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.

4503 Background: The combination of gemcitabine (G) and cisplatin (C) is a standard therapy for metastatic urothelial carcinoma (mUC). Based on data that angiogenesis plays a role in UC growth and progression, a randomized placebo-controlled trial was performed. Methods: Patients mUC, no prior chemotherapy for metastatic disease and >12 months from prior (neo)adjuvant chemotherapy and ECOG PS 0-1 were randomized 1:1 to G 1000 mg/m 2 IV days 1 and 8 and C IV 70 mg/m 2 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 overall survival (OS) defined as the time from randomization to death or last follow-up (FU). 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. The primary analysis was based on the stratified log-rank test adjusting on stratification factors. Alliance Data Safety and Monitoring Board approved the final OS analysis be performed at 420 events due to lower than expected event rates. Results: 506 patients were randomly assigned (252 GCB, 254 GCP) stratified by the presence of visceral disease and prior chemotherapy for UC. The median FU for patients still alive was 46.2 months. Median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP with a HR of 0.87 (95%CI 0.72-1.06; 2-sided Wald p=0.17). The HR for PFS was 0.77 (95%CI 0.63-0.93) in favor of GCB (p=0.0074). Grade 3 or greater adverse event rate was 83.5% with GCB compared to 80.7% with GCP. Conclusions: The addition of bevacizumab to GC chemotherapy did not result in improved OS (primary endpoint) in patients with mUC but there was a PFS improvement. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180853, U10CA180888, Genentech https://acknowledgments.alliancefound.org. Clinical trial information: NCT00942331.