Clinical development of nintedanib for advanced non-small-cell lung cancer

Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study.