Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity

Noah M. Hahn, Beatrice S. Knudsen, Siamak Daneshmand, Michael O. Koch, Richard Bihrle, Richard S. Foster, Thomas A. Gardner, Liang Cheng, Ziyue Liu, Timothy Breen, Mark T. Fleming, Raymond Lance, Christopher Corless, Ajjai S. Alva, Steven S. Shen, Fangjin Huang, Arkadiusz Gertych, Gary E. Gallick, Jayati Mallick, Christopher RyanMatthew D. Galsky, Seth P. Lerner, Edwin M. Posadas, Guru Sonpavde

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).

MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB 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.

RESULTS: 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 DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had<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 nonsignificant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3.

CONCLUSIONS: Neo-D in miUCB patients 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 miUCB is unlikely.

Original languageEnglish (US)
JournalUrologic Oncology: Seminars and Original Investigations
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Bladder
  • Dasatinib
  • Neoadjuvant therapy
  • Protein kinase inhibitors
  • Src-family kinases
  • Translational medical research
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

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