As reported in the Journal of Clinical Oncology by Jonathan E. Rosenberg, MD, and colleagues, the phase III CALGB 90601/Alliance trial has shown no improvement in overall survival with the addition of bevacizumab to gemcitabine/cisplatin in patients with metastatic urothelial carcinoma.
Jonathan E. Rosenberg, MD
Study Details
The double-blind trial included 506 patients who had not received prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months. They were randomly assigned between July 2009 and December 2014 to receive gemcitabine at 1,000 mg/m2 on days 1 and 8 and cisplatin at 70 mg/m2 on day 1 every 21 days for up to six cycles, plus either bevacizumab at 15 mg/kg every 21 days starting from day 1 of chemotherapy (n = 252) or placebo (n = 254).
Patients continued maintenance bevacizumab or placebo after completion of planned chemotherapy until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Overall Survival
Median follow-up was 76.3 months among surviving patients. Median overall survival was 14.5 months (95% confidence interval [CI] = 13.5–16.2 months) in the bevacizumab group vs 14.3 months (95% CI = 12.2–16.2 months) in the placebo group (hazard ratio [HR] = 0.87, 95% CI = 0.72–1.05, P = .15). Subgroup analyses showed no significant improvement with bevacizumab vs placebo in any patient subsets.
Median follow-up for progression-free survival was 46.0 months. Median progression-free survival was 8.0 months (95% CI = 7.1–8.5 months) in the bevacizumab group vs 6.7 months (95% CI = 6.3–7.4 months) in the placebo group (HR = 0.77, 95% CI = 0.63–0.95, P = .015). Objective response was observed in 40.4% vs 36.4% of patients (P = .56), with complete response in 8% of patients in each group.
KEY POINTS
- The addition of bevacizumab to gemcitabine/cisplatin did not improve overall survival.
- Median overall survival was 14.5 vs 14.3 months.
Adverse Events
The overall incidence of grade ≥ 3 adverse events did not differ significantly between groups. Among grade 3 and 4 hematologic adverse events, thrombocytopenia was more common in the bevacizumab group (27% vs 18%), with no marked differences in rates of anemia or febrile neutropenia being observed. An increased rate of toxicities associated with bevacizumab, such as hypertension (any-grade in 24% vs 6%, grade ≥ 3 in 21% vs 5%) and proteinuria (any-grade in 10% vs 3%, grade ≥ 3 in 5% vs < 1%), was observed in the bevacizumab group.
Serious adverse events occurred in 35% of patients in both groups. Adverse events led to discontinuation of chemotherapy in 16% vs 14% of patients and to discontinuation of bevacizumab vs placebo in 15% vs 8% of patients receiving maintenance therapy. Treatment-related adverse events led to death in seven patients in the bevacizumab group and in five patients in the placebo group.
The investigators concluded, “The addition of bevacizumab to gemcitabine and cisplatin did not result in improved overall survival. The observed median overall survival of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.”
Dr. Rosenberg, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Cancer Institute grants and by Genentech. For full disclosures of the study authors, visit ascopubs.org.
