ASCO GU 2019: Ramucirumab Exposure-Response Relationship in RANGE: Trial in Advanced Platinum-Refractory Urothelial Carcinoma

San Francisco, CA (  Patients with advanced or metastatic, platinum-refractory urothelial carcinoma (UC) have limited treatment options. RANGE is an international, randomized, double-blind, phase 3 trial that assessed the safety and efficacy of treatment with docetaxel plus either ramucirumab (RAM), a human IgG1 VEGFR-2 antagonist, or placebo. It was demonstrated that docetaxel plus RAM was associated with superior progression free survival (PFS) compared to docetaxel chemotherapy alone in platinum-refractory advanced UC, validating the VEGF-2 pathway as a therapeutic target in the treatment of such patients. The present study reports the exposure-response and overall survival relationships for RAM in the RANGE study. 

Patients received RAM + docetaxel or placebo + docetaxel on day 1 of a 21-day cycle until discontinuation criteria were met. Population pharmacokinetic analyses predicted RAM minimum concentrations after the first dose. Multivariate and matched case control analyses were performed to evaluate the exposure-response and overall survival relationship. 

Poor prognostic factors were more frequent in the lower exposure quartiles suggesting a possible disease-pharmacokinetic interaction. Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. Limitations of the study include small sample size, limited time point, disease-pharmacokinetic interaction which may be confounding. 

The RAM + docetaxel quartile with the highest exposure and more favorable prognostic features had better overall survival and objective response rates. There was an observed disease-pharmacokinetic interaction (for example from weight loss, inflammation, liver toxicity) that may impact exposure-response results and warrants further investigation. 

Presented by:  Ronald De Wit, MD, PhD, Erasmus MC Cancer Institute in Rotterdam, The Netherlands

Written by: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, Philadelphia, PA. Twitter:@selmasic at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA