Nintedanib: examining the development and mechanism of action of a novel triple angiokinase inhibitor

Abstract

Antiangiogenic agents are effective standard-of-care options in several malignancies, but are generally associated with only modest improvements in survival, as well as leading to additional toxicities. Furthermore, almost all patients develop acquired resistance to therapy, possibly due to the activation of alternative proangiogenic pathways. Here we discuss: the rationale for developing nintedanib, an agent that simultaneously inhibits signaling pathways activated by platelet-derived growth factor, FGF, as well as VEGF; how its distinctive inhibitory and pharmacokinetic profile could underlie promising efficacy and tolerability observed in Phase II trials in patients with relapsed/refractory non-small cell lung cancer, advanced ovarian cancer and metastatic colorectal cancer; the ongoing Phase III program that is assessing nintedanib in these areas of major unmet medical need; and recent progress in the development of biomarkers that may predict response to nintedanib.

Keywords:

• angiogenesis
• FGF
• nintedanib
• non-small cell lung cancer
• VEGF

Financial & competing interests disclosure

M Reck has participated in advisory board meetings for Boehringer Ingelheim and has received honoraria from Boehringer Ingelheim for lectures and presentations. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Duncan Campbell, of GeoMed, during the preparation of this manuscript. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Agents that target proangiogenic pathways have improved patient outcomes in a range of malignancies, including non-small cell lung cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and hepatocellular carcinoma.

• Tumors develop adaptive resistance to antiangiogenesis agents, which is probably attributable to activation of compensatory proangiogenic pathways.

• The novel triple angiokinase inhibitor, nintedanib, inhibits the kinase activity of all three VEGFR subtypes, PDGFR-α and -β, FGFR-1, -2 and -3.

• In Phase I/II studies of cancer patients and healthy volunteers, nintedanib has demonstrated a manageable tolerability profile, with dose-linear pharmacokinetics; significant drug–drug interactions are not anticipated.

• A Phase III study has demonstrated significant improvement in overall survival for patients with relapsed/refractory non-small cell lung cancer of adenocarcinoma histology (in combination with docetaxel) and promising efficacy in preliminary data from a Phase III study of patients with previously untreated ovarian cancer (in combination with carboplatin and paclitaxel). Nintedanib is also being evaluated in refractory colorectal cancer.