1 / 30

Papel de los nuevos Tki: AXITINIB

Papel de los nuevos Tki: AXITINIB. Dr. Javier Puente Vázquez Servicio Oncología Médica Hospital Universitario Clínico San Carlos. The challenge of treatment in mRCC. Benefits of tyrosine kinase inhibitors (TKIs) are well established; however, there are limitations

urania
Download Presentation

Papel de los nuevos Tki: AXITINIB

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Papel de los nuevos Tki: AXITINIB Dr. Javier Puente Vázquez Servicio Oncología Médica Hospital Universitario Clínico San Carlos

  2. The challenge of treatment in mRCC • Benefits of tyrosine kinase inhibitors (TKIs) are well established; however, there are limitations • There are few complete responses • Initial partial responses are followed by progression • In other cases there is no objective benefit • Drug resistance remains an ongoing obstacle to successful treatment of mRCC • Limits the success of therapy and reduces survival rates • Motzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol 2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N Engl J Med 2007

  3. Patterns of tumor progression on VEGF or VEGFR inhibitors Late progressors Group C Change in TumorMeasurements (%) Change in TumorMeasurements (%) Change in TumorMeasurements (%) Group A Group B Primary refractory Early progressors

  4. Targeted therapy in mRCC: mechanisms of resistance Group A Group B-C TTP > 6 months. TKI´s sensitive TTP < 6 months. TKI´s resistance Cont. VEGFrinhibitors ? SwitchtomTORinhibitors ?

  5. Inhibiting VEGF Receptors 1, 2, 3 Axitinib is an Oral, Potent, and Highly Selective Inhibitor of VEGF Receptors 1, 2, 3 Axitinib C O N H M e H S N N • 5 mg Film Coated Tablet N • BID = twice daily • Hu-Lowe DD, et al. Clin Cancer Res. 2008;14:7272–7283. • Small molecule indazole derivative • Orally administered: 5 mg BID

  6. Disrupting Tumour Progression Axitinib comprehensively disrupts tumour progression by inhibiting the VEGF receptor signalling system. PIGF VEGF C VEGF A VEGF D VEGF B Axitinib VEGFR 2 VEGFR 3 VEGFR 1 Tumour Spreadvia Tumour Growthvia • Vascular Angiogenesis Tumour Cell Proliferation • Metastatic Tumour Colonisation via Lymphangiogenesis • Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579–591.

  7. Axitinib is a Selective Inhibitor of VEGF Receptors 1, 2, 3 Selective Inhibitor Hu-Lowe DD, et al. Clin Can Res. 2008;14:7272–7283. • Low IC50 indicates higher affinity. • Axitinib inhibits VEGF receptors 1, 2, and 3 at picomolar concentrations, suggesting potent and highly selective activity against these receptors.

  8. Axitinib is More Potent Than Most VEGF Receptor Kinase Inhibitors VEGFR-1 VEGFR-2 VEGFR-3 1,000 100 10 1 0.1 0.01 Less potent Potency: IC50 (nM) More potent Axitinib Motesanib AMG-706 Cediranib Vatalanib PTK787 AV-951 Vandetanib Pazopanib Sunitinib ABT-869 Sorafenib • Figure modified using data from: Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25:884–896; Eskens FALM, et al. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research. 2008. Abstract LB-201;and Hu-Lowe DD, et al. Clin Cancer Res 2008;14:7272-7283

  9. Decreasing VEGFR-2 in Animal Models Axitinib Decreases VEGFR-2 in Animal Models • Significant reductions in intensity of VEGFR-2 and VEGFR-3 of RIP-Tag2† tumour vessels after 7 days of axitinib treatment Axitinib7 days Vehicle Axitinib 7 days • *Different from corresponding vehicle (P< 0.05) • †The RIP-Tag2 animal model is of pancreatic islet cell cancer. • MVD = microvessel density • Inai T, McDonald D. J Am Pathol. 2004;165:35–52. Olsson AK, et al. Molec Cell Biol. 2006;7:359–371. • Blockade of VEGFR-2 may lead to a decrease in MVD and blood flow.

  10. Reduces Tumour Blood Vessels Axitinib Reduces the Number of Tumour Blood Vessels CD31 Untreated Axitinib 7 days Withdrawal 7 days Withdrawal 2 days RIP-Tag2 • Mancuso MR, et al. J Clin Invest. 2006;116:2610–2621. • Axitinib reduced MVD and normalised tumour vasculature in 7 days • Withdrawal resulted in regrowth of vessels.

  11. Decreasing Tumour Blood Flow Axitinib Decreases Tumour Blood Flow Vehicle Axitinib 1 Day Reduction of Flow Reduction of Angiogenic Vessels Overlay • Inai T, McDonald D. J Am Pathol. 2004;165:35–52 • Axitinib rapidly decreases tumour blood vessel patency, blood flow, and vessel number within 24 hours of exposure.

  12. Axitinib Blocks Vascular Sprouting in Animal Models Untreated Axitinib 7 days Vascular Sprouting • Axitinib effectively blocks vascular sprouting. • Tammela T, et al. Nature. 2008;454:656–660; Inai T, McDonald D. J Am Pathol. 2004;165:35–52. • Vascular sprouting is one of the initial processes associated with angiogenesis.

  13. Axitinib Reduces Tumour Growth Reduction in Vascular Permeability KPS (mL/100 g/min) Color maps of Kps values in the central tumour slice 0.100 Control 1 Control 2 Axitinib 1 Axitinib 2 0.075 0.050 0.025 0.010 Baseline 7 days post-treatment • MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficientWilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327. • Axitinib decreased vascular permeability after 7 days.

  14. Axitinib Reduces Tumour Growth Control Axitinib Reduction in Tumour Volume • Axitinib reduced tumour volume in mice. MRI enhanced tumour measurements showed significant decreases in tumour volume for the axitinib vs. control group. Mean volume change after 7 days 400 + 213 mm3 300 200 - 160 mm3 (mm3) 100 0 –100 • MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficientWilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327. –200

  15. RR: 44.2% • TTP: 15.7 meses • SG: 29.9 meses

  16. Motzer, et al. ASCO 2011

  17. Motzer, et al. ASCO 2011

  18. Reflexiones ASPECTOS POSITIVOS ASPECTOS ???? 45% de los pacientes no recibieron sunitinib. En pre-Sunit, PFS: 4.8 meses ¿Porqué tanta discrepancia entre IRC e investigadores? ¿Porqué dar la opción de incrementar la dosis? • Estudio Fase III randomizado. • Estudio PURO de 2ª línea. • Mediana PFS: 6.7 meses • TR: 19% • Tolerancia similar Tki • Baja tasa de discontinuación

  19. Conclusiones - Axitinib es un nuevo inhibidor de tirosina quinasa de alto poder inhibitorio sobre VEGFR 1, 2 y 3.- En el contexto de la segunda línea, y en comparación con sorafenib, prolonga la SLP de forma significativa.- Axitinib presenta un perfil de tolerabilidad semejante a otros Tki (hipertensión, hipotiroidismo) pero, en comparación con sorafenib, presenta menos SMP, rash y alopecia.- Axitinib se postula como una alterantiva terapéutica en el contexto de la segunda línea del CCRm.

More Related