12Department of Medicine, Indiana University, Indianapolis
  • 13Cedars-Sinai Medical Center, Los Angeles, California
  • 14Medstar Washington Hospital Center, Washington, DC
  • 15Department of Pediatrics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
  • 16Department of Oncology, Mayo Clinic, Rochester, Minnesota
  • 17Sarcoma Alliance for Research Through Collaboration, Ann Arbor, Michigan
JAMA Oncol. 2018;4(6):814-820. doi:10.1001/jamaoncol.2018.0601
Key Points

Question  What is the clinical activity of dasatinib in patients with advanced gastrointestinal stromal tumors (GISTs) after treatment with imatinib mesylate?

Findings  In this nonrandomized, uncontrolled single-arm clinical trial that included 50 patients with GIST treated with dasatinib, 70 mg twice daily, and used Choi tumor response criteria, the estimated 6-month progression-free survival rate was 29%, and the partial response rate was 25%. The observed progression-free survival rate was lower than the study prespecified rate of 30% to define an active drug.

Meaning  Dasatinib may be active as anticancer therapy in a few unselected patients with imatinib-refractory GIST, but further study is needed to define a subset of gastrointestinal stromal tumors most likely to respond.

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-refractory metastatic 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 or magnetic 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 α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017.

Interventions  Dasatinib, 70 mg orally twice daily.

Main Outcomes and Measures  The primary end point was 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.

Introduction

Gastrointestinal stromal tumors (GISTs) arise predominantly in the muscularis mucosa of the gastrointestinal tract, of which most contain activating mutations in V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) (OMIM 164920), which encodes a transmembrane tyrosine kinase. A few GISTs (5%-10%) contain activating mutations in the platelet-derived growth factor receptor α (PDGFRA) (OMIM 173490) gene; the most common PDGFRA mutation is in exon 18, resulting in a change in residue 842 from aspartic acid to valine (D842V).1,2 Those GISTs that lack mutation in KIT or PDGFRA frequently have loss of the succinate dehydrogenase (SDH) complex through mutation of a gene that encodes 1 of the subunits or epigenetic regulation that affects gene expression.3 The initial treatment for patients with unresectable, recurrent, or metastatic GISTs is imatinib mesylate based on drug activity, drug tolerability, and long-term control of GISTs in randomized clinical trials.4-6 Patients with GISTs that are primary refractory to imatinib frequently have mutations in KIT or PDGFRA within an exon that renders the protein less sensitive to inhibition of kinase activity by imatinib or unmutated (wild-type) KIT and PDGFRA.1 In patients whose GISTs initially respond to imatinib but later progress during treatment, secondary mutations in KIT frequently occur and contribute to the development of resistance.7

Sunitinib malate and regorafenib are inhibitors of KIT, PDGFRA, and vascular endothelial growth factor receptor kinases and have activity in imatinib-resistant GISTs. A randomized, placebo-controlled trial of sunitinib in patients with GISTs refractory to imatinib demonstrated a 6-month progression-free survival (PFS) rate of 16% among patients treated with sunitinib and 1% among patients given placebo.8 The median PFS was shorter among patients with secondary mutation in KIT exon 17 or 18 (the kinase activation domain) compared with patients with secondary mutation in KIT exon 13 or 14 (the adenosine triphosphate and drug-binding pocket). An in vitro study9 suggests that the difference in clinical outcome was related to differences in potency of imatinib and sunitinib in the inhibition of KIT activity based on the location of secondary mutation(s) within KIT. A randomized, placebo-controlled trial10 of regorafenib in patients with imatinib- and sunitinib-resistant GISTs led to a 6-month PFS rate of 38% with regorafenib compared with 0% with placebo.

Preclinical investigations suggest that the development of imatinib- and/or sunitinib-resistant mutations may be overcome by other small molecule tyrosine kinase inhibitors, such as nilotinib or dasatinib.11-14 However, nilotinib produced mixed results in limited phase 2 studies of patients with metastatic GISTs previously treated with imatinib and sunitinib.15,16 Dasatinib is a small molecule, adenosine triphosphate–competitive inhibitor of KIT, PDGFR, and the proto-oncogene tyrosine-protein kinase Src (SRC) family of kinases among others.13,17 Preclinical models suggest that dasatinib is a potent inhibitor of mutations in the activation domain of KIT and PDGFRA that are resistant to imatinib and sunitinib.12,13 In addition, SRC is expressed in GISTs; however, the role of SRC in the pathogenesis of the disease is undefined.18 We sought to estimate the 6-month PFS rate using Choi tumor response criteria of patients with imatinib-resistant GISTs treated with dasatinib. In a prior study,19 the Choi criteria correlated better with survival than Response Criteria in Solid Tumors in patients with GISTs treated with imatinib. We also sought to examine the association of total SRC and activated SRC (phosphorylated tyrosine residue 529) (pSRC) expression and KIT and PDGFRA genotype in patient GIST samples with tumor response and patient outcome in exploratory analyses.

Methods

We performed a nonrandomized, multi-institutional, open-label, single-arm clinical trial of dasatinib from June 1, 2008, through December 31, 2009, in 14 academic sarcoma referral centers coordinated and monitored by the Sarcoma Alliance for Research Through Collaboration. A control group was not included. Data analysis was performed from May 19, 2017, through December 20, 2017. The study database was developed and maintained by Cancer Research and Biostatistics (http://www.crab.org). Results of dasatinib treatment in patients with non-GIST sarcomas were previously reported.20,21 The study was conducted using Good Clinical Practice and approved by all participating sites’ institutional review boards (University of Michigan Health System Institutional Review Board, Fox Chase Cancer Center Institutional Review Board, University of Texas MD Anderson Cancer Center Institutional Review Board 5, Kootenai Medical Center Institutional Review Board, Dana-Farber Cancer Institute Institutional Review Board, Emory University Institutional Review Board, University of Pennsylvania Health System Institutional Review Board 6, Administrative Panel on Human Subjects in Medical Research, City of Hope Medical Center Institutional Review Board, Indiana University Institutional Review Board, Cedars-Sinai Institutional Review Board, MedStar Research Institute–Georgetown University Oncology Institutional Review Board, Johns Hopkins Medical Institutional Review Board 1, and Western Institutional Review Board).

Study enrollment into the GIST substudy was restricted to patients 13 years or older with measurable, unresectable, recurrent or metastatic, histologically confirmed GISTs previously treated with imatinib. Prior treatment with sunitinib and regorafenib was not required but was allowed. All patients provided written informed consent before undergoing study procedures. Patients self-identified race/ethnicity, information that was collected per National Cancer Institute Cancer Center guidelines. All data were deidentified.

Dasatinib was given at a dose of 70 mg twice daily. Dose and schedule adjustments were made for intolerable grade 2 or grade 3 or 4 toxic effects. Baseline tumor measurements were assessed using computed tomography or magnetic resonance imaging within 2 weeks of enrollment, and tumor response was assessed by the treating site using the same modality as baseline imaging every 8 weeks for 24 weeks and then every 12 weeks until disease progression was documented in patients who continued to undergo treatment. Safety evaluations were performed according to the schedule described in the protocol. Adverse events were recorded according to Common Terminology Criteria for Adverse Events, version 3.0.

The primary study end point was 6-month PFS rate using the Choi criteria. Secondary end points included overall survival (OS), response rate, and safety of dasatinib. Patients were contacted at least every 12 months for 5 years from enrollment or until patient withdrawal from the study or death.

Correlative Studies

Details of archival tumor preparation, immunohistochemical analysis, and polymerase chain reaction are described in the eMethods in the Supplement.

