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Pazopanib en el tratamiento del Carcinoma de Células Renales

Pazopanib en la primera línea del cáncer renal avanzado. Pazopanib en el tratamiento del Carcinoma de Células Renales. Luis León Servicio de Oncología Médica Santiago de Compostela. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P.

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Pazopanib en el tratamiento del Carcinoma de Células Renales

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  1. Pazopanib en la primera línea del cáncer renal avanzado Pazopanib en el tratamiento del Carcinoma de Células Renales Luis León Servicio de Oncología Médica Santiago de Compostela

  2. P P P P P P P P P P P P P P P P P P P P Pazopanib bloquea moléculas clave implicadas en la angiogénesis PDGFR VEGFR-1 VEGFR-2 VEGFR-3 c-KIT Tumour cell membrane PI3K FAK PLC RAS Proliferation Survival Migration 1. Sonpavde et al. Expert Opin Investig Drugs 2008;17:253–61.

  3. Inhibidor multikinasa Pazopanib 32 Sunitinib 54 Sorafenib 25 Kinases inhibited with IC50 <1 μM 1. Kumar et al. Br J Cancer 2009;101:1717–23. Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32.

  4. Datos de Eficacia

  5. Phase II study: VEG1026161 • Inclusion • ECOG performance status 0 or 1 • Treatment-naïve or one prior cytokine or bevacizumab failure Patients with advancedor metastatic RCC (N=225) Pazopanib 800 mg once daily for 12 weeks Complete/partial response Stable disease Progressive disease Randomization Pazopanib 800 mg once daily(n=27) Matching placebo (n=28) Pazopanib 800 mg once daily (n=170) Patients received pazopanib after interim analysis Clinicaltrials.gov identifier NCT002447642 • Hutson et al. J Clin Oncol 2010;28:475–80. • US NIH. Available from: http://clinicaltrials.gov/ct2/show/NCT00244764?term=pazopanib+renal&rank=2 (last updated Jan 6, 2011)

  6. Objetivos del estudio (revisados)1 • Objetivo principal • % de respuestas según RECIST (PFS antes de la modificación) • Objetivos secundarios • Duración de respuesta • PFS durante la fase de aleatorización • Seguridad y tolerabilidad • Análisis global PFS • Hutson et al. J Clin Oncol 2010;28:475–80.

  7. Características de los pacientes • Hutson et al. J Clin Oncol 2010;28:475–80.

  8. Tasa de respuesta global1 • Hutson et al. J Clin Oncol 2010;28:475–80.

  9. Pazopanib es superior a placebo en PFS1 1.0 Median: 51.7 weeks2(95% CI: 43.9, 60.3) 0.8 Week 12 randomization point Log-rank, p=0.01282 6.2 months (4.6, 10.9) 11.9 months (10.0, –) 0.6 Proportion progression-free 0.4 0.2 Pazopanib Placebo 0.0 0 10 20 30 40 50 60 70 80 90 100 Weeks on study La comparación de PFS por un comité independiente demostró una ventaja a favor de pazopanib Los pacientes cruzados a pazopanib no se censuraron • Hutson et al. J Clin Oncol 2010;28:475–80.

  10. Phase III study: VEG1051921 Patients with advanced/metastatic RCC (N=435) • Stratification • ECOG performance status • 0 versus 1 • Prior nephrectomy • Treatment-naïve (n=233) versus one cytokine failure (n=202) Randomization2:1 Pazopanib 800 mg once daily (n=290) Matching placebo (n=145) Option to receive pazopanib via an open-label study at progression Clinicaltrials.gov identifier NCT00334282 VEG107769 open-label study 71 patients enrolled* 11 • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  11. Objetivos del estudio1 • Objetivo principal • PFS • Objetivos secundarios • OS • ORR • Duración de respuesta • Seguridad y tolerabilidad • Análisis global PFS • Otros: calidad de vida • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  12. Característica basales1 • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  13. Porcentaje de respuestas Pazopanib Placebo p<0.001 • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  14. Pazopanib Placebo Supervivencia libre de progresión en toda la población1 1.0 Median PFS (months) Placebo 4.2 Pazopanib 9.2 0.8 Hazard ratio (95% CI) 0.46 (0.34, 0.62) p value (1-sided) <0.0001 0.6 Proportion progression-free 0.4 0.2 0.0 0 5 10 15 20 Time (month) Number at risk, n Pazopanib Placebo 290 145 159 38 76 14 29 2 6 In the overall study population, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001) • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  15. Pazopanib Placebo Supervivencia libre de progresión en los pacientes no pretratados1,2 1.0 Median PFS (months) Placebo 2.8 Pazopanib 11.1 Hazard ratio (95% CI) 0.40 (0.27, 0.60) 0.8 p value (1-sided) <0.0001 0.6 Proportion progression-free 0.4 0.2 0.0 0 5 10 15 20 Time (month) Number at risk, n Pazopanib Placebo 155 78 84 22 39 7 11 2 1 In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001) • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  16. Median PFS (months) Placebo 4.2 Pazopanib 7.4 Hazard ratio (95% CI) 0.54 (0.35, 0.84) p value (1-sided) <0.001 Pazopanib Placebo Supervivencia libre de progresión en los pacientes tratados con citoquinas1,2 1.0 0.8 0.6 Proportion progression-free 0.4 0.2 0.0 0 5 10 15 20 Time (month) Number at risk, n Pazopanib Placebo 135 67 75 16 37 7 18 5 In the cytokine-pretreated subpopulation, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.001) • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  17. Beneficio en todos los subgrupos Baseline factor Hazard ratio (95% CI) Primary analysis • PFS was significantly improved with pazopanib across all sub-groups: Age, gender, PS and MSKCC risk status MSKCC risk: favourable MSKCC risk: intermediate Female Male Age <65 years Age ≥65 years ECOG performance status 0 ECOG performance status1 0.2 0.4 0.8 1.0 1.2 0.6 p<0.001 by log-rank test for all Favours pazopanib Favours placebo • Sternberg et al.J Clin Oncol 2010;28:1061-1068

  18. Objetivo principal: OS 1.0 Hazard ratio=0.91 95% CI (0.71–1.16) p=0.224 0.8 Median OS Pazopanib: 22.9 months Placebo: 20.5 months 0.6 Proportion surviving 0.4 Pazopanib Placebo 0.2 54% of placebo patients crossed over Time of crossover 0.0 0 10 20 30 40 Time (months) Patients at risk Pazopanib Placebo 290 145 213 93 147 71 95 53 25 9 Sternberg et al. Annals Oncol2010; 21(Suppl 8): Abstract LBA22 and oral presentation

  19. Toxicidad

  20. Efectos de clase en ensayo fase III (VEG105192)1 • Sternberg et al.J Clin Oncol 2010;28:1061-1068; 2. Wolter ASCO 2011

  21. Efectos adversos de Pazopanib en ensayos fase II y III *presentes en ≥10% of pacientes • Hutson et al. J Clin Oncol 2010;28:475–80. • . Sternberg et al.J Clin Oncol 2010;28:1061-1068

  22. Pazopanib: elevación de transaminasas y Br • Liver enzyme elevations were largely reversible following dose modification, interruption or cessation1 • Many subjects were able to continue on pazopanib and adapted • Fatal hepatic events were reviewed across the entire safety database (N=1830) • Out of 1830 subjects there were two fatal cases, which were possibly attributable to pazopanib. This is equivalent to 0.1% (95% CI: 0.03, 0.4)1 • US FDA. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM186338.pdf • Kapadia, ASCO 2011.

  23. La elevación de ALT asociada a Pazopanib se produce de forma temprana1 0.16 0.14 • Elevations in ALT levels were detected in the first 18 weeks of pazopanib treatment in the vast majority of subjects who developed such abnormalities 0.12 0.10 Cumulative incidence 0.08 0.06 0.04 ALT >5X ULN (N=586) 0.02 0.0 0 6 12 24 32 48 64 80 96 112 Weeks • US FDA. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM186338.pdf

  24. Modificación o retraso de dosis debidos a efectos secundarios • Hutson et al. J Clin Oncol 2010;28:475–80. • Sternberg et al.J Clin Oncol 2010;28:1061-1068 • GlaxoSmithKline. Data on file.

  25. Comparison of 20% QoL Deterioration Rates for Pazopanib-Treated and Placebo Patients, EORTC QLQ-C30 All Patients Treatment-Naive Patients 100 100 Pazopanib Placebo Pazopanib Placebo 90 90 80 80 70 70 60 60 Event Rates (%) Event Rates (%) 50 50 40 40 30 30 20 20 10 10 0 0 56 168 224 280 336 392 448 504 56 168 224 280 336 392 448 504 0 112 0 112 Number of Days Until Event Number of Days Until Event Cytokine-Pretreated Patients 100 Pazopanib Placebo 90 80 70 60 Event Rates (%) 50 40 30 20 10 0 56 168 224 280 336 392 0 112 Number of Days Until Event ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

  26. HRQoL Deterioration EORTC QLQ-C30 GlobalHealth Status/QOL Scale EQ-5D Utility Index 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Cumulative DistributionFunction Cumulative DistributionFunction 0.5 0.5 0.4 0.4 Pazopanib Placebo Pazopanib Placebo 0.3 0.3 0.2 0.2 0.1 0.1 0 0 10 20 40 50 70 80 90 100 10 50 80 90 100 0 30 60 0 20 30 40 60 70 HRQoL Deterioration From Baseline HRQoL Deterioration From Baseline EQ-5D VAS Score 1.0 0.9 0.8 0.7 0.6 Cumulative DistributionFunction 0.5 0.4 Pazopanib Placebo 0.3 0.2 0.1 0 10 20 40 50 70 80 90 100 0 30 60 HRQoL Deterioration From Baseline ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

  27. (A) IL8 2767AT (rs1126647) (A) IL8 2767AT (rs1126647); (B) IL8 251TA (rs4073); (C) HIF1A 1790GA (rs11549467). (C) HIF1A 1790GA (rs11549467) (B) IL8 251TA (rs4073)

  28. CONCLUSIONES • Pazopanib es superior a placebo (PFS) en primera línea de cáncer renal metastásico • Pazopanib obtiene un porcentaje de respuestas del 30% en esta población • La tolerancia a pazopanib es buena, y las toxicidades manejables • Debe prestarse especial atención a las alteraciones en la función hepática • Pazopanib no produce un deterioro en la calidad de vida • Necesitamos marcadores predictivos de respuesta

  29. ¿Cuál es el camino?

  30. Gracias

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