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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

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Papel de los nuevos Tki: AXITINIB

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  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.

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