Angiokinase inhibitors

Angiokinase inhibitors are a new therapeutic target for the management of cancer. They inhibit tumour angiogenesis, one of the key processes leading to invasion and metastasis of solid tumours, by targeting receptor tyrosine kinases.[1] Examples include nintedanib (BIBF 1120), afatinib (BIBW 2992) and motesanib (AMG 706).

History

The term angiokinase was first documented by Auerswald et al. in a paper published in 1971.[2] However, angiokinase inhibitors were not described until 2008 by Hilberg and colleagues.[1] More recently, a number of phase I and II trials have been published, with further phase III trials currently in development.

Drugs

BIBF 1120 (nintedanib)
Main article: nintedanib

BIBF 1120 is a triple angiokinase inhibitor developed by Boehringer Ingelheim which blocks the receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF).[1]

In a phase I study of 25 patients with advanced solid tumours, BIBF 1120 showed a favourable safety and pharmacokinetic profile with a maximum tolerated dose of 250mg.[3] Twice-daily dosing was not associated with increased toxicity.[3]

In another phase I dose-escalation study, in 22 patients with advanced gynaecological malignancies, the maximum tolerated dose of BIBF 1120 twice-daily combined with paclitaxel and carboplatin was 200mg.[4] The combination had an acceptable safety profile; the main side effects were gastrointestinal disorders and there were no clinically relevant drug–drug interactions.[4]

In a phase II study, 73 patients with stage IIIB/IV cancer were randomly assigned to 250mg or 150mg BIBF 1120 monotherapy twice-daily.[5] The median progression-free survival (PFS) was 1.6 months and the stable disease rate was 48%. Patients with an ECOG score of 0–1 (n=57) had a median PFS of 2.9 months and a stable disease rate of 59%. The median overall survival of all patients was 22 weeks (ECOG 0–2) and 38 weeks in patients with ECOG performance status 0 or 1. BIBF 1120 was well tolerated; the most frequent adverse events were grade 1 or 2 and included nausea, diarrhoea, vomiting, anorexia and fatigue.[5]

A randomised phase II trial examined the use of continuous BIBF 1120 (250mg twice daily) for 9 months compared with placebo in 84 patients with relapsed ovarian cancer.[6] After 36 weeks, PFS was 15.6% for BIBF 1120 and 2.9% for placebo. Median time to RECIST progression was 4.8 months for BIBF 1120 compared with 2.8 months for placebo. Grade 3/4 adverse events were observed in 7% and 3% of BIBF 1120 and placebo patients respectively. The authors conclude that BIBF 1120 could delay disease progression in patients with ovarian cancer who had previously responded to chemotherapy.[6]

Phase III trials are currently underway to examine the safety and efficacy of BIBF 1120 in non-small-cell lung cancer (NSCLC) and advanced ovarian cancer.

BIBW 2992 (afatinib)
Main article: afatinib

BIBW 2992 is a next-generation tyrosine kinase inhibitor developed by Boehringer Ingelheim which irreversibly blocks both epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase.

In the first human study of BIBW 2992, the maximum tolerated dose in a two-week-on, two-week off schedule was 70 mg once-daily.[7] BIBW 2992 was well tolerated, with reversible adverse events including rash, diarrhoea, elevations in transaminases.[7]

BIBW 2992 is a promising treatment for patients with NSCLC who have either primary (exon 20 insertion) or acquired (T790M) erlotinib resistance mutations.[8] BIBW 2992 inhibits survival of cancer cell lines and induces tumour regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib.[8]

Several phase III studies investigating the safety and efficacy of BIBW 2992 in NSCLC and in breast cancer are currently recruiting patients.

AMG 706 (motesanib)
Main article: motesanib

AMG 706 is a new, oral, small-molecule multikinase inhibitor developed by Amgen. It selectively targets vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor and Kit (stem-cell factor) receptors, which have been implicated in the pathogenesis of several human cancers.[9][10] By blocking multiple signalling pathways, AMG 706 offers a new targeted approach for patients with metastatic disease.[9]

In vitro studies have shown that AMG 706 inhibits human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor, as well as vascular permeability induced by VEGF in mice.[10] Oral administration of AMG 706 potently inhibits VEGF-induced angiogenesis in a rat corneal model and induces regression of established A431 xenografts.[10]

A number of phase I studies have established that AMG 706 is well tolerated in patients with advanced solid tumours[11][12] and NSCLC.[9]

A placebo-controlled phase III study, examining overall survival in patients with advanced NSCLC treated with AMG 706 in combination with paclitaxel and carboplatin, is currently ongoing.[13]

