Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy

Ronald de Wit*, Thomas Powles, Daniel Castellano, Andrea Necchi, Jae Lyun Lee, Michiel S. van der Heijden, Nobuaki Matsubara, Aristotelis Bamias, Aude Fléchon, Cora N. Sternberg, Alexandra Drakaki, Evan Y. Yu, Annamaria H. Zimmermann, Amanda Long, Richard A. Walgren, Ling Gao, Katherine M. Bell-McGuinn, Daniel P. Petrylak

*Corresponding author for this work

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Abstract

Aims: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial. Methods: Pharmacokinetic (PK) samples were collected (cycle 1-3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (Cmin,1, or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to evaluate the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was assessed descriptively. Results: Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease-PK interaction. A significant association was identified between Cmin,1 and OS (P =.0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks). Conclusions: This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease-PK relationship.

Original languageEnglish
Pages (from-to)3182-3192
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume88
Issue number7
DOIs
Publication statusPublished - Jul 2022

Bibliographical note

ACKNOWLEDGMENTS
Eli Lilly and Company provided funding and support for the RANGE
trial. The authors would like to thank all the patients who participated in this trial, as well as their caregivers, and all the investigators and
their support staff who graciously contributed to this work. We thank Ryan Widau and Sophie Callies from Eli Lilly and Company for their
medical and pharmacokinetic contributions to this work. Eli Lilly and Company provided medical writing support for this manuscript.
Eli Lilly and Company provided funding and support for the RANGE trial.

Publisher Copyright:
© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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