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

Area of Science:

• Oncology
• Biomarker Discovery
• Clinical Trials

Background:

• Advanced nonsquamous non-small-cell lung cancer (NSCLC) requires novel therapeutic strategies.
• Predictive biomarkers are crucial for optimizing targeted therapy efficacy.
• Motesanib is an investigational agent targeting angiogenesis.

Purpose of the Study:

• To evaluate placental growth factor (PlGF) as a predictive pharmacodynamic biomarker for motesanib efficacy.
• To assess PlGF as a biomarker in first-line therapy for advanced NSCLC.

Main Methods:

• Exploratory analysis of a phase 2 study and a prespecified analysis of the phase 3 MONET1 study.
• PlGF levels were measured at baseline and week 4.
• Associations between PlGF fold-change and overall survival were analyzed using Cox models.

Main Results:

• In phase 2, a ≥2.2-fold increase in PlGF correlated with significantly longer overall survival (22.9 vs 7.9 months).
• In phase 3 (MONET1), no association was found between PlGF fold-change and overall survival (HR 0.98).
• MONET1 did not meet its primary endpoint; median overall survival was similar regardless of PlGF change.

Conclusions:

• Biomarker findings from phase 2 studies may not translate to phase 3 clinical trials.
• PlGF is not a reliable predictive biomarker for motesanib in advanced NSCLC.
• Challenges exist in biomarker validation across different study phases.