TY - JOUR
T1 - Exposure-response analysis of rilotumumab in gastric cancer
T2 - The role of tumour MET expression
AU - Zhu, M.
AU - Tang, R.
AU - Doshi, S.
AU - Oliner, K. S.
AU - Dubey, S.
AU - Jiang, Y.
AU - Donehower, R. C.
AU - Iveson, T.
AU - Loh, E. Y.
AU - Zhang, Y.
N1 - Funding Information:
We thank the patients, investigators, and the medical, nursing, and laboratory staff who participated in the rilotumumab clinical trials; Mark Ma and Teresa Wong of Amgen Inc. for support of the analytical assay development and sample analysis; and Kerri Hebard-Massey and Jenilyn Virrey of Amgen Inc. for medical writing assistance. This study was funded by Amgen Inc.
Publisher Copyright:
© 2015 Cancer Research UK. All rights reserved 0007 - 0920/15.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - Background:Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships.Methods:Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg -1), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure.Results:Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients.Conclusions:Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.
AB - Background:Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships.Methods:Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg -1), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure.Results:Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients.Conclusions:Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.
KW - MET
KW - exposure-response analysis
KW - gastric cancer
KW - pharmacokinetics
KW - rilotumumab
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U2 - 10.1038/bjc.2014.649
DO - 10.1038/bjc.2014.649
M3 - Article
C2 - 25584489
AN - SCOPUS:84922141174
SN - 0007-0920
VL - 112
SP - 429
EP - 437
JO - British journal of cancer
JF - British journal of cancer
IS - 3
ER -