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

AbstractBACKGROUND:
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.
AuthorsM Zhu, R Tang, S Doshi, K S Oliner, S Dubey, Y Jiang, R C Donehower, T Iveson, E Y Loh, Y Zhang
JournalBritish journal of cancer (Br J Cancer) Vol. 112 Issue 3 Pg. 429-37 (Feb 03 2015) ISSN: 1532-1827 [Electronic] England
PMID25584489 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • rilotumumab
  • MET protein, human
  • Proto-Oncogene Proteins c-met
Topics
  • Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
  • Adult
  • Aged
  • Antibodies, Monoclonal (administration & dosage, pharmacokinetics)
  • Antibodies, Monoclonal, Humanized
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins c-met (genetics)
  • Stomach Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Treatment Outcome

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