Adding ramucirumab to docetaxel led to a statistically significant improvement in progression-free survival (PFS) as compared to docetaxel plus placebo in patients with advanced or metastatic platinum refractory urothelial carcinoma, according to findings from the phase III RANGE trial presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Daniel P. Petrylak of the Department of Medical Oncology, Yale University School of Medicine in New Haven, USA and colleagues conducted the randomised, double-blind, phase III trial, RANGE (NCT02426125) to confirm phase II results in a similar patient population demonstrating significantly improved PFS with ramucirumab plus docetaxel of 5.4 versus 2.8 months with docetaxel, hazard ratio (HR) 0.389; 95% confidence interval (CI) 0.235, 0.643 (p = 0.0002).
The phase III RANGE study enrolled 530 patients with progressive advanced or metastatic urothelial carcinoma after platinum-based chemotherapy. Prior treatment with one immune checkpoint inhibitor was allowed. The investigators randomised 263 patients to docetaxel at 75 mg/m2 plus ramucirumab at 10 mg/kg and 267 patients to docetaxel at the same dose plus placebo on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Radiographic assessment occurred every 6 weeks.
Beyond the primary investigator assessed PFS endpoint, secondary outcome measures included overall survival (OS), objective response rate (ORR), safety, and quality of life (QoL).
The RANGE study confirms earlier results from a phase II trial
Prolonged PFS was demonstrated by investigator assessed PFS that was consistent with a blinded central analysis. Patients treated with ramucirumab/docetaxel had significantly longer median PFS of 4.1 months compared to 2.8 months with placebo/docetaxel, HR 0.757; 95% CI 0.607, 0.943 (p = 0.0118). These results were consistent with PFS results from a blinded central analysis, HR, 0.672; 95% CI 0.536, 0.842 (p=0.0005).
The response was nearly doubled by the addition of ramucirumab: the ORR was 24.5% (95% CI 18.8, 30.3) with ramucirumab/docetaxel versus 14.0% (95% CI, 9.4-18.6) with placebo/docetaxel.
The OS data are not yet mature.
The safety data in RANGE study were also consistent with the earlier findings. Grade 3 or higher adverse events (AEs) were reported at a similar frequency in both arms with no unexpected toxicities. The most commonly reported grade 3 or higher AE was neutropenia, which occurred in 15% of patients in the ramucirumab arm versus 14% of patients in the placebo arm.
The QoL analysis revealed that the mean scores for global quality of life were relatively unchanged over time, with no differences between arms.
The authors concluded that docetaxel plus ramucirumab is the first regimen to show superior PFS over chemotherapy in a phase III trial in patients with platinum refractory advanced urothelial cancer.
Yohann Loriot of the Gustave Roussy, University of Paris Saclay, Villejuif, France who discussed the study results said that ramucirumab plus docetaxel may be treatment chosen post ICI for most clinicians, however the issues are insufficient number of patients in subgroup analyses to suggest that ramucirumab plus docetaxel may not be active in post ICI, many patients (approximately 60%) do not receive any subsequent treatment after ICI failure, there is no evidence of efficacy of ramucirumab on visceral disease. He questioned, if ramucirumab is active and well-tolerated in unselected patients in daily practice and pointed out that the study inclusion criteria were restrictive to patients with good performance status, no (untreated) brain metastasis, no recent cardiovascular event, no thromboembolic event within 6 months prior treatment.
This trial was sponsored by Eli Lilly and Company.
LBA4_PR – Petrylak DP, et al. RANGE: a randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma.