TY - JOUR
T1 - Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy
AU - de Wit, Ronald
AU - Powles, Thomas
AU - Castellano, Daniel
AU - Necchi, Andrea
AU - Lee, Jae-Lyun
AU - van der Heijden, Michiel S.
AU - Matsubara, Nobuaki
AU - Bamias, Aristotelis
AU - Fléchon, Aude
AU - Sternberg, Cora N.
AU - Drakaki, Alexandra
AU - Yu, Evan Y.
AU - Zimmermann, Annamaria H.
AU - Long, Amanda
AU - Walgren, Richard A.
AU - Gao, Ling
AU - Bell-McGuinn, Katherine M.
AU - Petrylak, Daniel P.
N1 - Funding Information: D.P.P. reports consultant fees from Ada Cap (Advanced Accelerator Applications) Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly and Company, Exelixis, Incyte, Ipsen, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Seattle Genetics, Urogen; grant support from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Eli Lilly and Company, Endocyte, Genentech, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, Seattle Genetics; and previous ownership interest/investment in Bellicum and Tyme. Funding Information: D.C. reports consulting or advisory roles with Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ispen, Bristol‐Myers Squibb, MSD Oncology, Bayer, Eli Lilly and Company, Sanofi, Pierre Fabre, Boehringer Ingelheim; research funding from Janssen Oncology; and travel/accommodation expenses Pfizer, Roche, Bristol‐Myers Squibb and AstraZeneca Spain. Funding Information: J.‐L.L. reports grants, personal fees and other from Pfizer Korea, Ipsen Korea, BMS, MSD; personal fees from Novartis Korea; personal fees and other from Sanofi Aventis, Astellas Korea; other from Myovant Science, Johnson and Johnson and Amgen; grants and other from Merck, Esai, Amgen; grants and personal fees from AstraZeneca; and grants from Exelixis, Roche, SeaGen. Funding Information: R.deW. serves as an advisor for Merck, Sanofi‐Genzyme, Astellas, Eli Lilly and Company, Bayer and Janssen; reports speaker fees from Sanofi and Merck; grants (institutional) from Bayer and Sanofi; and travel support from Bayer. Publisher Copyright: © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - exposure-response
KW - overall survival
KW - progression-free survival
KW - ramucirumab
KW - urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85124573579&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bcp.15233
DO - https://doi.org/10.1111/bcp.15233
M3 - Article
C2 - 35029306
SN - 0306-5251
VL - 88
SP - 3182
EP - 3192
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 7
ER -