Ramucirumab (Cyramza), a vascular endothelial growth factor receptor 2 inhibitor, added to docetaxel improved progression-free survival (PFS) and nearly doubled the objective response rate (ORR) compared with docetaxel monotherapy in patients with advanced or metastatic urothelial cancer that progressed with platinum-based chemotherapy in the phase 3 RANGE clinical trial.1 This is the first phase 3 clinical trial to show a PFS advantage over chemotherapy alone in this setting. Lead investigator Daniel P. Petrylak, MD, Professor of Medicine and of Urology, Yale School of Medicine and Yale Cancer Center, New Haven, CT, presented the results at the 2017 European Society for Medical Oncology (ESMO) Congress.
Ramucirumab plus docetaxel significantly improved PFS by 24% versus docetaxel plus placebo, with an absolute improvement of approximately 1.3 months. Overall survival data are not mature yet. Some experts questioned whether a 1.3-month improvement in PFS is important, but Dr Petrylak emphasized that “the results are clinically meaningful. I think this study is potentially practice-changing, with a doubling in objective response rate. There are currently no other options for patients who fail on checkpoint inhibitors and other therapies.”
Dr Petrylak added, “Ramucirumab plus docetaxel is a new treatment option that could become a standard of care in patients with platinum-refractory advanced or metastatic urothelial cancer who have either progressed on checkpoint inhibitors or are not eligible to receive them.”
ESMO expert Richard Cathomas, MD, Deputy Chief Physician of Oncology and Haematology, Kantonsspital Graubünden, Chur, Switzerland, was more restrained in his comments, saying, “This is the first trial to show a progression-free survival compared with chemotherapy alone in platinum-refractory urothelial cancer. However, the magnitude of benefit was about 1.3 months and, while statistically significant, it raises the question of whether this is clinically relevant.”
In the earlier, phase 2 clinical trial conducted by Dr Petrylak and colleagues, ramucirumab plus docetaxel nearly doubled the duration of PFS.2 The phase 3 RANGE study failed to replicate such a robust benefit in terms of PFS.
Overall Survival Data Will Be Crucial
Dr Cathomas said that overall survival data will determine the true benefit of this approach. “Other trials that combine chemotherapy and angiogenesis in other cancers have shown that such a small progression-free survival benefit often does not translate into overall survival,” he said.
“The strengths of the study are that it met its primary end point, reported the best objective response rates in second-line treatment of unselected patients, had manageable safety, and improved progression-free survival. Limitations of the study are the small PFS benefit, lack of survival data, no improvement in quality of life, and no biomarkers to identify which patients will respond,” said discussant of this presentation, Yohann Loriot, MD, PhD, Gustave Roussy, University of Paris Saclay, Villejuif, France.
The RANGE Study
The phase 3 RANGE trial included 530 patients with progressive advanced or metastatic urothelial cancer within 14 months of platinum-based chemotherapy. Patients who had previously received 1 checkpoint inhibitor were included in the study (7% in the ramucirumab plus docetaxel arm and 10% in the placebo plus docetaxel arm).
At baseline, the treatment arms had similar demographic and disease characteristics. Patients were randomized in a 1:1 ratio to receive ramucirumab 10 mg/kg plus docetaxel 75 mg/m2 or to placebo plus docetaxel at the same dose. Patients were followed for a median of 5 months.
The median PFS (investigator-assessed) was 4.07 months with ramucirumab plus docetaxel versus 2.76 months with docetaxel plus placebo (hazard ratio [HR], 0.75; P = .0118), representing a 25% reduction in disease progression favoring the experimental arm. A blinded central review showed a median PFS of 4.04 months with ramucirumab plus docetaxel versus 2.46 months with docetaxel plus placebo (HR, 0.672; P = .0005). The 12-month disease-free survival rate was 8.5% with ramucirumab plus docetaxel versus 5.1% with docetaxel plus placebo.
The investigator-assessed ORR was 24.5% in the ramucirumab-containing arm versus 14% in the comparator arm; the complete response rate was 4.2% and 1.4%, respectively. The side effects were similar between the 2 treatment arms.
References
- Petrylak DP, de Wit R, Chi KN, et al; for the RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017;390:2266-2277.
- Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016;34:1500-1509.