What is the clinical activity of dasatinib in patients with advanced gastrointestinal stromal tumors (GISTs) after treatment with imatinib mesylate?
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.
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.
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.
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.
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.
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.
Schuetze SM, Bolejack V, Thomas DG, et al. Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib. JAMA Oncol. 2018;4(6):814–820. doi:10.1001/jamaoncol.2018.0601
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