Challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience.

ABSTRACT: 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.

SUBMITTER: Bass MB 

PROVIDER: S-EPMC4196848 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature