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Nuevas opciones terapéuticas en CCR diseminado

Nuevas opciones terapéuticas en CCR diseminado. 2005. 2006. 2007. 2008. 2009. Sorafenib vs Placebo 2 nd línea Células claras Post immuno. Sunitinib vs Interf 1 st line B / Int Clear Cell. Axitinib vs Sorafenib 2 line B / Int Clear Cell. Inf+Beva vs

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Nuevas opciones terapéuticas en CCR diseminado

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  1. Nuevas opciones terapéuticas en CCR diseminado

  2. 2005 2006 2007 2008 2009 Sorafenib vs Placebo 2nd línea Células claras Post immuno Sunitinib vs Interf 1stline B / Int Clear Cell Axitinib vs Sorafenib 2 line B / Int Clear Cell Inf+Beva vs Interf 1stline B / Int Clear Cell Inf+Beva vs Interf 1stline B / Int Clear Cell Pazopanib vs Placebo 1-2 line B / Int Clear Cell Temsirolimus vs Interf 1er línea Mal Pronóstico RCC RAD001 vs placebo 2nd - 3rd line post-TKis

  3. Axitinib en segunda línea Tras Inmunoterapia Tras Sunitinib ó Sorafenib Tras Sorafenib

  4. AXIS trial: AG-013736 (axitinib) as second line therapy for mRCC R A N D O M I S E Axitinib 5 mg bid (4-week cycles)* Histologically-confirmed mRCC with clear cell component Failure of prior first-line regimen containing ≥1 of: • Sunitinib • Bevacizumab+IFN- • Temsirolimus • Cytokine(s) (N=540) Sorafenib 400 mg bid (4-week cycles) Stratification by prior regimen andECOG PS (0 vs 1) Primary endpoint:PFS *Starting dose 5 mg BID with option for dose titration to 10 mg BID WW PI: Brian Rini; EU Pi: Bernard Escudier NCT00678392 www.clinicaltrials.gov

  5. Patient Characteristics Axitinib Sorafenib Characteristic (n=361) (n=362) Prior nephrectomy, (%) 91 91 Sites of disease involvement (%) Lung 76 81 Lymph node 58 56 Bone 33 30 Liver 28 29 Prior Systemic Therapy, (%) 54 54 Sunitinib 35 35 Cytokines 8 8 Bevacizumab 3 3 Temsirolimus

  6. Progression-free Survival mPFS, mo 95% CI 1.0 Axitinib 6.7 6.3-8.6 0.9 Sorafenib 4.7 4.6-5.6 0.8 P<0.0001 (log-rank) Stratified HR 0.665 (95% CI 0.544-0.812) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 8 10 12 14 16 18 20 Time (months) 0 2 4 6 Subjects at risk, n Axitinib 361 256 202 145 362 224 157 100 96 64 38 20 10 1 0 51 28 12 6 3 1 0 Sorafenib IRC = Independent Review Committee 12

  7. PFS by Prior Regimen Prior Treatment Axitinib Sorafenib P Regimen (n=361) (n=362) HR value* Cytokines (n=251) 12.1 6.5 0.464 <0.0001 IRC Investigator 12.0 8.3 0.636 0.005 Sunitinib (n=389) 4.8 3.4 0.741 0.011 IRC Investigator 6.5 4.5 0.636 0.0002 Temsirolimus (n=24) 10.1 5.3 2.6 5.7 0.511 0.142 IRC Investigator 1.210 0.634 Bevacizumab (n=59) 4.2 4.7 1.147 0.637 IRC Investigator 6.5 4.5 0.753 0.213 *One-sided log-rank test stratified by ECOG PS

  8. Hazard Ratios for PFS by Prognostic Factors and Baseline Characteristics

  9. Best Response by RECIST Best Overall Response, % Axitinib Sorafenib Partial response* 19.4 9.4 Stable disease 49.9 54.4 Progressive disease 21.6 21.0 Indeterminate 6.1 11.6 Risk ratio (95% CI) 2.1 (1.4-3.0) *Axitinib vs. Sorafenib: P = 0.0001

  10. Drug Delivery Axitinib Sorafenib (n=359) (n=355) Dose interruptions, % 76.9 80.3 Due to AEs, % 54.0 63.1 Patients with dose increase, % 36.8 NA Patients with dose decrease, % 30.6 52.1 Median relative dose intensity, % 98.6 91.7 Discontinuations due to treatment-related AEs, %* 3.9 8.2 *Adverse events as determined by investigators

  11. Adverse Events* Axitinib (%) All grade Grade 3/4 Sorafenib (%) All grade Grade 3/4 Event Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Nausea 32 3 22 1 Vomiting 24 3 17 1 Hypothyroidism 19 <1 8 0 Stomatitis 15 1 12 <1 Hand-foot syndrome 27 5 51 16 Rash 13 <1 32 4 Alopecia 4 0 32 0 18 *All-causality; highest AEs of interest

  12. Laboratory Abnormalities* Axitinib (%) Sorafenib (%) Event All grade Grade 3/4 All grade Grade 3/4 Neutropenia 6 1 8 1 35 <1 52 4 Anemia Elevation of Hgb 9 NA 1 NA Thrombocytopenia 15 <1 14 0 Lymphopenia 33 3 36 4 13 2 50 16 Hypophosphatemia Hypercalcemia 30 <1 7 0 Hypocalcemia 10 1 28 1 Elevation of Lipase 27 5 46 15 *All-causality; highest AEs of interest

  13. Conclusions These data support the hypothesis that more potent biochemical targeting of the VEGF receptor is associated with superior clinical activity in RCC

  14. Análisis de respuesta Escudier B.. J Clin Oncol; 27:1280-1289 2009

  15. SLP: Genotype group of pazopanib-treated patients: (A) IL8 2767A>T (B) IL8 −251T>A (C) HIF1A 1790G>A Xu C et al. JCO 2011;29:2557-2564

  16. CYP3A4

  17. El plateau de las nuevas terapias? % Spv mTOR Citoquinas + Cx Cronología AntiANGI

  18. Cel Endoteliales circulantes Niveles basales Peor Px Mayor carga tumoral Peor respuesta niveles Respuesta/ Spv

  19. Estudio prospectivo ( 1º linea) • 75 pacientes en RP/EE • CEC como predictoras precoces progresión

  20. Tivozanib: Ensayo discontinuación

  21. Tivozanib: SLP según desarrollo de HTA

  22. Tivozanib: Conclusiones fase II HTA como marcador de respuesta Tolerabilidad superior a otros Itks (mucositis 4%!!!!) Combinabilidad: fase II con everolimus y temsirolimus (único Itk) Más potente

  23. La expresión sucesiva de factores de crecimiento apoyaría el uso inicial de inhibidores específicos de VEGF...... bFGF TGF-1 bFGF TGF-1 bFGF TGF-1 bFGF VEGF VEGF VEGF VEGF VEGF TGF-1 PIGF PIGF PD-ECGF PIGF PD-ECGF Pleiotrophin Crecimiento tumoral Adapted from Folkman 2005 Cancer: Principles and Practice of Oncology 2005

  24. AXIS trial: Dovitinib como 3ª línea de tto en CCR R A N D O M I S E Dovitinib 1000 mg/day (4-week cycles) Histologically-confirmed mRCC with clear cell component Failure of prior at least tow regimen containing 1 of each: • m-TOR inhibitor • ITK (N=540) Sorafenib 400 mg bid (4-week cycles)

  25. Objectives and study design Efficacy (ORR) and safety of GSK1363089 in PRCC Key results n=31 patients 2 Stratum: (A) patients with evidence of cMET activation (n=9) and (B) no evidence of cMET activation (n=16) ORR: 8 %, Strat A: 11 %, Strat B: 6 % PFS: 13 months, Strat A: 13 months, Strat B 11.6 months 74 % of patients experienced AEs Conclusions In this interim analysis of an ongoing trial, GSK1363089 demonstrated antitumour efficacy in patients with PRC GSK1363089 was generally well tolerated, with manageable toxicities Citation Srinivasan R, et al. A phase II study of the dual MET-VEGFR2 inhibitor GSK1363089 (formerly XL880) in patients with papillary renal carcinoma (PRC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 5103) A phase II study of the dual MET-VEGFR2 inhibitor GSK1363089 (formerly XL880) in patients with papillary renal carcinoma

  26. . Fong L , Small E J JCO 2008;26:5275-5283

  27. Ipilimumab: Toxicidad

  28. Ipilimumab: Respuesta

  29. Conclusiones En los próximos meses: resultados de más ensayos randomizados en 1ª-2ª línea y estudios de combinación El panorama CCR cambiará, no radicalmente, quizá, pero cambiará, con estos resultados Necesidad de centrarnos en individualizar el tratamiento

  30. Gracias

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