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

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Presentación del tema: "Papel de los nuevos Tki: AXITINIB Dr. Javier Puente Vázquez Servicio Oncología Médica Hospital Universitario Clínico San Carlos."— Transcripción de la presentación:

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 Change in Tumor Measurements (%) Primary refractoryEarly progressors Late progressors Group A Group B Group C

4 Targeted therapy in mRCC: mechanisms of resistance TTP > 6 months. TKI´s sensitive TTP < 6 months. TKI´s resistance Cont. VEGFr inhibitors ? Switch to mTOR inhibitors ? Group B-C Group A

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

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

7 Axitinib is a Selective Inhibitor of VEGF Receptors 1, 2, 3 Low IC 50 indicates higher affinity. Axitinib inhibits VEGF receptors 1, 2, and 3 at picomolar concentrations, suggesting potent and highly selective activity against these receptors. Selective Inhibitor Receptors RTKCellular IC 50 (nM) VEGFR-10.1 * VEGFR-20.2 VEGFR-30.1–0.3 PDGFR-α5.0 PDGFR-β1.6 KIT1.7 CSF-1R73 FGFR-1231 FLT3>1000 RET>1000 Hu-Lowe DD, et al. Clin Can Res. 2008;14:7272–7283.

8 Axitinib is More Potent Than Most VEGF Receptor Kinase Inhibitors 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 Abstract LB-201; and Hu-Lowe DD, et al. Clin Cancer Res 2008;14: Less potent More potent Potency: IC 50 (nM) VEGFR-1 VEGFR-2 VEGFR-3 1, AV-951 Cediranib Motesanib AMG-706 SunitinibABT-869 Pazopanib Sorafenib Vatalanib PTK787 Vandetanib Axitinib

9 Decreasing VEGFR-2 in Animal Models Blockade of VEGFR-2 may lead to a decrease in MVD and blood flow. 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 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.

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

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

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

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

14 Axitinib Reduces Tumour Growth Axitinib reduced tumour volume in mice. Mean volume change after 7 days –200 – (mm 3 ) Control Axitinib mm mm3 MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficient Wilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327. MRI enhanced tumour measurements showed significant decreases in tumour volume for the axitinib vs. control group. Reduction in Tumour Volume

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16 - RR: 44.2% - TTP: 15.7 meses - SG: 29.9 meses

17 Motzer, et al. ASCO 2011

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29 Reflexiones ASPECTOS POSITIVOS Estudio Fase III randomizado. Estudio PURO de 2ª línea. Mediana PFS: 6.7 meses TR: 19% Tolerancia similar Tki Baja tasa de discontinuación 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?

30 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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