Dasatinib shows limited activity in unselected imatinib-resistant GISTs
medwireNews: A trial of dasatinib in patients with imatinib-resistant gastrointestinal stromal tumors (GISTs) found that the drug did not meet the criteria for clinical activity overall, but may be suitable for a subset of patients with phosphorylated SRC (pSRC).
However, further study is needed to determine which GISTs are most likely to respond to dasatinib chemotherapy, and whether pSRC is a prognostic biomarker, Scott Schuetze (University of Michigan, Ann Arbor, USA) and co-investigators remark.
This single-arm trial included 50 patients (median age 60 years, 62% men) with imatinib-refractory metastatic GISTs who received oral dasatinib 70 mg twice daily until tumor progression, unacceptable toxic effects, or patient or physician decision to stop.
The 6-month progression-free survival (PFS) rate, estimated using Choi tumor response criteria, was 29%, which was lower than the prespecified rate of 30% to define an active drug.
However, the researchers point out that this rate is higher than that previously reported for nilotinib (7%) and sunitinib (16%).
Median PFS was 2.9 months, while median overall survival (OS) was 19 months, with 17% of patients still alive at 5 years.
The objective tumor response rate was 25%, and included one patient with an imatinib-resistant mutation in PDGFRA exon 18.
Exploratory analyses showed that the 6-month PFS rate was higher in a subset of 14 patients with pSRC than in 28 with unphosphorylated SRC, at 50% versus 9%, but the difference was not statistically significant due to the small number of patients.
In addition, median PFS was 4.9 months among patients with pSRC and 2.1 months among patients with unphosphorylated SRC.
Of note, two patients with a mutation in PDGFRA exon 18 had a median PFS of 22 months, while it was just 1.8 months among 14 patients with no mutations in PDGFRA or KIT.
Schuetze and team report that 24% of patients experienced serious adverse events that were consistent with those seen previously and included pleural effusion in three patients, two cases each of nausea or vomiting and muscle weakness, and one case each of intestinal obstruction and pneumonia, tumor-associated hemorrhage, pancreatitis, tumor-associated pain, and cerebral vascular hemorrhage.
Writing in JAMA Oncology, the authors conclude: “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.”
They add: “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.”
By Laura Cowen
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