Daniel P. Petrylak, MD
As reported in The Lancet Oncology by Daniel P. Petrylak, MD, and colleagues, the phase III RANGE trial has shown no significant improvement in overall survival with the addition of ramucirumab to docetaxel in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based chemotherapy.
The primary analysis from the study showed a significant improvement in progression-free survival with the addition of ramucirumab; a progression-free survival benefit was maintained at the current analysis.
In the double-blind trial, 530 patients from 23 countries were randomly assigned between July 2015 and April 2017 to receive ramucirumab at 10 mg/kg (n = 263) or placebo (n = 267) followed by docetaxel at 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of 21-day cycles. Randomization was stratified by geographic region, Eastern Cooperative Oncology Group performance status, and visceral metastasis. Treatment continued until disease progression or unacceptable toxicity.
Overall survival was a key secondary endpoint and was assessed in the intention-to-treat population.
At database lock in March 2018 for the final overall survival analysis, median follow-up was 7.4 months. Median overall survival was 9.4 months in the ramucirumab group vs 7.9 months in the placebo group (stratified hazard ratio [HR] = 0.887, 95% confidence interval [CI] = 0.724–1.086, P = .25). Overall survival was 67.7% vs 62.6% at 6 months, 40.0% vs 35.2% at 1 year, and 17.1% vs 12.3% at 2 years. In a prespecified exploratory analysis, the HR among 357 patients with the bladder as the primary tumor site was 0.786 (95% CI = 0.615–1.004).
A sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock showed median durations of 4.1 months vs 2.8 months (HR = 0.696, P = .0002). Subsequent systemic therapy was received by 27% of patients in both groups, with chemotherapy being the most common.
Grade ≥ 3 treatment-related adverse events occurred in 48% vs 41% of patients. Events that were more common in the ramucirumab group included febrile neutropenia (9% vs 6% of patients in the placebo group) and neutropenia (7% vs 2%). Serious adverse events occurred in 43% vs 40% of patients. Treatment-related adverse events led to death in eight patients (3%) in the ramucirumab group and five patients (2%) in the placebo group.
The investigators concluded, “Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population.”
Petrylak DP et al: Lancet Oncol. November 18, 2019 (early release online). ■