Statistical Analysis

The 6-month PFS target rate for preliminary evidence of dasatinib activity was greater than 30%, and less than 10% was selected as evidence that dasatinib is inactive in patients with imatinib-treated GISTs. We assumed a mean enrollment rate of 2 patients per month for a total enrollment period of approximately 2 years and follow-up of at least another 6 months. A continuous Bayesian monitoring rule was used after the first 10 evaluable patients were treated and followed up for 6 months to stop enrollment if the probability that the 6-month PFS was at least 30% was P < .01. On the basis of a mean enrollment of 2 patients per month, there was a 10% chance of stopping the trial early if the true 6-month PFS was 30% and a 99% chance of stopping the trial early if the true 6-month PFS was 10%. A maximum of 50 patients were to be enrolled and treated if the stopping rule was not met. Patients were monitored for progression of disease and survival from the date of enrollment. Patients who had not experienced disease progression were censored at the date of last response evaluation. Patients who had not died were censored at the date of last contact. Clinically significant adverse events that required interruption of dasatinib or change in dose or schedule and serious adverse events were tabulated by system and event according to Common Terminology Criteria for Adverse Events, version 3.0. Association between categorical tumor characteristics or size and expression of SRC was evaluated using the Fisher exact test and Kruskal-Wallis test, respectively. Cox regression analysis was used to evaluate association between tumor characteristics and PFS and OS.22 Both PFS and OS were evaluated using the Kaplan-Meier method.23P < .05 was considered to be statistically significant.

Results
Patient Demographics and Tumor Characteristics

Fifty 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. Patient characteristics are given in Table 1. Nine patients (18%) survived more than 5 years after enrollment. Four patients withdrew from the study or were unavailable for follow-up.

Forty-eight archival tumor samples were received of which 42 were informative for evaluation of SRC and pSRC expression by immunohistochemical analysis and 44 for genotype. Tumor characteristics are summarized in Table 2. Secondary mutations were not detected in cases with a KIT exon 11 mutation; however, we did not require submission of tumor sample from a mass that demonstrated resistance to imatinib therapy for genotype analysis. Tumor samples without mutation in KIT or PDGFRA were stained for succinate dehydrogenase complex iron sulfur subunit B (SDHB) expression, which was not detected in 8 of the 14 cases. SRC expression was detected in 34 of the tumors; in 14, pSRC (indicating kinase in the activated state) was detected (eFigure in the Supplement). Activated SRC was present in 6 cases (25%) with KIT exon 11 mutations, 1 case (25%) with KIT exon 9 mutation, 2 cases (33%) with unmutated KIT and PDGFRA and retained SDHB expression, and 4 cases (50%) with unmutated KIT and PDGFRA and absent SDHB expression. The size of the primary GIST was associated with tumor expression of SRC (but not pSRC). Location of the primary tumor, mitotic cell count, and GIST genotype did not correlate with SRC or pSRC expression.

Dasatinib Treatment and Safety

All patients began treatment with dasatinib, 70 mg twice daily (Figure 1). Two patients stopped treatment before completing 1 cycle of therapy. One patient stopped treatment with dasatinib after 2 cycles because of medical need for therapeutic anticoagulation. A median of 2 (range, 1-31) cycles was completed. A temporary hold on study treatment occurred in 18 patients, and reduction in dose was required for 9 because of toxic effects. Two patients required dose reduction to 100 mg once daily because of toxic effects. The adverse events experienced by patients that were reported to be related to dasatinib are listed in eTable 1 in the Supplement. Serious adverse events were experienced by 12 patients (24%) and included pleural effusion (3 patients), nausea or vomiting (2 patients), muscle weakness (2 patients), and 1 case each of intestinal obstruction and pneumonia, tumor-associated hemorrhage, pancreatitis, tumor-associated pain, and cerebral vascular hemorrhage. No deaths were attributed to dasatinib; however, a patient with intestinal obstruction and pneumonia died within 30 days of stopping dasatinib treatment. The primary reason for discontinuation of study treatment was disease progression. All patients enrolled in the study stopped dasatinib treatment.

