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Published in: Targeted Oncology 2/2015

01-06-2015 | Adis Drug Evaluation

Nintedanib: A Review of Its Use as Second-Line Treatment in Adults with Advanced Non-Small Cell Lung Cancer of Adenocarcinoma Histology

Author: Sohita Dhillon

Published in: Targeted Oncology | Issue 2/2015

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Abstract

Nintedanib (Vargatef®) is a triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors and fibroblast growth factor receptors. In the EU, nintedanib in combination with docetaxel is indicated for adults with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy. Nintedanib in combination with docetaxel relative to placebo plus docetaxel significantly prolonged progression-free survival (PFS), but did not increase overall survival (OS), in the overall population of patients with advanced NSCLC in the phase III LUME-Lung 1 study. Notably, the subgroup of patients with adenocarcinoma histology experienced a significant improvement in both PFS and OS with nintedanib plus docetaxel, with a greater benefit seen in patients with rapidly progressing disease. Nintedanib is the first antiangiogenic agent to have shown a survival benefit in the second-line treatment of these patients. Health-related quality of life (HR-QOL) was not adversely affected with the addition of nintedanib to docetaxel in the overall population or in the adenocarcinoma subgroup. Nintedanib combination therapy had a generally manageable tolerability profile. Adverse events typically associated with antiangiogenic agents (e.g. bleeding and hypertension) were not greatly increased with nintedanib plus docetaxel relative to placebo plus docetaxel. To conclude, nintedanib in combination with docetaxel is an effective treatment option for patients with advanced NSCLC of adenocarcinoma histology after first-line chemotherapy.
Literature
1.
go back to reference Reck M, Popat S, Reinmuth N et al (2014) Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii27–39PubMedCrossRef Reck M, Popat S, Reinmuth N et al (2014) Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii27–39PubMedCrossRef
3.
go back to reference Crino L, Metro G (2014) Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev 23(131):79–91PubMedCrossRef Crino L, Metro G (2014) Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev 23(131):79–91PubMedCrossRef
4.
go back to reference Gori B, Ricciardi S, Fulvi A et al (2011) New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond. Ther Clin Risk Manag 7:429–40PubMedCentralPubMedCrossRef Gori B, Ricciardi S, Fulvi A et al (2011) New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond. Ther Clin Risk Manag 7:429–40PubMedCentralPubMedCrossRef
5.
6.
7.
go back to reference Roth GJ, Heckel A, Colbatzky F et al (2009) Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem 52(14):4466–80PubMedCrossRef Roth GJ, Heckel A, Colbatzky F et al (2009) Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem 52(14):4466–80PubMedCrossRef
9.
go back to reference Hilberg F, Roth GJ, Krssak M et al (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–82PubMedCrossRef Hilberg F, Roth GJ, Krssak M et al (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–82PubMedCrossRef
10.
go back to reference Kutluk Cenik B, Ostapoff KT, Gerber DE et al (2013) BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 12(6):992–1001PubMedCrossRef Kutluk Cenik B, Ostapoff KT, Gerber DE et al (2013) BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 12(6):992–1001PubMedCrossRef
11.
go back to reference Hilberg F, Brandstetter I (2007) Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy [abstract no. C7-03]. J Thorac Oncol 2(8):S380CrossRef Hilberg F, Brandstetter I (2007) Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy [abstract no. C7-03]. J Thorac Oncol 2(8):S380CrossRef
12.
go back to reference Xiang QF, Wang F, Su XD et al (2011) Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance. Cell Oncol (Dordr) 34(1):33–44CrossRef Xiang QF, Wang F, Su XD et al (2011) Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance. Cell Oncol (Dordr) 34(1):33–44CrossRef
13.
go back to reference Mross K, Stefanic M, Gmehling D et al (2010) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 16(1):311–9PubMedCrossRef Mross K, Stefanic M, Gmehling D et al (2010) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 16(1):311–9PubMedCrossRef
