2. Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Centro de Oncologia-Hospital São José maluffc@uol.com.br Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Centro de Oncologia-Hospital São José maluffc@uol.com.br Novidades no tratamento sistêmico dos tumores avançados de endométrio

5. A Transformação..............

7. Molecular Abnormalities in Endometrial Cancer Dedes et al. Nat Rev Clin Oncol, 2011

8. Molecular Carcinogenesis in Type 1 Endometrial Cancer

9. Molecular Carcinogenesis in Type 2 Endometrial Cancer

10. Molecular Abnormalities in Endometrial Cancer Dedes et al. Nat Rev Clin Oncol, 2011

11. Molecular Abnormalities in Endometrial Cancer Dedes et al. Nat Rev Clin Oncol, 2011

12. We have to lead with TWO different Endometrial Cancers Type 1 Endometrioid adenocarcinoma (90%) Variant with squamous differentiation Type 2 NON-Endometrioid adenocarcinoma Serous adenocarcinoma (2.9-10.5% Villograndular differentiation Secretory or cilliated cell variant Clear-cell adenocarcinoma (2.2-3.2%) Carcinosarcoma

13. We have to lead with TWO different Endometrial Cancers Type 1 ER/PR positive: > 90% HER-2/neu overexpression: 3% Type 2 ER/PR positive: 0-31% HER-2/neu overexpression: 18% EGFR expression: 46% P53 mutations: 5-10% PTEN: 50-80% P16 inactivation: 10% K-ras: 13-26% E-cadherin reduced: 10-20% EGFR expression: 34% P53 mutations: 80-90% PTEN: 10-11% P16 inactivation: 40% K-ras: 0-10% E-cadherin reduced: 62-87%

14. Molecular Abnormalities in Endometrial Cancer x Potential Targets Dedes et al. Nat Rev Clin Oncol, 2011

15. We have to lead with TWO different Endometrial Cancers

16. Results as of today

17. Hormonal Therapy in advanced endometrial cancer  Response rates:  30%  Progestagens > Non-progestagens  Duration of response: 2-3 months  Overall Survival: 7-11 months

18. Chemotherapy in advanced endometrial cancer GOG#177 n = 266 Stage III/IV or Recurrent Cisplatin 50mg/m 2 + Doxorubicin 60mg/m 2 Cisplatin 50mg/m 2 + Doxorubicin 45mg/m 2 + Paclitaxel 160mg/m 2 Fleming et al. Ann Oncol, 2004

19. Chemotherapy in advanced endometrial cancer GOG#177 n = 266 Stage III/IV or Recurrent Cisplatin 50mg/m 2 + Doxorubicin 60mg/m 2 Cisplatin 50mg/m 2 + Doxorubicin 45mg/m 2 + Paclitaxel 160mg/m 2 Fleming et al. Ann Oncol, 2004 Overall Survival

20. Chemotherapy in advanced endometrial cancer GOG#177 n = 266 Stage III/IV or Recurrent Cisplatin 50mg/m 2 + Doxorubicin 60mg/m 2 Cisplatin 50mg/m 2 + Doxorubicin 45mg/m 2 + Paclitaxel 160mg/m 2 Fleming et al. Ann Oncol, 2004 Overall Survival < 1,5 years

21. Salvage Therapy: Chemotherapy

22. Second-line CT in endometrial cancer Summary of Results AgentN0N0 Response Ifosfamide3324% Topotecan299% Stable Disease Response Duration (months) Overall Survival (months) NR 3.2 NR 55% 2.1-6.9 NR L-Doxo429% Paclitaxel4427% Docetaxel268% Oxaliplatin5413% 29% 1.1-5.4 8.2 NR 4.2 10.3 31% NR 6.4 29% 10.9 NR Ixabepilone5012% 60% NR 8.7

23. Microtubules inhibitors and endometrial cancer: Ixabepilone Dizon et al. J Clin Oncol, 2009 * Ixabepilone 40mg/m 2 every 3 weeks ActivityN = 50 pts Overall Response12.0% Complete Response2.0% Partial Response10.0% Stable Disease60.0%

24. Microtubules inhibitors and endometrial cancer: Ixabepilone Dizon et al. J Clin Oncol, 2009 Progression-free and Overall Survival

25. Trabectedin McMeekin et al. Gynecol Oncol, 2009 * Trabectedin 1.3mg/m 2 every 3 weeks ActivityN = 46 pts Overall Response2.2% Complete Response2.2% Partial Response0% Stable Disease39.0%

26. McMeekin et al. Gynecol Oncol, 2009 Time to Progression Overall Survival Trabectedin

27. Salvage Therapy: Target Agents

28. mTOR inhibitors

29. - Activation of PI3K/AKT pathway occurs frequently in endometrial carcinoma - Loss of tumor suppressor genes PTEN, as well as activation mutations and/or amplification in oncogenes PI3K and AKT - Loss of PTEN expression leads to deregulated activation of protein kinase B (PKB)/Akt signaling  selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle turnover. 25 - PTEN inactivation may be associated with adverse prognosis mTOR inhibitors and endometrial cancer

31. mTOR inhibitors and endometrial cancer: synergistic effects with chemotherapy Bae-Jump et al. Cancer, 2009

32. mTOR inhibitors and endometrial cancer: synergistic effects with chemotherapy Bae-Jump et al. Cancer, 2009

33. mTOR inhibitors and endometrial cancer Summary of Results AgentN0N0 Population Tensirolimus19No prior tx Tensirolimus271 prior tx Response Clinical Benefit Duration (months) 25% 82% 8.7 7% 51% 3.5 Deforolimus45 Up to 2 prior tx Tensirolimus27 1 or 2 prior tx 7% 33% < 4 0% 43% 4.5

34. mTOR inhibitors and endometrial cancer: Temsirolimus Oza et al. J Clin Oncol, 2011 CT naive pts (29 pts) CT pretreated (25 pts) Response24%4% Stable disease 69%46% * Temsirolimus 25mg IV d1,8,15,22

35. Oza et al. J Clin Oncol, 2011 Tumor Response (CT naive patients n = 33) Tumor Response (CT pretreated patients n = 27) mTOR inhibitors and endometrial cancer: Temsirolimus

36. Oza et al. J Clin Oncol, 2011 Duration of Response mTOR inhibitors and endometrial cancer: Temsirolimus

37. Salvage Therapy: Target Agents VEGF inhibitors

38. - Increased levels of VEGF in endometrial cancer have been associated with dismal prognosis - Preclinical models demonstrate the activity of bevacizumab, in combination with CT against endometrial cancer cell line VEGF inhibitors and endometrial cancer Kamat et al. Clin Cancer Res, 2007

39. Welch et al. J Clin Oncol, 2009 ActivityN = 16 pts Overall Response12.5% Complete Response0% * Sunitinib 50mg/d 4 weeks every 6 weeks VEGF inhibitors and endometrial cancer: Sunitinib Partial Response12.5% Stable Disease12.5%

40. Aghajanian et al. J Clin Oncol, 2011 ActivityN = 52 pts Overall Response13.5% Complete Response2% * Bevacizumab 15mg/kg every 3 weeks Partial Response11.5% Progression-free 6 months40.4% VEGF inhibitors and endometrial cancer: Bevacizumab

41. Aghajanian et al. J Clin Oncol, 2011 Progression-free and Overall Survival VEGF inhibitors and endometrial cancer: Bevacizumab

42. Aghajanian et al. J Clin Oncol, 2011 Progression-free Survival vs VEGF-A levels VEGF inhibitors and endometrial cancer: Bevacizumab

43. Aghajanian et al. J Clin Oncol, 2011 Overall Survival vs VEGF-A levels VEGF inhibitors and endometrial cancer: Bevacizumab

44. Mackay et al. Gynecol Oncol, 2012 ActivityN = 18 pts Overall Response0% Progression-free 6 months5.6% * Aflibercept 4mg/kg every 2 weeks VEGF inhibitors and carcinosarcoma: Aflibercept

45. Mackay et al. Gynecol Oncol, 2012 * Aflibercept 4mg/kg every 2 weeks Response VEGF inhibitors and carcinosarcoma: Aflibercept

46. Mackay et al. Gynecol Oncol, 2012 * Aflibercept 4mg/kg every 2 weeks Progression-free Survival VEGF inhibitors and carcinosarcoma: Aflibercept

47. Salvage Therapy: Target Agents EGFR inhibitors

48. EGFR inhibitors and endometrial cancer Overexpression of EGFR in endometrial cancer has been documented in several studies in between 36% and 87% of the patients High levels of EGFR expression and possible association with inferior prognosis

49. Oza et al. J Clin Oncol, 2008 * Erlotinib 150mg daily EGFR inhibitors and endometrial cancer: Erlotinib ActivityN = 32 pts Overall Response12.5% Complete Response0% Partial Response12.5% Stable Disease46.9%

50. Leslie et al. J Clin Oncol, 2009 abst # 6542 * Gefitinib 150mg daily ActivityN = 29 pts Overall Response3.8% Complete Response0% Partial Response3.8% Stable Disease27.0% EGFR inhibitors and endometrial cancer: Gefitinib

51. Salvage Therapy: Target Agents HER-2/neu inhibitors

52. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006

53. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006

54. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006 Disease-specific survivalOverall survivalProgression-free survival

55. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006 Disease-specific survival (stage III/IV)Overall survival (stage III/IV)

56. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006 Disease-specific survival (grade III)Overall survival (grade III)

57. HER-2 inhibitors and endometrial cancer Morrison et al. J Clin Oncol, 2006 Disease-specific survival (endometrioid)Overall survival (endometrioid)

58. HER-2 inhibitors and endometrial cancer: Trastuzumab Fleming et al. Gynecol Oncol, 2010 ActivityN = 34 pts Overall Response0% * Trastuzumab 6mg/kg every 3 weeks * N = 286: Her-2 amplified: 11.5%

59. Santin et al. Int J Gynecol Obstet, 2008 Patient 1 HER-2 inhibitors and endometrial cancer: Trastuzumab

60. Santin et al. Int J Gynecol Obstet, 2008 Patient 2 HER-2 inhibitors and endometrial cancer: Trastuzumab

61. Salvage Therapy: Ongoing Trials

62. Ixabepilone Paclitaxel or doxorubicin R A N D O M I Z E D 1:1 R A N D O M I Z E D 1:1 Progressive pretreated endometrial carcinoma patients Patients Microtubules inhibitors and endometrial cancer

63. Carboplatin + Paclitaxel + Temsirolimus Carboplatin + Paclitaxel + BEV P H A S E II R A N D O M I Z E D 1:1 P H A S E II R A N D O M I Z E D 1:1 Progressive pretreated endometrial carcinoma patients Patients VEGF inhibitors and endometrial cancer Carboplatin + Ixabepilone + BEV

64. Ongoing Clinical Trials in Endometrial Cancer

65. Obrigado maluffc@uol.com.br