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.
|
Authors | M Zhu, R Tang, S Doshi, K S Oliner, S Dubey, Y Jiang, R C Donehower, T Iveson, E Y Loh, Y Zhang |
Journal | British journal of cancer
(Br J Cancer)
Vol. 112
Issue 3
Pg. 429-37
(Feb 03 2015)
ISSN: 1532-1827 [Electronic] England |
PMID | 25584489
(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
|