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

Abstract

Purpose Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab. Methods Patients were treated with escalating doses of nintedanib (150mg or 200mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes. Results Eighteen patients with advanced tumors (lung (n=9), colon (n=8), and cervical (n=1)) previously treated with at least two lines of chemotherapy including bevacizumab (n=9, 50%) were enrolled. The highest dose of nintedanib was 200mg twice a day with no observed dose limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1–3) and diarrhea (grade 1–2). Durable clinical response was observed in 55% patients pre-treated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α. Conclusion Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.

Nintedanib in an elderly non-small-cell lung cancer patient with severe steroid-refractory checkpoint inhibitor-related pneumonitis: A case report and literature review

“…Nintedanib in combination with afatinib (BIBW 2992), an ErbB family blocker, has shown limited antitumor activity in patients with advanced castration-resistant prostate cancer ( 164 ). Combined nintedanib plus bevacizumab treatment achieved a disease control rate of 72.2% in patients with solid tumors (lung, colon, and cervical), even in those with bevacizumab resistance ( 165 ).…”

“…Blockade of VEGF leads to decreased platelet activity and decreased leukocyte adhesion ( 194 ). It has anticoagulant effects and increases the risk of bleeding and thrombosis ( 165 ). In addition, blocking PDGF-α and PDGF-β can lead to thrombocytopenia by affecting platelet production ( 161 ).…”

Bioinformatics Analyzes of Selectins Polymorphisms Reveal New Potential Cancer Biomarkers

“…Targeting E-selectin has emerged as a potential therapeutic strategy for the treatment of cancer [72][73][74]. Several approaches have been developed to target E-selectin, including monoclonal antibodies and small molecule inhibitors and have shown promise in preclinical studies by reducing tumor growth and metastasis [75][76][77][78][79]. SELE polymorphisms have been reported as possible risk indicators for a number of medical conditions such as hypertension in cases of occupational stress [80], risk of coronary artery disease [81], enlargement of renal cyst in patients with polycystic kidney disease [82], type 2 diabetes [83] and subclinical atherosclerosis and increased platelet activity in systemic lupus erythematosus [84].…”

Nintedanib en un paciente anciano con cáncer de pulmón no-microcítico y neumonitis grave, refractaria a esteroides, inducida por inhibidores de puntos de control: Reporte de un caso y revisión de la literatura

“…El nintedanib, en combinación con afatinib (BIBW 2992), un bloqueador de la familia ErbB, ha mostrado una actividad antitumoral limitada en pacientes con cáncer de próstata avanzado resistente a la castración [164]. El tratamiento combinado de nintedanib más bevacizumab logró una tasa de control de la enfermedad de 72.2% en pacientes con tumores sólidos (pulmón, colon y cuello uterino), incluso en aquellos con resistencia al bevacizumab [165].…”