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Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience
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Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience
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Journal Article
Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience
2014
Overview
We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer.
Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models.
In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12-0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79-1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67-1.15, P = 0.340).
Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.
ClinicalTrials.gov NCT00460317, NCT00369070.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Angiogenesis Inhibitors - administration & dosage
/ Antineoplastic Combined Chemotherapy Protocols - therapeutic use
/ Biomarkers, Tumor - metabolism
/ Carboplatin - administration & dosage
/ Carcinoma, Non-Small-Cell Lung - drug therapy
/ Carcinoma, Non-Small-Cell Lung - mortality
/ Drug Administration Schedule
/ Female
/ Hazards
/ Humans
/ Indoles - administration & dosage
/ Kinases
/ Lung Neoplasms - drug therapy
/ Male
/ Medicine and health sciences
/ Niacinamide - administration & dosage
/ Niacinamide - analogs & derivatives
/ Paclitaxel - administration & dosage
/ Patients
/ Placenta
/ R&D
/ Research and Analysis Methods
/ Studies
/ Survival
/ Tumors