14.
go back to reference Okamoto I, Kaneda H, Satoh T et al (2010) Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 9(10):2825–33PubMedCrossRef Okamoto I, Kaneda H, Satoh T et al (2010) Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 9(10):2825–33PubMedCrossRef
15.
go back to reference Okamoto I, Miyazaki M, Takeda M et al (2014) Tolerability of nintedanib (BIBF 1120) in combination with docetaxel: a phase 1 study in Japanese patients with previously treated non-small-cell lung cancer. J Thorac Oncol 10(2):346–52CrossRef Okamoto I, Miyazaki M, Takeda M et al (2014) Tolerability of nintedanib (BIBF 1120) in combination with docetaxel: a phase 1 study in Japanese patients with previously treated non-small-cell lung cancer. J Thorac Oncol 10(2):346–52CrossRef
16.
go back to reference Doebele RC, Conkling P, Traynor AM et al (2012) A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 23(8):2094–102PubMedCentralPubMedCrossRef Doebele RC, Conkling P, Traynor AM et al (2012) A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 23(8):2094–102PubMedCentralPubMedCrossRef
17.
go back to reference Ellis PM, Kaiser R, Zhao Y et al (2010) Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 16(10):2881–9PubMedCrossRef Ellis PM, Kaiser R, Zhao Y et al (2010) Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 16(10):2881–9PubMedCrossRef
18.
go back to reference Daga H, Takeda K, Okada H, et al. Safety and efficacy of nintedanib (BIBF 1120) plus pemetrexed in Japanese patients with advanced or recurrent non-small cell lung cancer (NSCLC): a phase I study [abstract no. 8056]. J Clin Oncol. 2013;31(15 Suppl). Daga H, Takeda K, Okada H, et al. Safety and efficacy of nintedanib (BIBF 1120) plus pemetrexed in Japanese patients with advanced or recurrent non-small cell lung cancer (NSCLC): a phase I study [abstract no. 8056]. J Clin Oncol. 2013;31(15 Suppl).
19.
go back to reference Quintela-Fandino M, Urruticoechea A, Guerra J et al (2014) Phase I clinical trial of nintedanib plus paclitaxel in early HER-2-negative breast cancer (CNIO-BR-01-2010/GEICAM-2010-10 study). Br J Cancer 111(6):1060–4PubMedCrossRef Quintela-Fandino M, Urruticoechea A, Guerra J et al (2014) Phase I clinical trial of nintedanib plus paclitaxel in early HER-2-negative breast cancer (CNIO-BR-01-2010/GEICAM-2010-10 study). Br J Cancer 111(6):1060–4PubMedCrossRef
20.
go back to reference Reck M, Kaiser R, Eschbach C et al (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22(6):1374–81PubMedCrossRef Reck M, Kaiser R, Eschbach C et al (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22(6):1374–81PubMedCrossRef
21.
go back to reference Ledermann JA, Hackshaw A, Kaye S et al (2011) Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 29(28):3798–804PubMedCrossRef Ledermann JA, Hackshaw A, Kaye S et al (2011) Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 29(28):3798–804PubMedCrossRef
22.
go back to reference du Bois A, Kristensen G, Ray-Coquard I et al (2013) AGO-OVAR 12: a randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy +/− nintedanib for advanced ovarian cancer [abstract no. 37397]. Int J Gynecol Cancer 23(8 Suppl 1):7–8 du Bois A, Kristensen G, Ray-Coquard I et al (2013) AGO-OVAR 12: a randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy +/− nintedanib for advanced ovarian cancer [abstract no. 37397]. Int J Gynecol Cancer 23(8 Suppl 1):7–8
23.
go back to reference Reck M, Kaiser R, Mellemgaard A et al (2014) Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15(2):143–55PubMedCrossRef Reck M, Kaiser R, Mellemgaard A et al (2014) Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15(2):143–55PubMedCrossRef
24.
go back to reference Hanna NH, Kaiser R, Sullivan RN, et al. Lume-lung 2: a multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy [abstract no. 8034]. J Clin Oncol. 2013;31(15 Suppl). Hanna NH, Kaiser R, Sullivan RN, et al. Lume-lung 2: a multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy [abstract no. 8034]. J Clin Oncol. 2013;31(15 Suppl).
25.
go back to reference Kaiser R, Barrueco JR, Reck M et al (2013) Identification of a clinical biomarker for 2nd line combination with nintedanib in adenocarcinoma non-small cell lung cancer (NSCLC) patients in two phase Ill trials [abstract no. 3479]. Eur J Cancer 49(Suppl 2):S822 Kaiser R, Barrueco JR, Reck M et al (2013) Identification of a clinical biomarker for 2nd line combination with nintedanib in adenocarcinoma non-small cell lung cancer (NSCLC) patients in two phase Ill trials [abstract no. 3479]. Eur J Cancer 49(Suppl 2):S822
26.
go back to reference Eisen T, Shparyk Y, Macleod N et al (2013) Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. Invest New Drugs 31(5):1283–93PubMedCrossRef Eisen T, Shparyk Y, Macleod N et al (2013) Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. Invest New Drugs 31(5):1283–93PubMedCrossRef
27.
go back to reference Stopfer P, Rathgen K, Bischoff D et al (2011) Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 41(4):297–311PubMedCrossRef Stopfer P, Rathgen K, Bischoff D et al (2011) Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 41(4):297–311PubMedCrossRef
28.
go back to reference Mellemgaard A, Orlov S, Krzakowski M et al (2014) Effect of nintedanib (BIBF 1120) combined with standard 2nd-line docetaxel in NSCLC patients who received prior pemetrexed in LUME-Lung 1: a randomised, placebo-controlled Phase III trial [abstract no. 471P]. Ann Oncol 25(Suppl 4):iv157 Mellemgaard A, Orlov S, Krzakowski M et al (2014) Effect of nintedanib (BIBF 1120) combined with standard 2nd-line docetaxel in NSCLC patients who received prior pemetrexed in LUME-Lung 1: a randomised, placebo-controlled Phase III trial [abstract no. 471P]. Ann Oncol 25(Suppl 4):iv157
29.
go back to reference Krzakowski M, Mellemgaard A, Orlov S et al (2014) Prior taxane use in the LUME-Lung 1 phase III trial and the effect on outcome following 2nd-line treatment with nintedanib (BIBF 1120) and docetaxel in patients with advanced NSCLC [abstract no. 473P]. Ann Oncol 25(Suppl 4):iv158 Krzakowski M, Mellemgaard A, Orlov S et al (2014) Prior taxane use in the LUME-Lung 1 phase III trial and the effect on outcome following 2nd-line treatment with nintedanib (BIBF 1120) and docetaxel in patients with advanced NSCLC [abstract no. 473P]. Ann Oncol 25(Suppl 4):iv158
30.
go back to reference Novello S, Kaiser R, Mellemgaard A et al (2014) Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled, phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. Eur J Cancer 51(3):317–26PubMedCrossRef Novello S, Kaiser R, Mellemgaard A et al (2014) Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled, phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. Eur J Cancer 51(3):317–26PubMedCrossRef
31.
go back to reference Reck M, Mellemgaard A, Orlov SV, et al. Antiangiogenic-specific adverse events (AEs) in patients with non-small cell lung cancer (NSCLC) treated with nintedanib (N) and docetaxel (D) [abstract no. 8100 plus poster]. J Clin Oncol. 2014;32(15 Suppl). Reck M, Mellemgaard A, Orlov SV, et al. Antiangiogenic-specific adverse events (AEs) in patients with non-small cell lung cancer (NSCLC) treated with nintedanib (N) and docetaxel (D) [abstract no. 8100 plus poster]. J Clin Oncol. 2014;32(15 Suppl).
32.
go back to reference Reck M, Heigener D, Reinmuth N (2014) Nintedanib for the treatment of patients with advanced non-small-cell lung cancer. Expert Rev Clin Pharmacol 7(5):579–90PubMedCrossRef Reck M, Heigener D, Reinmuth N (2014) Nintedanib for the treatment of patients with advanced non-small-cell lung cancer. Expert Rev Clin Pharmacol 7(5):579–90PubMedCrossRef
33.
go back to reference Hilberg F, Haslinger C, Garin Chesa P, et al. Molecular correlates of clinical benefit from antiangiogenic therapy for patients with lung adenocarcinoma: a hypothesis [abstract no. e22080]. J Clin Oncol. 2014;32(15 Suppl). Hilberg F, Haslinger C, Garin Chesa P, et al. Molecular correlates of clinical benefit from antiangiogenic therapy for patients with lung adenocarcinoma: a hypothesis [abstract no. e22080]. J Clin Oncol. 2014;32(15 Suppl).
35.
go back to reference Popat S, Mellemgaard A, Fahrbach K et al (2015) Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis. Future Oncol 11(3):409–20PubMedCrossRef Popat S, Mellemgaard A, Fahrbach K et al (2015) Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis. Future Oncol 11(3):409–20PubMedCrossRef
Metadata
Title
Nintedanib: A Review of Its Use as Second-Line Treatment in Adults with Advanced Non-Small Cell Lung Cancer of Adenocarcinoma Histology
Author
Sohita Dhillon
Publication date
01-06-2015
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 2/2015
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-015-0367-8

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