Exposure‐response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy. Issue 7 (7th February 2022)

• Record Type: Journal Article
• Authors: de Wit, Ronald; Powles, Thomas; Castellano, Daniel; Necchi, Andrea; Lee, Jae‐Lyun; van der 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; Bell‐McGuinn, Katherine M.; Petrylak, Daniel P.
• Is Part Of: British journal of clinical pharmacology. Volume 88:Issue 7(2022)
• Page Start: 3182
• Page End: 3192
• Publication Date: 2022-02-07
• Subjects: exposure‐response -- overall survival -- progression‐free survival -- ramucirumab -- urothelial carcinoma; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.15233
• Languages: English
• ISSNs: 0306-5251

Abstract

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 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 Cmin, 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.