Ramucirumab Misses OS Endpoint in Phase III Urothelial Carcinoma Trial

Levi Garraway, MD, PhD

Combining ramucirumab (Cyramza) with docetaxel in patients with locally advanced or unresectable metastatic urothelial carcinoma who progressed on platinum-based chemotherapy led to a positive trend, but not a statistically significant improvement, in overall survival (OS), according to Eli Lilly and Company, the manufacturer of the VEGFR2 inhibitor.

The findings come from an analysis of the secondary endpoint of OS from the phase III RANGE trial. Previously reported findings showed that the study met its primary endpoint, with an improvement in progression-free survival (PFS) of 1.31 months. The ramucirumab combination also led to a near doubling in the objective response rate (ORR) compared with docetaxel alone.

"People with advanced urothelial carcinoma who experience disease progression urgently need treatment options that can control the disease—to help stop or slow the cancer from growing and spreading," Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology, said in a press release.

"Although this study didn't reach statistical significance for overall survival, we are encouraged by the totality of the RANGE results and look forward to reviewing the data with internal and external experts to determine next steps,” added Garraway.

In the phase III RANGE trial, 530 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 6 cycles, with up to 4 additional cycles allowed after trial sponsor approval.

Patients enrolled had locally advanced or unresectable metastatic bladder cancer that progressed within 14 months of prior chemotherapy, either a cisplatin- or carboplatin-based regimen. Patients were permitted to receive 1 prior immune checkpoint therapy—7% in the experimental arm and 10% in the docetaxel monotherapy arm received prior checkpoint inhibitor therapy.

Most patients enrolled had poor prognosis—61% had at least 2 adverse prognostic risk factors at baseline.

Median follow-up in the full intent-to-treat population was 5.0 months. Median PFS as assessed by the investigators, 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 randomized to ramucirumab and docetaxel were without progression versus 4.5% of those assigned to docetaxel alone. The corresponding percentages at 1 year by independent blinded assessment were 8.3% versus 5.1%, again favoring the combination. PFS outcomes were consistent across a variety of patient subgroups.

There was an approximate doubling of the objective response rate with combined ramucirumab and docetaxel versus docetaxel alone (24.5% vs 14.0%) and a tripling of the complete response rate (4.2% vs 1.4%).

Despite administration of a second drug, 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.

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%).

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

Petrylak D Chi KN, Drakaki A, et al. RANGE: A randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma. Presented at 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA4_PR.