Neoadjuvant Dasatinib for muscle-invasive bladder cancer: Src inhibition appears ineffective in unselected patients
Preclinical urothelial carcinoma models suggest activity of Dasatinib ( Sprycel ), an oral Src-family kinase ( SFK ) inhibitor.
Researchers have determined the feasibility and biologic activity of neoadjuvant Dasatinib ( Neo-D ) in patients with muscle-invasive urothelial carcinoma of the bladder ( miUCB ) preceding radical cystectomy.
A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable muscle-invasive urothelial carcinoma of the bladder ( T2–T4a, N0, M0 ), and Eastern Cooperative Oncology Group ( ECOG ) performance status 0 to 1.
Patients received oral Neo-Dasatinib 100 mg once daily for 28±7 days followed by radical cystectomy 8 to 24 hours after the last dose.
The primary end point was feasibility, defined as greater than or equal to 60% of patients with muscle-invasive urothelial carcinoma of the bladder completing therapy without treatment-related dose-limiting toxicity ( DLT ).
Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK ( pSFK ), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.
The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility.
The study achieved its primary end point with 15 patients ( 65% ) completing therapy without treatment-related dose-limiting toxicities.
Dose-limiting toxicities included: fatigue ( n = 2 ), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea ( n = 1 each ).
At radical cystectomy, 5 patients ( 23% ) had less than pT2 disease.
Analysis of pre- and posttreatment tumors demonstrated significantly decreased pSFK ( P = 0.003 ) but no overall significant changes in Ki-67 or Cas3.
In total, 4 cases demonstrated a non-significant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3.
In conclusion, Neo-D in patients with muscle-invasive urothelial carcinoma of the bladder was feasible and safe.
Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients.
These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with muscle-invasive urothelial carcinoma of the bladder is unlikely. ( Xagena )
Hahn NM et al, Urol Oncol 2016; 34: 4.e11–4.e17
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