Phase II trial of gemcitabine, carboplatin, and bevacizumab in chemotherapy-naive patients (Pts) with advanced/metastatic urothelial carcinoma (UC).

Abstract

248 Background: Effective treatment for pts with advanced UC unfit to receive cisplatin-based therapy remains an unmet need. A recent phase III study showed limited benefit of gemcitabine-carboplatin (GC) alone (median OS 9.3 months) (DeSantis ASCO 2010). We recently identified the VEGF-axis as a viable pathway for UC treatment (JCO 2010;Mar 10). We propose that bevacizumab, a monoclonal antibody against VEGFR, may be safely added to GC and improve time to progression (TTP) in pts with advanced UC. Methods: Primary endpoints (N=47 planned enrollment) were median TTP, to test an improvement of 50% over a 4.8 months median TTP seen with GC alone (Urology 2004;64:479), and safety. Secondary endpoints were response rate (RR) and overall survival (OS). Pts first received a single dose of bevacizumab 10 mg/kg. 2 weeks later they received 6 cycles of gemcitabine 1,000 mg/m2 on day(D) 1 and D 8, and both carboplatin AUC 4.5 and bevacizumab 15 mg/kg on D1 every 21 days. Pts who achieved at least stable disease were eligible to receive maintenance bevacizumab at 15 mg/kg q21 days for 18 additional doses. Restaging evaluations were performed after every 3 cycles of therapy. Results: 51 pts (37 M, 14 F; median age 67 (Range 42-83)) were enrolled from 6/06 to 6/10. Primary tumor sites include bladder (31), renal pelvis (17) and ureter (2). 38 pts (74.5%) had visceral disease including lung (22), liver (13), bone (9) and adrenal (2). 13 pts had LN only disease. 46 of 51 pts were evaluable for response rate (RR) and TTP, 51 for toxicity. RR by RECIST was 46% (21 pts; PR 18, CR 3). 12 achieved stable disease; 1 too early to assess. Responses by MSKCC Risk Scores of 0, 1 and 2 were seen in 8/11(73%), 10/29 (35%), and 3/6 (50%) pts, respectively. 39% of pts had grade 3/4 toxicity, notably vascular thromboembolic events (VTE) in 18%. Conclusions: Bevacizumab can be safely added to GC in the treatment of advanced UC. The 16% VTE rate is similar to the 17% rate seen at MSKCC with GC alone. (JCO 2009;27:15s). Addition of bevacizumab does not improve the RR seen with GC alone in phase II and III studies (Bellmunt Eur J Cancer 2001; DeSantis ASCO 2010). Analysis of bevacizumab's impact on TTP and OS is ongoing and will be updated. [Table: see text]