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.
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Authors | 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 |
Journal | British journal of clinical pharmacology
(Br J Clin Pharmacol)
Vol. 88
Issue 7
Pg. 3182-3192
(07 2022)
ISSN: 1365-2125 [Electronic] England |
PMID | 35029306
(Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Docetaxel
- Platinum
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Topics |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Combined Chemotherapy Protocols
(adverse effects)
- Carcinoma, Transitional Cell
(drug therapy)
- Docetaxel
- Humans
- Platinum
(therapeutic use)
- Urinary Bladder Neoplasms
(drug therapy)
- Ramucirumab
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