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, Ross C Donehower, T. Iveson, E. Y. Loh, Y. Zhang

Research output: Contribution to journalArticle

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

Fingerprint

Stomach Neoplasms
Neoplasms
Esophagogastric Junction
Survival
Disease-Free Survival
Stomach
rilotumumab
Proportional Hazards Models
Cisplatin
Therapeutics
Multivariate Analysis
Pharmacokinetics
Biomarkers
Monoclonal Antibodies
Placebos
Safety
Population

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Zhu, M., Tang, R., Doshi, S., Oliner, K. S., Dubey, S., Jiang, Y., ... Zhang, Y. (2015). Exposure-response analysis of rilotumumab in gastric cancer: The role of tumour MET expression. British Journal of Cancer, 112(3), 429-437. https://doi.org/10.1038/bjc.2014.649

Exposure-response analysis of rilotumumab in gastric cancer : The role of tumour MET expression. / Zhu, M.; Tang, R.; Doshi, S.; Oliner, K. S.; Dubey, S.; Jiang, Y.; Donehower, Ross C; Iveson, T.; Loh, E. Y.; Zhang, Y.

In: British Journal of Cancer, Vol. 112, No. 3, 03.02.2015, p. 429-437.

Research output: Contribution to journalArticle

Zhu, M, Tang, R, Doshi, S, Oliner, KS, Dubey, S, Jiang, Y, Donehower, RC, Iveson, T, Loh, EY & Zhang, Y 2015, 'Exposure-response analysis of rilotumumab in gastric cancer: The role of tumour MET expression', British Journal of Cancer, vol. 112, no. 3, pp. 429-437. https://doi.org/10.1038/bjc.2014.649
Zhu, M. ; Tang, R. ; Doshi, S. ; Oliner, K. S. ; Dubey, S. ; Jiang, Y. ; Donehower, Ross C ; Iveson, T. ; Loh, E. Y. ; Zhang, Y. / Exposure-response analysis of rilotumumab in gastric cancer : The role of tumour MET expression. In: British Journal of Cancer. 2015 ; Vol. 112, No. 3. pp. 429-437.
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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.",
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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, Ross C

AU - Iveson, T.

AU - Loh, E. Y.

AU - Zhang, Y.

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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.

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