References
  1. Hilberg, F.; Roth, G. J.; Krssak, M.; Kautschitsch, S.; Sommergruber, W.; Tontsch-Grunt, U.; Garin-Chesa, P.; Bader, G.; et al. (2008). "BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy". Cancer Research. 68 (12): 4774–82. doi:10.1158/0008-5472.CAN-07-6307. PMID 18559524.
  2. Auerswald, W; Binder, B; Doleschel, W (1971). "'Angiokinase' – Molecular Weights of Proteins Representing a Perivascular Plasminogen Activator". Thrombosis et Diathesis Haemorrhagica. 26 (2): 411–3. ISBN 978-3-7945-0170-0. PMID 5134490.
  3. Mross, K.; Stefanic, M.; Gmehling, D.; Frost, A.; Baas, F.; Unger, C.; Strecker, R.; Henning, J.; et al. (2009). "Phase I Study of the Angiogenesis Inhibitor BIBF 1120 in Patients with Advanced Solid Tumors". Clinical Cancer Research. 16 (1): 311–9. doi:10.1158/1078-0432.CCR-09-0694. PMID 20028771.
  4. Du Bois, A.; Huober, J.; Stopfer, P.; Pfisterer, J.; Wimberger, P.; Loibl, S.; Reichardt, V. L.; Harter, P. (2009). "A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies". Annals of Oncology. 21 (2): 370–5. doi:10.1093/annonc/mdp506. PMID 19889612.
  5. Mornex, Francoise; Rosell, Rafael (23–26 April 2008). Report (PDF). European Lung Cancer Conference. Geneva, Switzerland. Archived from the original (PDF) on October 13, 2009. Retrieved May 12, 2011.
  6. Ledermann, J. A.; Rustin, G. J.; Hackshaw, A.; Kaye, S. B.; Jayson, G.; Gabra, H.; James, L. E.; Bell, S.; Temple, G. (2009). "A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)". Journal of Clinical Oncology. 27 (15S): 5501. Archived from the original on 2013-04-14. Retrieved 2011-05-12.
  7. Eskens, F A L M; Mom, C H; Planting, A S T; Gietema, J A; Amelsberg, A; Huisman, H; Van Doorn, L; Burger, H; et al. (2007). "A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours". British Journal of Cancer. 98 (1): 80–5. doi:10.1038/sj.bjc.6604108. PMC 2359721. PMID 18026190.
  8. Li, D; Ambrogio, L; Shimamura, T; Kubo, S; Takahashi, M; Chirieac, L R; Padera, R F; Shapiro, G I; et al. (2008). "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models". Oncogene. 27 (34): 4702–11. doi:10.1038/onc.2008.109. PMC 2748240. PMID 18408761.
  9. Blumenschein, G. R.; Reckamp, K.; Stephenson, G. J.; O'Rourke, T.; Gladish, G.; McGreivy, J.; Sun, Y.-N.; Ye, Y.; et al. (2009). "Phase 1b Study of Motesanib, an Oral Angiogenesis Inhibitor, in Combination with Carboplatin/Paclitaxel and/or Panitumumab for the Treatment of Advanced Non-Small Cell Lung Cancer". Clinical Cancer Research. 16 (1): 279–90. doi:10.1158/1078-0432.CCR-09-1675. PMID 20028752.
  10. Polverino, A.; Coxon, A; Starnes, C; Diaz, Z; Demelfi, T; Wang, L; Bready, J; Estrada, J; et al. (2006). "AMG 706, an Oral, Multikinase Inhibitor that Selectively Targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors, Potently Inhibits Angiogenesis and Induces Regression in Tumor Xenografts". Cancer Research. 66 (17): 8715–21. doi:10.1158/0008-5472.CAN-05-4665. PMID 16951187.
  11. Rosen, L. S.; Kurzrock, R.; Mulay, M.; Van Vugt, A.; Purdom, M.; Ng, C.; Silverman, J.; Koutsoukos, A.; et al. (2007). "Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors". Journal of Clinical Oncology. 25 (17): 2369–76. doi:10.1200/JCO.2006.07.8170. PMID 17557949.
  12. Tolcher, A. W.; Sarantopoulos, J.; Patnaik, A.; Papadopoulos, K.; Lin, C.-C.; Rodon, J.; Murphy, B.; Roth, B.; et al. (2009). "Phase I, Pharmacokinetic, and Pharmacodynamic Study of AMG 479, a Fully Human Monoclonal Antibody to Insulin-Like Growth Factor Receptor 1". Journal of Clinical Oncology. 27 (34): 5800–7. doi:10.1200/JCO.2009.23.6745. PMID 19786654.
  13. Clinical trial number NCT00460317 for "MONET1-MOtesanib NSCLC Efficacy and Tolerability Study" at ClinicalTrials.gov
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