Results of Bevacizumab-Chemotherapy Combinations for Patients with Advanced Urothelial Cancer - Expert Commentary

Immune checkpoint inhibitors, FGFR3 inhibitors, and antibody drug-conjugates are recent additions to the armamentarium of agents used to treat advanced urothelial cancer (UC). However, cisplatin-based therapy remains a standard front-line treatment for eligible patients with metastatic UC. Angiogenesis is a critical pathway in UC development and progression. Early-phase clinical trials suggested that targeting angiogenesis could potentially improve outcomes in advanced UC. However, sufficiently powered randomized controlled trials testing the efficacy of antiangiogenic agents were lacking.


The Alliance for Clinical Trials in Oncology initiated a randomized, double-blind, placebo-controlled phase III trial CALGB 90601 to investigate the efficacy of adding the antiangiogenic agent, bevacizumab, to first-line cisplatin-based chemotherapy. Rosenberg and colleagues recently published the mature data analysis of the CALGB 90601 in the Journal of Clinical Oncology.1 The investigators randomized 506 patients with metastatic UC over 5-years. Patients were chemotherapy naïve or with a 1-year treatment-free interval from neo/adjuvant therapy. Enrolled patients were randomized in a 1:1 ratio to cisplatin/gemcitabine with or without bevacizumab. Bevacizumab was continued until disease progression or toxicity. The study was powered to detect overall survival (OS) difference as its primary endpoint.

After median follow up of 4 years, median progression-free survival was 1.3 months longer in bevacizumab arm compared to placebo (hazard ratio (HR): 0.77, 95% Confidence Intervals (CI): 0.63–0.95, P = 0.016). There was no statistically significant improvement in OS between both groups (14.5 vs. 14.3 months, HR: 0.87, 95% CI: 0.72–1.05, P = 0.15). There was no observed meaningful improvement using bevacizumab in any particular patient subgroup. Bevacizumab was generally well tolerated with an expected toxicity profile, including known hypertension and proteinuria adverse events.

The addition of bevacizumab to the standard chemotherapy failed to improve overall survival in other solid malignancies, including gastric and ovarian cancers. Thus, investigating whether gene expression signatures associated with angiogenesis could potentially identify a subset of patients who are more likely to respond to antiangiogenic agents.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, et al. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 May 14; doi.10.1200/jco.21.00286. PMID: 33989025
  2. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011; 2011 Oct 20;29(30):3968-76. PMID: 21844504
  3. Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without Bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):928-36. PMID: 26115797

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