1. Goodwin, Peter M.

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MADRID-Progression-free survival (PFS) was improved by treatment when the vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist ramucirumab was combined with docetaxel chemotherapy in patients with advanced or metastatic urothelial cancers with disease progression after treatment with standard first-line platinum-based chemotherapy in the phase III RANGE study reported at the ESMO 2017 Congress (LBA4_PR).

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"We have a new alternative treatment for patients with metastatic urothelial carcinoma," said first author Daniel Petrylak, MD, Professor of Medicine and Urology at Yale School of Medicine, New Haven, Conn., though some experts at ESMO were more cautious.


Petrylak said that second-line options for treating metastatic cancers arising from the urinary tract had been urgently needed because only around 5 percent of patients could be expected to survive 5 years with first-line systemic chemotherapy.

Daniel Petrylak, MD.... - Click to enlarge in new windowDaniel Petrylak, MD. Daniel Petrylak, MD

The RANGE study investigators sought to improve on the typical median survival of around 7 months with second-line treatment of chemotherapy alone, he said. So the idea was to use the anti-angiogenesis agent ramucirumab that targets VEGFR-2 and had shown activity in the laboratory-and was synergistic-when combined with docetaxel giving better outcomes in animal models than docetaxel alone.


Petrylak said their 2016 randomized phase II study demonstrating a doubling of PFS in patients treated with ramucirumab and docetaxel compared to docetaxel alone led to the RANGE study in patients with locally-advanced or unresectable metastatic bladder cancer that had progressed within 14 months of prior chemotherapy-including patients who had received prior immune checkpoint therapy.


Although "dramatic responses" were seen with immune therapy, Petrylak said this was in only about a quarter of patients, so another approach was needed.


The RANGE trial randomized 530 patients to ramucirumab plus docetaxel (263 patients) who were then compared with 267 patients who had placebo plus docetaxel.


The primary endpoint-median PFS-was 4.07 months for the combination therapy compared to 2.76 months for patients who received docetaxel alone (a hazard ratio of 0.757).


At 1 year, 11.9 percent of patients in the ramucirumab arm were free from progression compared with 4.5 percent in the control arm of the study.


Objective response rate nearly doubled. It was 24.5 percent in patients treated with ramucirumab compared to 14.0 percent in the control arm. And 4.2 percent of patients treated with the combination had complete responses compared to 1.4 percent in the monotherapy arm. Overall survival data were still maturing.



Toxicities were similar between groups with slightly less anemia with ramucirumab compared to the control therapy and discontinuations of treatment (primarily due to progressive disease) in similar numbers of patients in both arms: 209 with the active drug compared with 229 patients receiving placebo plus docetaxel.


Quality of life was unchanged, said Petrylak. "Despite administration of a second drug, we did not see any degradation of the quality of life parameters that we measured."


He said that RANGE was the first study to demonstrate PFS advantage over chemotherapy alone in platinum-refractory advanced and metastatic urothelial carcinoma.


He described the study cohort as "a sick group of patients." Sixty-one percent of them had at least two adverse prognostic risk factors at baseline, he noted, but the PFS outcomes were "consistent across a variety of different patient subgroups."


"Ramucirumab plus docetaxel 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," Petrylak explained.


Richard Cathomas, MD, Deputy Chief Physician of Oncology and Hematology at Kantonsspital Graubunden in Chur, Switzerland, commented that this was the first trial to show a PFS 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," he said.


"We need to know if the improvement in progression-free survival translates into an overall survival benefit. We have seen from other trials combining chemotherapy with angiogenesis inhibitors in different cancers that such a small progression-free survival benefit often does not translate into overall survival," Cathomas stated.


He said it was too early for these results alone to change the standard of care in second line treatment-which he said was immune checkpoint inhibition. "But the improvement in response rate shows that ramucirumab does have an impact on the disease. So in future angiogenesis inhibition may become part of the treatment armamentarium for urothelial cancer," Cathomas concluded.


Peter M. Goodwin is a contributing writer.