Abstract
Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel, gemcitabine, pemetrexed, and erlotinib and for patients with target-specific oncogenes afatinib, osimertinib, crizotinib, alectinib, and ceritinib. In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.
Highlights
Lung cancer is one of the most common malignancies in the world and is the leading cause of cancer-related deaths worldwide, accounting for 1.59 million deaths yearly
With the use of molecularly targeted therapies, such as erlotinib [15], afatinib [16] for EGFR mutations (EGFRm), osimertinib [17] for EGFRm T790, and crizotinib [18], alectinib, and ceritinib [19, 20] for anaplastic lymphoma kinase (ALK) positive (Table 1), a higher response rates and prolonged progression-free survival (PFS) have been obtained when compared to chemotherapy in the first- and second-line setting [21]
The results demonstrated a nonstatistically significant higher response rate in patients receiving pemetrexed/sunitinib and a better PFS and overall survival (OS) in the single agent pemetrexed arm
Summary
Lung cancer is one of the most common malignancies in the world and is the leading cause of cancer-related deaths worldwide, accounting for 1.59 million deaths yearly. Growing knowledge of NSCLC molecular pathobiology has led to the development of new treatments that target specific oncogenes [10] and have changed the natural history of the disease with a clear improvement of patient’s survival [11] It is still characterized by a significantly low survival for second-line treatment [12, 13] with a median progression-free survival (PFS) from 2 to 3 months and a median survival rarely exceeding 8 months [14]. Recent evidence shows that nintedanib is a potent endothelial cell proliferation inhibitor with a good safety profile, proven in both in vitro and in vivo studies This molecule, an indolinone derivative, occupies the adenosine triphosphate-binding sites in the kinase domain of pro-angiogenic receptors previously mentioned, inhibiting the downstream signaling pathways. The major route of elimination is fecal/biliary excretion [45]
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