ASCO 2019: CALGB 90601 (Alliance): Randomized, Double-blind, Placebo-controlled Phase III Trial Comparing Gemcitabine and Cisplatin with Bevacizumab or Placebo in Patients with Metastatic Urothelial Carcinoma

Chicago, IL ( Preclinical data suggest that VEGF-mediated angiogenesis is associated with poor clinical outcomes among patients with urothelial cancer and that targeting VEGF may have therapeutic efficacy.1 Following an impressive 19.1 month, overall survival achieved in a nonrandomized phase II study2, Jonathan E. Rosenberg, MD, and colleagues through the Alliance for Clinical Trials in Oncology, conducted CALGB 90601, a randomized double-blind phase III trial of gemcitabine + cisplatin with or without the VEGF antibody bevacizumab.

Between 2009 and 2014, a total of 506 patients with metastatic or locally advanced and unresectable urothelial cancer were randomized 1:1 to receive up to 6 cycles of either gemcitabine (1000 mg/m2 days 1 and 8) and cisplatin (70 mg/m2 day 1) with or without bevacizumab (15 mg/kg q3 weeks). Patients were required to not have received prior chemotherapy for metastatic disease, and have good performance status (ECOG 0-1). The study was powered to detect a hazard ratio (HR) of 0.74 with respect to overall survival (OS).


At baseline, these patients constituted a relatively poor prognostic cohort, with visceral metastases present in 69% of each treatment arm. A minority of patients (13% in each arm) had received prior perioperative platinum-based chemotherapy, and approximately 30% of the patients had an upper tract primary.


The study failed to meet its primary endpoint, with overall survival of 14.5 months versus 14.3 months with bevacizumab and placebo, respectively (log rank P=0.17). Investigators did identify a 1.1-month improvement in progression-free survival (7.7 months versus 6.6 months in favor of bevacizumab) which was statistically significant (HR 0.79, log-rank p=0.013); however, this result was not felt to be clinically significant. Additionally, no difference in overall response rate (ORR) was observed, with ORRs of 40.4% (6CR and 74PR) and 33.0% (7 CR and 60 PR) in the bevacizumab and placebo arms, respectively (P=0.12). Subsequent per-protocol versus intention-to-treat analysis and subgroup analysis did not yield any significant differences.


While CALGB 90601 was a negative study, Dr. Rosenberg emphasized the importance of randomized clinical trials in the clinical drug development for advanced bladder cancer and indicated the need for predictive biomarkers, noting that ongoing correlative analyses may help differentiate responders and non-responders.

Presented by: Jonathan E. Rosenberg, MD, Medical Oncologist, Chief of the Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Michael Lattanzi, MD, Internal Medicine Resident, Department of Medicine, NYU School of Medicine, Twitter: @MikeLattanzi at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. Inoue K, Slaton JW, Davis DW, Hicklin DJ, McConkey DJ, Karashima T, Radinsky R, Dinney CP. Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clinical Cancer Research. 2000 Jul 1;6(7):2635-43.
  2. Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, Johnson CS, Perkins SM, Waddell MJ, Sweeney CJ. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. Journal of Clinical Oncology. 2011 Mar 21;29(12):1525-30.