Nintedanib in non-small cell lung cancer: from preclinical to approval

Abstract

Angiogenesis is a driving force of a tumor's development. Targeting this process is an attractive option, as this is a feature shared by most of the solid tumors. A lot of antiangiogenic drugs have been developed following this path, including bevacizumab, sorafenib, sunitinib, vandetanib, ramucirumab, motesanib and many others. The latest drug of this class to be approved for patients with non-small cell lung cancer (NSCLC) was nintedanib, a triple angiokinase inhibitor. This molecule targets vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways, avoiding the tumor's switch to normal escape mechanisms. The pharmacokinetic, pharmacodynamic and toxicity profiles of nintedanib have been tested in several studies. These trials revealed it to be very interesting, as this agent did not lead to the classical adverse events of other tyrosine kinase inhibitors. A phase III clinical trial that recently concluded provided us with relevant information in patients with NSCLC of adenocarcinoma histology. Here we present a short overview of the tumor angiogenesis pathways and antiangiogenic drugs. In particular, we will focus on nintedanib, from the preclinical studies to the latest phase III clinical trial that allowed this new agent to be approved by the European Medicines Agency as a second-line treatment option in association with docetaxel for NSCLC patients with adenocarcinoma histology.

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

“…FGFR1, 2, and 3; PDGF receptor-α and -β; and VEGF receptor-1, −2, and −3 are receptors that are targeted by nintedanib (35). Nintedanib was originally developed for the treatment of malignancies as an agent to inhibit angiogenesis, cell proliferation, and migration (36). Nintedanib also reduced the mRNA and protein expression of extracellular matrix components in fibroblasts from human IPF (37), indicating the ability of nintedanib to treat IPF.…”

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

“…Nintedanib, a small-molecule FGFR/PDGFR/VEGFR TKI, demonstrated efficacy in clinical trials against lung cancer and is approved for second-line treatment of lung adenocarcinoma [15]. Additionally, it is currently being evaluated clinically in SCLC [5]. As observed for all targeted anticancer agents, treatment of lung cancer patients with nintedanib is not curative and leads to disease recurrence due to acquired resistance development [15, 16].…”

“…Due to detection at rather advanced stages, accompanied by intrinsic chemoresistance in non-small cell lung cancer (NSCLC) and rapid metastasis and therapy resistance development in small cell lung cancer (SCLC) as well as frequent relapse after surgical intervention, prognosis of this disease is very poor [3-5]. For these reasons it is clear that new strategies for rational treatment of lung cancer are urgently needed.…”

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

“…Nintedanib, a triple angiokinase inhibitor of VEGFR, PDGFR, and FGFR, is one of these investigational targeted agents. Nintedanib has been used for treating several malignancies, including non-small cell lung cancer, prostate cancer, and ovarian cancer, because of its potent antiangiogenic ability 35–37…”