Title | Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | de Wit R, Powles T, Castellano D, Necchi A, Lee J-L, van der Heijden MS, Matsubara N, Bamias A, Fléchon A, Sternberg CN, Drakaki A, Yu EY, Zimmermann AH, Long A, Walgren RA, Gao L, Bell-McGuinn KM, Petrylak DP |
Journal | Br J Clin Pharmacol |
Volume | 88 |
Issue | 7 |
Pagination | 3182-3192 |
Date Published | 2022 Jul |
ISSN | 1365-2125 |
Keywords | Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Transitional Cell, Docetaxel, Humans, Platinum, Urinary Bladder Neoplasms |
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 (C , 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 C and OS. The C 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 C 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. |
DOI | 10.1111/bcp.15233 |
Alternate Journal | Br J Clin Pharmacol |
PubMed ID | 35029306 |
PubMed Central ID | PMC9302693 |
Grant List | UL1 TR001863 / TR / NCATS NIH HHS / United States |