Profile of nintedanib in the treatment of solid tumors: the evidence to date

Abstract

Angiogenesis is an essential process for tumor growth and metastasis, and remains a promising therapeutic target process in cancer treatment for several cancer types. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), was the first antiangiogenic agent approved for cancer therapy. Novel antiangiogenic agents, such as sunitinib, sorafenib, pazopanib, or vandetanib that target additional proangiogenic signaling pathways beyond VEGF, have also been approved for the treatment of various malignant diseases. While most of these agents are approved in combination with cytotoxic chemotherapy for indications including metastatic colorectal cancer, non-small-cell lung cancer, breast cancer, renal cell carcinoma (RCC), and gastric cancer, some are used as approved monotherapy for advanced RCC, hepatocellular carcinoma and medullary thyroid cancer. Major challenges to the success of antiangiogenic therapy include associated toxicity risks, limitation of efficacy through the possible development of resistance and induction or promotion of metastatic progression. Nintedanib (formally known as BIBF 1120) is a triple angiokinase inhibitor of VEGF, fibroblast growth factor, platelet-derived growth factor signaling with lesser activity against RET, Flt-3, and Src. Through this unique targeting profile nintedanib has demonstrated significant antitumor activity in several tumor types in preclinical studies. Nintedanib has also shown promising clinical efficacy in combination with docetaxel and has been approved for treating patients with locally advanced and metastatic non-small-cell lung cancer in Europe. Nintedanib has also been found to be clinically promising in terms of efficacy and safety in several other solid tumors including ovarian cancer (Phase III), RCC (Phase II), and prostate cancer (Phase II). This review article provides a comprehensive summary of the preclinical and clinical efficacy of nintedanib in the treatment of solid tumors.

Keywords: BIBF 1120; VEGF; angiogenesis; nintedanib; tyrosine kinase inhibitors.

Figure 1

Summary of nintedanib. Notes: (A) Molecular structure of nintedanib. (B) In vitro kinase inhibition profile of nintedanib (IC₅₀). Data presented as mean ± standard error of at least three determinations. Abbreviations: VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; IGF1R, insulin-like growth factor 1 receptor; InsR, insulin receptor; Flt-3, fms-like tyrosine protein kinase 3; Lck, lymphocyte-specific tyrosine kinase; Src, proto-oncogene tyrosine protein kinase src; Lyn, tyrosine-protein kinase lyn; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; CDK, cyclin-dependent kinase.

Figure 2

Triple angiokinase inhibition mechanism of nintedanib targeting tumor angiogenesis. Abbreviations: VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor.