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Exposure‐response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy
Author(s) -
Wit Ronald,
Powles Thomas,
Castellano Daniel,
Necchi Andrea,
Lee JaeLyun,
Heijden Michiel S.,
Matsubara Nobuaki,
Bamias Aristotelis,
Fléchon Aude,
Sternberg Cora N.,
Drakaki Alexandra,
Yu Evan Y.,
Zimmermann Annamaria H.,
Long Amanda,
Walgren Richard A.,
Gao Ling,
BellMcGuinn Katherine M.,
Petrylak Daniel P.
Publication year - 2022
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.15233
Subject(s) - ramucirumab , medicine , docetaxel , oncology , quartile , proportional hazards model , hazard ratio , population , placebo , gastroenterology , chemotherapy , urology , confidence interval , pathology , alternative medicine , environmental health
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 min,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 C min,1 and OS. The C min,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 C min,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.