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

Chicago IL, (UroToday.com) The combination of gemcitabine and cisplatin is a standard therapy for metastatic urothelial carcinoma (mUC) based on reduced toxicity and similar outcomes as compared to MVAC. In pre-clinical models, anti-angiogenic therapies inhibit the progression of urothelial carcinoma, and vascular endothelial growth factor (VEGF) is a primary pro-angiogenic mediator of urothelial carcinoma. However, single-agent VEGF-targeted tyrosine kinase inhibitors (TKIs) have previously produced low response rates in metastatic urothelial carcinoma.1 Bevacizumab has previously been tested in bladder cancer in a single-arm phase II study in combination with gemcitabine and cisplatin.2 There was a 19.1-month overall survival benefit, which compared favorably to 14-15 months in prior studies of cisplatin-based chemotherapy. Additionally, there was a 72% objective response rate, including 19% experiencing a complete response. A single-arm phase II study of gemcitabine, carboplatin, and bevacizumab also showed an improved overall survival (OS) (13.9 months) compared to historical controls (9 months).3 At ASCO 2019, Jonathan Rosenberg, MD, and colleagues presented results of a phase III randomized control trial (RCT) comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma.

Patients with metastatic urothelial carcinoma with no prior chemotherapy for metastatic disease and >12 months from prior (neo)adjuvant chemotherapy and ECOG PS 0-1 were randomized 1:1 to gemcitabine 1000 mg/m2 IV days 1 and 8 and cisplatin IV 70 mg/m2 day 1 with bevacizumab (GCB) 15 mg/kg IV or placebo (GCP) day 1 every 21 days. Randomization was stratified by the presence of visceral metastases and prior chemotherapy. The primary endpoint was OS defined as the time from randomization to death or last follow-up. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and ≥ grade 3 toxicity. With 445 deaths, the log-rank test had an 87% power to detect a hazard ratio (HR) of 0.74 with a 2-sided α=0.05. A schema of the trial is as follows:
ASCO2019_Studydesign_CALGB.png
There were 506 patients randomly assigned to either GCB (n=252) or GCP (n=254) stratified by the presence of visceral disease and prior chemotherapy for urothelial carcinoma. Baseline characteristics were well-balanced between the two groups, including >90% white patients, >50% ECOG 0, and nearly 2/3 with visceral metastasis. The median follow-up for patients still alive was 46.2 months. Median OS was 14.5 months (95% CI 13.5-16.2) for patients treated with GCB and 14.3 months (95% CI 12.1-16.2) for patients treated with GCP with a HR of 0.87 (95% CI 0.72-1.06).
ASCO2019_percentalive_CALGB.png
The HR for PFS was 0.77 (95% CI 0.63-0.93) in favor of GCB (p=0.0074).
ASCO2019_Percentaliveanddiseasefree_CALGB.png
Per protocol analysis for OS and PFS showed similar findings as those reported in the ITT population. Grade 3 or greater adverse event rate was 83.5% with GCB compared to 80.7% with GCP – these were most commonly neutropenia, and hypertension (20.3% in the GCB group vs 4.7% in the GCP group).

Dr. Rosenberg concluded his presentation of CALGB 90601 with several concluding statements:

  • The addition of bevacizumab did not improve overall survival when added to gemcitabine and cisplatin chemotherapy as first-line therapy for metastatic urothelial carcinoma
  • However, the addition of bevacizumab did improve PFS although the improvement of 1.1 months was not clinically significant
  • Toxicity of the GCB combination was comparable to historical data
  • Currently, the standard of care remains cisplatin-based chemotherapy without the addition of biologic agents
  • Ongoing correlative work may identify subsets of patients who may benefit from anti-angiogenic therapy
  • This study shows the importance of confirming phase II results in phase III randomized trials – pretreatment prognostic factors can heavily influence outcomes in advanced urothelial carcinoma
  • Although accrual took more than five years, it showed that the US could complete a large randomized phase III trial in mUC
Clinical trial information: NCT00942331

Presented by: Jonathan E. Rosenberg, Memorial Sloan Kettering Cancer Center, New York, NY

Co-Authors: Karla V. Ballman, Susan Halabi, Colleen Watt, Olwen Mary Hahn, Preston D. Steen, Robert Dreicer, Thomas W. Flaig, Walter Michael Stadler, Christopher Sweeney, Amir Mortazavi, Michael J. Morris; Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medicine, New York, NY; Duke University Medical Center, Durham, NC; University of Chicago, Chicago, IL; University of Chicago Medical Center, Chicago, IL; Roger Maris Cancer Center, Fargo, ND; Cleveland Clinic, Cleveland, OH; Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, CO; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH

Written By: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Bellmunt J, Gonzalez-Larriba JL, Prior C, et al. Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol 2011;22(12):2646-2653.
  2. Hahn NM, Stadler WM, Zon RT, et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol 2011;29(12):1525-1530.
  3. Balar AV, Apolo AB, Ostrovnaya, et al. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol 2013;31(6);724-730.
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