Dasatinib Activity

Partial response was reported in 12 patients (25%). Two patients had partial response by decrease in tumor size (1 patient with D842V mutation in PDGFRA and 1 with no mutation in KIT or PDGFRA and loss of SDHB expression) and 10 by decrease in density of target lesions (7 with KIT exon 11 mutation, 1 with KIT exon 9 mutation, 1 without mutation in KIT or PDGFRA and retained expression of SDHB, and 1 without tumor available for genotyping). Partial response was sustained for at least 8 weeks in 5 patients. A significant association between tumor characteristic(s) and response was not found (eTable 2 in the Supplement).

The 6-month PFS estimate was 29% among the 48 patients evaluable for response to treatment. The median PFS time was 2.9 months, and the OS time was 19 months (Figure 2). The OS rates were 43% (95% CI, 28%-57%) at 2 years and 17% (95% CI, 5%-28%) at 5 years. The study was not designed to evaluate the influence of tumor characteristics on response and patient outcomes as primary or secondary objectives, but exploratory analyses were conducted. Results of exploratory analyses are hampered by the small number of samples. The PFS and OS estimates were similar in patients with tumor that expressed SRC compared with patients without SRC expression in tumor. The median PFS time and 6-month PFS rate were better in patients with tumor with pSRC (4.9 months and 50%, respectively) compared with those with tumor without SRC activation (2.1 months and 9%, respectively); however, the difference did not reach significance in univariate analysis (hazard ratio, 0.47; 95% CI, 0.20-1.04; P = .06) (eTable 3 in the Supplement). Univariate analysis identified an association between SDH-deficient GISTs and improved PFS (hazard ratio, 0.18; 95% CI, 0.03-0.93; P = .02). Median OS was 19 months among patients with pSRC and 12.6 months among patients with unphosphorylated SRC. Among patients with mutation in KIT exon 9, the PFS time was 2.1 months and the OS time was 7.8 months. Among patients with mutation in KIT exon 11, the PFS time was 2.7 months and the OS time was 19.6 months. Among patients with mutation in PDGFRA exon 18, the PFS time was 22 months and the OS time was not reached. Among patients without mutation in KIT or PDGFRA, the PFS time was 1.8 months and the OS time was 12 months. Univariate analysis identified an association between primary small-bowel GISTs and worse OS (hazard ratio, 2.51; 95% CI, 1.20-5.21; P < .001).

Discussion

We began this study to estimate the 6-month PFS rate as preliminary evidence of dasatinib activity in imatinib-refractory GISTs after the approval of sunitinib but before the approval of regorafenib for the treatment of GISTs. Most patients enrolled in this trial had been treated with sunitinib. Preclinical research suggested that dasatinib had higher potency against mutations in the activation domain of KIT and PDGFRA than imatinib and sunitinib.12,13 Objective tumor response to dasatinib was infrequent, but 1 patient with a mutation in PDGFRA exon 18 (D842V) had a confirmed partial response by size after approximately 14 months of treatment. Another patient with a mutation in KIT exon 13 and PDGFRA exon 18 had prolonged stable disease that lasted more than 6 months. In vitro studies12,24,25 have suggested that dasatinib is a more potent inhibitor of cells that harbor the D842V mutation in PDGFRA than is imatinib and exhibits inhibition of cell growth at the nanomolar concentrations achieved in humans using the recommended dose of dasatinib. Partial response by tumor density on computed tomography was detected in 28% of patients with primary mutation in KIT exon 11 compared with 20% of patients with primary mutation in KIT exon 9 and 14% of patients with unmutated KIT and PDGFRA. The study did not require submission of tumor biopsy samples with disease after development of resistance to imatinib or sunitinib for determination of secondary KIT mutations; therefore, we were unable to determine whether there was a different rate of objective tumor response based on secondary mutations. Prior studies7,26 have demonstrated that secondary mutations associated with imatinib resistance in GISTs frequently arise in KIT exon 17 (the kinase activation domain) and may be more likely to occur in GISTs with primary mutation in KIT exon 11 vs 9.

