MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.
Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).
“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.
But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”
He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”
He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.
In the RANGE trial, results of which werein The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.
Patients were randomly assigned to receive intravenous docetaxel 75 mg/m2 plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.
As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).
Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.
Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.
In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.
There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.
Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.
However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.
The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.