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

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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).

CONCLUSIONS:

Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00460317, NCT00369070.

• Authors: Michael B Bass, Bin Yao, Yong-Jiang Hei, Yining Ye, Gerard J Davis, Michael T Davis, Barbara A Kaesdorf, Sabrina S Chan, Scott D Patterson
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e108048 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25314641 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Biomarkers, Tumor
• Indoles
• Oligonucleotides
• PGF protein, human
• Pregnancy Proteins
• Placenta Growth Factor
• Niacinamide
• Carboplatin
• imetelstat
• Paclitaxel

Topics

• Aged
• Angiogenesis Inhibitors (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Area Under Curve
• Biomarkers, Tumor (blood, metabolism)
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality)
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Indoles (administration & dosage)
• Lung Neoplasms (drug therapy, mortality)
• Male
• Middle Aged
• Neoplasm Staging
• Niacinamide (administration & dosage, analogs & derivatives)
• Oligonucleotides
• Paclitaxel (administration & dosage)
• Placebo Effect
• Placenta Growth Factor
• Pregnancy Proteins (blood)
• Proportional Hazards Models
• ROC Curve
• Survival Rate