The 6-month PFS rate guided enrollment into the trial. The actual mean rate of accrual of 2.8 patients per month was within the a priori statistical assumption and conformed with our initial modeling for Bayesian monitoring for study size. The probability that the estimated 6-month PFS rate was at least 30% did not fall below the prespecified value of 1.1% during study enrollment; therefore, accrual proceeded to the maximum of 50 patients. Both the rate of accrual and performance of the study provide evidence that the clinical trial was appropriately modeled. We selected a 6-month PFS of less than 10% as suggestive of no antitumor activity of dasatinib based on patients with GISTs treated with placebo. The final 6-month PFS rate of 29% fell just short of our goal of 30%. This rate is lower than the rate reported for regorafenib (38%) but higher than the rate reported for nilotinib (7%), sunitinib (16%), and placebo (<2%).8,10,27

The 6-month PFS rate was similar between patients with and without tumor expression of SRC but was higher in patients with tumor expression of pSRC (50%) than unphosphorylated SRC (9%). This finding from our exploratory translational research requires prospective confirmation in GISTs biopsied just before dasatinib treatment to evaluate pSRC as a potential biomarker. Prior research on a small number of samples demonstrated that SRC was activated in GISTs compared with normal tissue, was higher in GISTs with mutation in the KIT exon 11 than in other GIST genotypes, and correlated with longer patient survival.18 However, 21 of the 29 tumor specimens obtained were from patients undergoing treatment with imatinib, which may have affected SRC activity. We did not record the timing of GIST collection relative to treatment with imatinib for the samples submitted for correlative studies and are unable to comment on the effect of drug therapy on SRC activity. Additional research is needed to determine whether activated SRC expression may be a prognostic biomarker in GISTs.

The median OS was 19 months, indicating that patients with imatinib-resistant GISTs have a poor prognosis. Only 18% of patients survived more than 5 years after enrollment. However, the median OS in the dasatinib trial was longer than that reported for nilotinib (361 days) or best supportive care (300 days) in a phase 3 trial of patients with imatinib- and sunitinib-resistant GISTs.27 The median OS in the dasatinib trial was twice as long as that reported in 223 patients with imatinib- and sunitinib-resistant GISTs treated at referral centers with agents other than dasatinib.28 The survival duration in our dasatinib trial may be biased by inclusion of 10 patients who did not previously receive sunitinib. The median OS was more than twice as long in patients with mutation in KIT exon 11 (19.6 months) compared with KIT exon 9 (7.8 months), which differs from the results seen in the trial of sunitinib after failure of imatinib, in which the median OS among patients with KIT exon 11 mutation was 12.3 months compared with 26.9 months among patients with KIT exon 9 GISTs.9 In the sunitinib trial, the median OS among patients with secondary mutation in KIT exon 17 or 18 was 4 months compared with 13 months among patients with secondary mutation in exon 13 or 14. The longer median OS in our dasatinib trial may be related to more potent inhibition of KIT-containing mutations in the activation domain by dasatinib compared with sunitinib, but this hypothesis requires confirmation in further clinical study.

This trial of dasatinib in patients with advanced GISTs demonstrated an adverse event profile consistent with that seen previously.20,21 Adverse events from dasatinib that differ from sunitinib and regorafenib were dyspnea and pleural effusion. The dose of 70 mg twice daily was tolerated in most patients, although dose reduction may be needed during longer duration of treatment.

Limitations

This study is limited by its design that did not randomly allocate patients to the intervention and did not include a control group. The PFS rate may have been affected by inclusion of patients who had not been treated with sunitinib, who accounted for 20% of the study population, and early discontinuation of drug therapy in 9 patients for reasons other than disease progression or toxic effect. Our estimates of the 5-year survival rate and median OS are affected by the patient who withdrew from the study and the 5 patients who did not complete the long-term survival follow-up portion of the trial. The correlation of GIST genotype and phenotype with tumor response, PFS, and OS is limited by a lack of tumor tissue obtained at time of study enrollment. Our use of archival tumor tissue may have missed secondary mutation or change in SRC or pSRC expression that developed during prior treatment with imatinib and sunitinib. In addition, tumor tissue of sufficient quantity or quality was not available in 6 cases for genotype and 8 cases for phenotype analysis.

Conclusions

Dasatinib was active in a subset of patients with advanced GISTs based on objective tumor responses and a 6-month PFS rate that was substantially higher than previously seen for nilotinib, placebo, and best supportive care but was not associated with a 6-month PFS rate of more than 30%. One patient with D842V mutation in PDGFRA had an objective tumor response and prolonged tumor control, which provides clinical evidence in support of preclinical studies that suggest dasatinib is active in GISTs with this imatinib-resistant mutation. Our prospective clinical trial corroborates previous findings that the presence of activated SRC in GISTs may be associated with longer survival among patients with advanced or metastatic GISTs. Further studies should explore whether activated SRC is a prognostic biomarker of more indolent disease or is a predictive biomarker of response to tyrosine kinase therapy.

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Article Information

Accepted for Publication: February 9, 2018.

Corresponding Author: Scott M. Schuetze, MD, PhD, Department of Internal Medicine, University of Michigan, C342 Med Inn, Special Postal Code 5848, 1500 E Medical Center Dr, Ann Arbor, MI 48109-5848 (scotschu@med.umich.edu).

Published Online: April 26, 2018. doi:10.1001/jamaoncol.2018.0601

Author Contributions: Dr Schuetze had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Schuetze, Thomas, Patel.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Schuetze, Bolejack, Thomas, Patel.

Critical revision of the manuscript for important intellectual content: Schuetze, Bolejack, von Mehren, Patel, Samuels, Choy, D'Amato, Staddon, Ganjoo, Chow, Rushing, Forscher, Priebat, Loeb, Chugh, Okuno, Reinke, Baker.

Statistical analysis: Bolejack, Patel, Okuno.

Obtained funding: Reinke, Baker.

Administrative, technical, or material support: Rushing, Loeb, Reinke.

Study supervision: Schuetze, Staddon, Priebat, Reinke.

Conflicts of Interest Disclosures: Dr Schuetze reported receiving honoraria from Novartis, Amgen, Janssen, Daiichi-Sankyo, and Eli Lilly and Company for scientific advisory board participation and clinical research support form Novartis, AB Science, Amgen, Janssen, Daiichi-Sankyo, and Eli Lilly and Company. Dr Chow reported serving on the speaker’s bureau for Novartis. Dr Choy reported receiving payments for consulting with EMD Serrono, Amgen, and Immune Design. Dr Chugh reported serving on the advisory board for Epizyme and EMD Serrano and receiving research funding from AADi, Novartis, Eli Lilly and Company, Medivation, Morphotek, MabVax, Advenchen, Epizyme, and Pfizer. Dr D’Amato reported serving on the speaker’s bureau for Eisai, Eli Lilly and Company, Janssen, and Novartis Pharmaceuticals. Dr Ganjoo reported serving on advisory boards for Daiichi-Sankyo and Janssen. Dr Thomas reported having a consultancy agreement with Resonant Therapeutics. Ms Reinke reported being an employee of Sarcoma Alliance for Research Through Collaboration, which received an unrestricted grant to fund this work. Dr Von Mehren reported serving as the chair of the Soft Tissue Panel for National Comprehensive Cancer Network Guidelines and receiving paid honoraria for consulting or serving on advisory boards for Blueprint, Arog, and Deciphera Pharmaceuticals. No other disclosures were reported.

Funding/Support: Dasatinib and trial funding were provided by Bristol-Myers Squibb; however, the study was conducted and data obtained and retained by the Sarcoma Alliance for Research Through Collaboration Investigators without input by Bristol-Myers Squibb. Research reported in this publication was supported award P30CA046592 from the National Cancer Institute of the National Institutes of Health by the use of the Tissue and Molecular Pathology Cancer Center Shared Resource.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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