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

• Published in: PloS one 2014-10, Vol.9 (10), p.e108048
• Main Authors: Bass, Michael B, Yao, Bin, Hei, Yong-Jiang, Ye, Yining, Davis, Gerard J, Davis, Michael T, Kaesdorf, Barbara A, Chan, Sabrina S, Patterson, Scott D
• Format: Article
• Language: English
• Subjects: Aged; Angiogenesis; Angiogenesis inhibitors; Angiogenesis Inhibitors - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Bioindicators; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - blood; Biomarkers, Tumor - metabolism; Biometrics; Cancer therapies; Carboplatin; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - mortality; Chemotherapy; Continuity (mathematics); Data analysis; Data processing; Design factors; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Experimental design; Female; Hazards; Health hazards; Humans; Indoles - administration & dosage; Kinases; Laboratories; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Male; Medicine and health sciences; Middle Aged; Neoplasm Staging; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Paclitaxel; Paclitaxel - administration & dosage; Patients; Pharmacodynamics; Pharmacology; Placebo Effect; Placenta; Placenta Growth Factor; Pregnancy Proteins - blood; Proportional Hazards Models; R&D; Randomization; Research & development; Research and Analysis Methods; ROC Curve; Statistical models; Studies; Survival; Survival Rate; Tumors; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108048

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