Exposure-response analysis of rilotumumab in gastric cancer: The role of tumour MET expression

M. Zhu, R. Tang, S. Doshi, K. S. Oliner, S. Dubey, Y. Jiang, R. C. Donehower, T. Iveson, E. Y. Loh, Y. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)429-437
Number of pages9
JournalBritish journal of cancer
Volume112
Issue number3
DOIs
StatePublished - Feb 3 2015

Keywords

  • MET
  • exposure-response analysis
  • gastric cancer
  • pharmacokinetics
  • rilotumumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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