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 - Medical Oncologist Perspective

Chicago, IL ( Combination gemcitabine and cisplatin is a standard of care front line treatment option for patients with advanced urothelial carcinoma.1 In a large phase III study published in 2000, gem/cis was compared against MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) and the overall survival was similar in both arms, as well as time to progressive disease, time to treatment failure, and response rates.2   In 2011, investigators from Indiana began exploring the role of vascular endothelial growth factor inhibition in UC, and added bevacizumab 15 mg/kg on day 1, every 21 days, to the standard regimen of gem/cis.3 Investigators conducted a single arm phase II study with 43 chemotherapy naïve patients. The objective response rates were a complete response (CR) in 19% of patients, partial response (PR) of 53%, and a median overall survival (OS) of 19.1 months.
ASCO 2019 Bevacizumab in BC

These positive results have led to an additional evaluation of bevacizumab to gem/cis. Here, the authors present the results of a randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma.
ASCO 2019 CALGB 90601 study design
This abstract provides data on 506 patients with metastatic urothelial carcinoma (mUC) who were randomly assigned 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. Eligibility criteria are shown below:
ASCO 2019 CALGB 90601 key eligibility criteria

To ensure balance in the two arms, patients were also stratified based on the presence of visceral metastases and prior chemotherapy. The primary endpoint was overall survival, as defined from the time of randomization to death or last follow up. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and ≥grade 3 toxicity.

In terms of overall survival, there was no difference between patients treated with GCB vs GCP (14.5 months vs 14.3 months, HR of 0.87 (95%CI 0.72-1.06, p=0.17).
ASCO 2019 Bev gem cis

Progression free survival (PFS) was improved with GCB (0.77 (95%CI 0.63-0.93, p=0.0074), with an absolute benefit of one month, which per the author was not clinically significant.
ASCO 2019 PFS improved with Bevacizumab

In terms of grade 3 or greater AEs, patients with GCB had 83.5% AEs compared with 80.7% with GCP.
ASCO 2019 Bevacizumab overall response rate

There was no overall survival benefit with the addition of bevacizumab to gemcitabine and cisplatin for patients with metastatic UC who are cisplatin eligible. Cisplatin-based chemotherapies remain standard of care for cisplatin eligible patients with metastatic urothelial carcinoma (mUC) and combination studies are important for improving our front line options. Unfortunately, chemotherapy alone is unlikely to result in durable responses for the majority of patients and a combination approach with immunotherapy may be of benefit -this is being examined in NCT03093922, a randomized phase II study testing two different schedules of atezolizumab combined with gemcitabine and cisplatin chemotherapy (GC) in patients with mUC who are eligible for cisplatin. A number of other ongoing phase III trials are ongoing as shown below.
ASCO 2019 Bevacizumab met UC

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

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Journal of clinical oncology 2005;23:4602-8.
  2. Maase Hvd, Hansen SW, Roberts JT, et al. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study. Journal of Clinical Oncology 2000;18:3068-77.
  3. 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. Journal of Clinical Oncology 2011;29:1525-30.