Two-drug therapy for advanced UC shows superior PFS

Adding ramucirumab (CYRAMZA) to standard docetaxel (Taxotere) improved progression-free survival (PFS) compared with docetaxel alone in patients with advanced or metastatic urothelial cancer who have progressed on platinum-based chemotherapy.

In the international phase III RANGE trial, PFS improved by more than 1 month by adding ramucirumab, reported Daniel P. Petrylak, MD, at the European Society for Medical Oncology 2017 Congress in Madrid.

“RANGE is the first phase III trial to demonstrate a PFS advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” he said. Further, the combination of ramucirumab and docetaxel did not result in significant additive toxicity or compromise quality of life compared with placebo plus docetaxel. Therefore, the combination represents a new treatment option for this patient population, he said.

“We don’t have other therapeutic options for patients who have failed checkpoint inhibition therapy or for patients who may not be eligible for checkpoint inhibition therapy,” said Dr. Petrylak, of Yale School of Medicine and Yale Cancer Center, New Haven, CT. “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.”

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Ramucirumab is a human IgG1 monoclonal antibody VEGFR2 antagonist that was previously shown superior to docetaxel on the endpoint of disease-free survival in a phase II study in patients with platinum-refractory urothelial carcinoma.

The phase III RANGE trial built on this experience, enrolling 530 patients with locally advanced or unresectable metastatic bladder cancer that progressed within 14 months of prior chemotherapy, either a cisplatin- or carboplatin-based regimen. Seven percent of patients in the experimental arm and 10% in the docetaxel monotherapy arm received prior checkpoint inhibitor therapy. Patients were randomized 1:1 to ramucirumab, 10 mg/kg, combined with docetaxel, 75 mg/m² intravenously, or placebo plus docetaxel. Docetaxel was limited to six cycles, with up to four additional cycles allowed after trial sponsor approval.

Some 61% enrolled had two or more adverse prognostic risk factors at baseline, said Dr. Petrylak, confirming that the study population was “a sick group of patients.”

Median follow-up in the full intent-to-treat population was 5.0 months. Investigator-assessed median PFS, the primary endpoint, was 4.07 months with the combination therapy compared with 2.76 months for patients who received docetaxel alone (HR=0.757, p=.018). By independent blinded assessment, median PFS was 4.04 months versus 2.46 months in favor of ramucirumab/docetaxel (HR=0.672, p=.0005). At 1 year, by investigator assessment, 11.9% of patients assigned to ramucirumab and docetaxel were progression free versus 4.5% of those assigned to docetaxel alone. The corresponding percentages by independent blinded assessment were 8.3% versus 5.1%, again favoring the combination. PFS outcomes were consistent across a variety of patient subgroups.

Next: 'Practice changing' ORR

The objective response rate (ORR) was approximately doubled by adding ramucirumab to docetaxel compared with docetaxel alone (24.5% vs. 14.0%), and the complete response rate tripled from 1.4% to 4.2%.

“The ORR in my mind is clinically significant and practice changing,” Dr. Petrylak said.

Treatment was discontinued, primarily due to progressive disease, in 209 patients in the ramucirumab/docetaxel arm and 229 patients on placebo/docetaxel. Forty-nine patients in the combination arm remain on treatment compared with 36 in the docetaxel monotherapy arm.

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There was no degradation in quality of life scores measured using either the EORTC QLQ-C30 Global Quality of Life or the EQ-5D-5L Index in patients on combination therapy versus docetaxel alone. Toxicities were similar between groups, with slightly less anemia with ramucirumab/docetaxel (16%) compared with placebo/docetaxel (24%), including grade ≥3 anemia (3% vs. 11%).

RANGE is designed to examine overall survival as a secondary endpoint, but those data are still maturing.

The activity and tolerability of ramucirumab/docetaxel in unselected patients remains uncertain, as RANGE had strict inclusion criteria: Patients could not have had brain metastases or a recent cardiovascular or thromboembolic event prior to entry, said invited discussant Yohann Loriot, MD, from Gustave Roussy, University of Paris Saclay, Villejuif, France.

Several of Dr. Petrylak’s co-authors have a financial or other relationship with Eli Lilly and Co. and/or other pharmaceutical companies. The study was funded by Eli Lilly and Co.

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