Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors

Area of Science:

• Oncology
• Translational Research
• Clinical Pharmacology

Background:

• Vascular endothelial growth factor (VEGF) inhibitors offer limited cancer treatment benefits due to resistance.
• Resistance mechanisms involve alternative pro-angiogenic pathways like platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).
• Nintedanib, a triple kinase inhibitor, targets these resistance pathways, potentially enhancing anti-VEGF therapy efficacy.

Purpose of the Study:

• To evaluate the safety and tolerability of nintedanib in combination with bevacizumab in a first-in-human clinical trial.
• To assess the anti-tumor activity of this combination in patients with advanced solid tumors.
• To explore the correlation between angiogenic biomarkers and clinical outcomes.

Main Methods:

• A standard 3+3 phase 1 design was used with escalating doses of oral nintedanib (150 mg or 200 mg twice daily) and intravenous bevacizumab (15 mg/kg every 3 weeks).
• Treatment continued until disease progression or unacceptable toxicity.
• Plasma angiogenic biomarkers were measured and correlated with clinical outcomes.

Main Results:

• Eighteen patients with advanced lung, colon, or cervical cancer were enrolled; 50% had prior bevacizumab treatment.
• The maximum tolerated dose of nintedanib was 200 mg twice daily, with no observed dose-limiting toxicities.
• Common adverse events included fatigue and diarrhea; durable clinical responses were seen in 55% of bevacizumab-pretreated patients.

Conclusions:

• Nintedanib in combination with bevacizumab is well-tolerated and demonstrates significant clinical activity.
• The combination shows promise in overcoming resistance to bevacizumab, even in previously treated patients.
• Biomarker analysis suggests potential predictive value for treatment response.