Ramucirumab Falls Short of OS Endpoint in Phase III Urothelial Carcinoma Trial

Levi Garraway, MD, PhD

Levi Garraway, MD, PhD

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

Analysis of the phase III RANGE trial included OS as a secondary endpoint, and previously reported findings demonstrated that the primary endpoint was reached. There was a progress-free survival (PFS) improvement of 1.31 months and the objective response rate (ORR) nearly doubled when compared to treatment 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," said Levi Garraway, MD, PhD, senior vice president of global development and medical affairs at Lilly Oncology. "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." 

In this trial, 530 patients were randomized at a 1:1 ratio to recieve either a combination of ramucirumab (10 mg/kg) and docetaxel (75 mg/m²intravenously) or a placebo plus docetaxel. There was a limit of 6 cycles for the docetaxel treatments, though patients could recieve up to 4 additional cycles after trial sponsor approval.

All patients had locally advanced or unresectable metastatic bladder cancer that had progressed within 14 months receiving a chemotherapy treatment of either a cisplatin- or carboplatin-based regimen. Patients were also allowed to receive 1 prior immune checkpoint therapy—7% of patientsin the experimental arm and 10% in the docetaxel monotherapy arm fell into this category.

Poor prognosis was deemed in most patients, 61% having at least 2 adverse prognostic risk factors at baseline.

There was a median follow-up with the intent-to-treat population of 5.0 months. The median PFS was assessed by the investigators as the primary endpoint,, fpund at 4.07 months with the combination therapy arm and 2.76 months for patients who received docetaxel alone (HR, 0.757;P=.018). An independent blinded assessment found a median PFS of 4.04 months in the combination arm compared to a median PFS of 2.46 months in the docetaxel alone arm (HR, 0.672;P= .0005).

After 1 year, an investigator assessment found that 11.9% of patients in the ramucirumab and docetaxel were without progression versus 4.5% of those assigned to docetaxel alone. The corresponding percentages were 8.3% versus 5.1%, again favoring the combination at the 1 year mark. The PFS outcomes remained consistent.

The objective response rate was doubled approximately 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%).

Quality-of-life scores suffered no degradation, despite administration of a second drug, measured using either the EORTC QLQ-C30 Global Quality of Life or the EQ-5D-5L Index.

The toxicities were similar between both groups with slightly less anemia with ramucirumab/docetaxel (16%) compared to the placebo/docetaxel (24%), including a grade ≥3 anemia (3% vs 11%) as well.

The primary reason for treatment discontinuation was progressive disease, affecting 209 patients in the ramucirumab/docetaxel arm and 229 patients the placebo/docetaxel arm. Also, 49 patients in the combination group remained on treatment versus 36 in the docetaxel monotherapy arm.

Reference:

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.