MADRID-Ramucirumab plus docetaxel improves progression-free survival (PFS) in patients with advanced or metastatic urothelial cancer who have progressed on platinum-based chemotherapy. However, there are questions as to whether the small improvement in PFS constitutes a true clinical benefit, according to a new study recently presented at the ESMO 2017 Congress (LBA4_PR). The results were also published the same week in The Lancet (2017; http://dx.doi.org/10.1016/S0140-6736(17)32365-6).
Limited treatment options are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. Survival following recurrence or progression on platinum-based chemotherapy is poor, with a median survival of approximately 7 months with single-agent cytotoxic chemotherapy, said lead investigator Daniel P. Petrylak, MD, Professor of Medicine and Urology at the Yale School of Medicine and Yale Cancer Center in New Haven, Conn.
"In the past 18 months, favorable reviews or approvals have been granted to five immune checkpoint inhibitors targeting PD-1/PD-L1," said Petrylak. "Response rates range from 15 to 21 percent; however, many patients have progressive disease as best response." The anti-PD-1 agent pembrolizumab has been shown to improve survival when compared to chemotherapy.
Ramucirumab is a human IgG1 monoclonal antibody that is a vascular endothelial growth factor receptor antagonist. In a previous randomized phase II study, adding ramucirumab to docetaxel nearly doubled PFS (5.4 months) compared to docetaxel alone (2.8 months) in patients with platinum-refractory advanced or metastatic urothelial cancer, with no unexpected toxicities. There was also a trend toward an improvement in overall response rate with ramucirumab (24%) compared to docetaxel (9%).
Methodology & Results
To confirm these results, researchers conducted a randomized phase III trial in a similar patient population. The RANGE trial included 530 patients, median age 65 years, with advanced or metastatic urothelial cancer who had progressed on first-line platinum-based chemotherapy within the previous 14 months. Patients were randomized to ramucirumab 10 mg/kg plus docetaxel 75 mg/m2 (263 patients) versus placebo plus docetaxel (267 patients) on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Additional prior treatment with one immune checkpoint inhibitor was permitted. Baseline demographics and patient characteristics were well-balanced between the two arms, Petrylak noted.
The primary endpoint of investigator-assessed PFS was significantly prolonged with ramucirumab plus docetaxel (4.07 months) compared to placebo plus docetaxel (2.76 months), with a hazard ratio of 0.757. A blinded central analysis demonstrated consistent PFS results-PFS was 4.04 months with ramucirumab/docetaxel compared to 2.46 months with placebo/docetaxel (hazard ratio, 0.672).
The objective response rate was 24.5 percent in the ramucirumab/docetaxel arm compared to 14.0 percent in the placebo/docetaxel arm. Overall survival data is still maturing.
Toxicities were similar between groups, with slightly less anemia with ramucirumab/docetaxel compared to placebo/docetaxel. Grade 3 or higher adverse events were reported at a similar frequency in both arms with no unexpected toxicities. Neutropenia was the most common grade 3 or higher adverse event (15% RAM arm vs. 14% placebo arm).
Mean scores for global quality of life were relatively unchanged over time, with no differences between the treatment arms. "No degradation of quality of life was seen over time, showing that ramucirumab plus docetaxel is not more toxic than docetaxel alone," Petrylak reported.
Treatment was discontinued, primarily due to progressive disease, in 209 patients on ramucirumab/docetaxel and 229 patients on placebo/docetaxel.
"Ramucirumab reduced the risk of disease progression by 24 percent and this was consistent across patient subgroups," said Petrylak. "The objective response rate nearly doubled with ramucirumab and there were no significant differences in toxicities between treatments."
Petrylak concluded: "Ramucirumab plus docetaxel is the first regimen in a phase III study to show superior PFS over chemotherapy in patients with platinum-refractory advanced urothelial cancer. PFS outcomes were consistent across most patient subgroups. The combination of ramucirumab plus docetaxel did not result in significant additive toxicity or compromise quality of life when compared to placebo plus docetaxel. Ramucirumab plus docetaxel is a new treatment option and 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."
Expert Commentary
Richard Cathomas, MD, Deputy Chief Physician of Oncology and Hematology, Kantonsspital Graubunden, Chur, Switzerland, commented: "This is the first trial to show a progression-free survival benefit compared to chemotherapy alone in patients with platinum-refractory urothelial cancer. However, the magnitude of benefit was 1.3 months and, while statistically significant, it raises the question of whether it is clinically relevant.
"We need to know if the improvement in PFS translates into an overall survival benefit," continued Cathomas. "We have seen from other trials combining chemotherapy with angiogenesis inhibitors in different cancers that such a small PFS benefit often does not translate into overall survival.
"It is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition," he concluded. "But the improvement in response rate shows that ramucirumab does have an impact on the disease, so in the future, angiogenesis inhibition may become part of the treatment armamentarium for urothelial cancer."
Mark L. Fuerst is a contributing writer.