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

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.

• Authors: 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 L Corless, Ajjai S Alva, Steven S Shen, Fangjin Huang, Arkadiusz Gertych, Gary E Gallick, Jayati Mallick, Christopher Ryan, Matthew D Galsky, Seth P Lerner, Edwin M Posadas, Guru Sonpavde
• Journal: Urologic oncology (Urol Oncol) Vol. 34 Issue 1 Pg. 4.e11-7 (Jan 2016) ISSN: 1873-2496 [Electronic] United States
• PMID: 26362343 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Dasatinib

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Dasatinib (therapeutic use)
• Feasibility Studies
• Female
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Male
• Middle Aged
• Muscle Neoplasms (drug therapy, metabolism, pathology)
• Neoadjuvant Therapy
• Neoplasm Invasiveness
• Neoplasm Staging
• Prognosis
• Prospective Studies
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology)