Ramucirumab Improves PFS in Phase III Urothelial Carcinoma Trial

Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology

Levi Garraway, MD, PhD

Adding ramucirumab (Cyramza) to docetaxel led to a statistically significant improvement in progression-free survival (PFS) versus docetaxel alone in previously treated patients with locally advanced or unresectable or metastatic urothelial carcinoma, according to results from the phase III RANGE trial.

Eli Lilly and Company, the manufacturer of the VEGFR-2 antagonist, announced the results in a press release. The company said these are the first phase III results to demonstrate superior PFS over chemotherapy in a post-platinum setting in urothelial cancer for any therapy. These are also the first phase III results to provide evidence that an antiangiogenic agent can extend PFS in urothelial cancer.

“People with advanced urothelial cancer—an aggressive disease—who have progressed on prior therapy need more treatment options that can help to control their disease,” Levi Garraway, MD, PhD, senior vice president of global development and medical affairs for Lilly Oncology, said in a statement. “These results are encouraging and we look forward to seeing the overall survival results (OS) when they are mature.”

The RANGE trial randomized 531 patients to docetaxel plus either ramucirumab or placebo. Beyond the primary PFS endpoint, secondary outcome measures included OS, objective response rate, disease control rate, and duration of response.

The safety data in RANGE were comparable to earlier findings with ramucirumab. Grade 3 or higher adverse events (AEs) that were more common in the ramucirumab arm versus the docetaxel-alone arm included neutropenia, febrile neutropenia, and hypertension.

A company spokesperson said the study data will be released at an as-yet-undetermined scientific meeting. Final OS results should be ready for publication next year.

The Journal of Clinical Oncology published results in May 2016 for a global, randomized, double-blind, placebo-controlled phase II trial involving 140 patients with locally advanced or metastatic urothelial carcinoma who progressed on platinum-based therapy.

From April 2011 to February 2014, patients were randomly assigned to 1 of 3 treatment arms: 75 mg/m² IV of docetaxel on day 1 of a 3-week cycle (arm A; n = 45); 75 mg/m2 IV of docetaxel plus 10 mg/kg IV of ramucirumab on day 1 of a 3-week cycle (arm B; n = 46); or 75 mg/m² IV of docetaxel on day 1 plus 12 mg/kg IV of icrucumab on days 1 and 8 of a 3-week cycle (arm C; n = 49). The median duration of therapy was 9.1 weeks.

The median PFS was 5.4 months in arm B compared with 2.8 months in arm A (stratified hazard rate [HR] = 0.389; 95% CI, 0.235-0.643; P = .0002). Median PFS was poorer for patients in arm C (1.6 months) compared with arm A (stratified HR, 0.863; 95% CI, 0.550-1.357; P = .5053).

At the time of this publication, researchers did not observe a statistically significant difference in OS between arms B and A (10.4 months vs 9.2 months; P = .201) or between arms A and C. Similarly, there was no statistically significant difference in objective response between arm A (8.9%) or arms B (24%) and C (12%).

The median duration of response was 4.6 months (95% CI, 2.6-5.6) in arm A compared with 4.6 months (95% CI, 0.7-7.0) in arm B. Duration of response was not evaluable in arm C. Disease control was superior in arm B (78%) compared with arm A (58%) and arm C (45%).

Grade 3 or higher treatment-emergent AEs were more common in arms B (83%) and C (84%) compared with arm A (67%). Grade 3 or higher AEs that were more common in arm B compared with arm A included fatigue, febrile neutropenia, and anemia.

Patients in arm B underwent a median of 4.5 cycles of docetaxel, compared with 3.0 for arm A and 2.0 for arm C. Similarly, more patients completed at least 6 cycles of treatment in arm B (41%) compared with arm A (22%) and arm C (27%). Median relative dose-intensities for docetaxel were 99% (IQR, 90%-100%) for arm A, 100% (IQR, 89%-101%) for arm B, and 99% (IQR, 91%-100%) for arm C.

Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase ii trial. J Clin Oncol. 2016;34(13):1500-1509.doi: 10.1200/JCO.2015.65.0218.