Fernando Cotait MalufFernando Cotait Maluf

Diretor do Departamento de Oncologia ClínicaDiretor do Departamento de Oncologia Clínica

Centro de Oncologia-Hospital São JoséCentro de Oncologia-Hospital São José

maluffc@uol.com.brmaluffc@uol.com.br

Novidades no tratamento Novidades no tratamento sistêmico dos tumores sistêmico dos tumores

avançados de endométrioavançados de endométrio

A Transformação..............

We have to lead with We have to lead with TWOTWO different different Endometrial CancersEndometrial 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

We have to lead with We have to lead with TWOTWO different different Endometrial CancersEndometrial 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%

Molecular Abnormalities in Molecular Abnormalities in Endometrial Cancer x Potential Endometrial Cancer x Potential

TargetsTargets

Dedes et al. Nat Rev Clin Oncol, 2011

Results as of todayResults as of today

Hormonal Therapy in Hormonal Therapy in advanced endometrial advanced endometrial

cancercancer

Response rates: Response rates: 30% 30%

Progestagens > Non-progestagensProgestagens > Non-progestagens

Duration of response: 2-3 monthsDuration of response: 2-3 months

Overall Survival: 7-11 monthsOverall Survival: 7-11 months

Chemotherapy in advanced Chemotherapy in advanced endometrial cancerendometrial cancer

GOG#177

n = 266Stage III/IV or Recurrent

Cisplatin 50mg/m2

+

Doxorubicin 60mg/m2

Cisplatin 50mg/m2

+

Doxorubicin 45mg/m2

+

Paclitaxel 160mg/m2

Fleming et al. Ann Oncol, 2004

Chemotherapy in advanced Chemotherapy in advanced endometrial cancerendometrial cancer

GOG#177

n = 266Stage III/IV or Recurrent

Cisplatin 50mg/m2

+

Doxorubicin 60mg/m2

Cisplatin 50mg/m2

+

Doxorubicin 45mg/m2

+

Paclitaxel 160mg/m2

Fleming et al. Ann Oncol, 2004

Overall Survival

Chemotherapy in advanced Chemotherapy in advanced endometrial cancerendometrial cancer

GOG#177

n = 266Stage III/IV or Recurrent

Cisplatin 50mg/m2

+

Doxorubicin 60mg/m2

Cisplatin 50mg/m2

+

Doxorubicin 45mg/m2

+

Paclitaxel 160mg/m2

Fleming et al. Ann Oncol, 2004

Overall Survival

< 1,5 years

Salvage Therapy: Salvage Therapy: ChemotherapyChemotherapy

Second-line CT in endometrial Second-line CT in endometrial cancercancer

Summary of ResultsSummary of ResultsAgent N0 Respons

e

Ifosfamide 33 24%

Topotecan 29 9%

Stable Disease

Response Duration (months)

Overall Survival (months)

NR 3.2 NR

55% 2.1-6.9 NR

L-Doxo 42 9%

Paclitaxel 44 27%

Docetaxel 26 8%

Oxaliplatin 54 13%

29% 1.1-5.4 8.2

NR 4.2 10.3

31% NR 6.4

29% 10.9 NR

Ixabepilone 50 12% 60% NR 8.7

TrabectedinTrabectedin

McMeekin et al. Gynecol Oncol, 2009 * Trabectedin 1.3mg/m2 every 3 weeks

Activity N = 46 pts

Overall Response 2.2%

Complete Response 2.2%

Partial Response 0%

Stable Disease 39.0%

McMeekin et al. Gynecol Oncol, 2009

Time to Progression Overall Survival

TrabectedinTrabectedin

Salvage Therapy: Target Salvage Therapy: Target AgentsAgents

Salvage Therapy: Target Salvage Therapy: Target AgentsAgentsmTOR inhibitorsmTOR inhibitors

- 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 mTOR inhibitors and endometrial cancercancer

mTOR inhibitors and endometrial mTOR inhibitors and endometrial cancercancer

Summary of ResultsSummary of ResultsAgent N0 Populatio

n

Tensirolimus

19No prior

tx

Tensirolimus

27 1 prior tx

Response

Clinical Benefit

Duration (months)

25% 82% 8.7

7% 51% 3.5

Deforolimus

45Up to 2 prior tx

Tensirolimus

271 or 2

prior tx

7% 33% < 4

0% 43% 4.5

mTOR inhibitors and endometrial mTOR inhibitors and endometrial cancer: Temsirolimuscancer: Temsirolimus

Oza et al. J Clin Oncol, 2011

CT naive pts (29 pts)

CT pretreated (25 pts)

Response

24% 4%

Stable disease

69% 46%

* Temsirolimus 25mg IV d1,8,15,22

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 mTOR inhibitors and endometrial cancer: Temsirolimuscancer: Temsirolimus

Oza et al. J Clin Oncol, 2011

Duration of Response

mTOR inhibitors and endometrial mTOR inhibitors and endometrial cancer: Temsirolimuscancer: Temsirolimus

Salvage Therapy: Target Salvage Therapy: Target AgentsAgentsVEGF inhibitorsVEGF inhibitors

- 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 VEGF inhibitors and endometrial cancercancer

Kamat et al. Clin Cancer Res, 2007

Welch et al. J Clin Oncol, 2009

Activity N = 16 pts

Overall Response 12.5%

Complete Response 0%

* Sunitinib 50mg/d 4 weeks every 6 weeks

VEGF inhibitors and endometrial VEGF inhibitors and endometrial cancer: Sunitinibcancer: Sunitinib

Partial Response 12.5%

Stable Disease 12.5%

Aghajanian et al. J Clin Oncol, 2011

Activity N = 52 pts

Overall Response 13.5%

Complete Response 2%

* Bevacizumab 15mg/kg every 3 weeks

Partial Response 11.5%Progression-free 6 months

40.4%

VEGF inhibitors and endometrial VEGF inhibitors and endometrial cancer: Bevacizumabcancer: Bevacizumab

Aghajanian et al. J Clin Oncol, 2011

Progression-free and Overall Survival

VEGF inhibitors and endometrial VEGF inhibitors and endometrial cancer: Bevacizumabcancer: Bevacizumab

Salvage Therapy: Target Salvage Therapy: Target AgentsAgentsEGFR inhibitorsEGFR inhibitors

EGFR inhibitors and endometrial EGFR inhibitors and endometrial cancercancer

• 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

Oza et al. J Clin Oncol, 2008 * Erlotinib 150mg daily

EGFR inhibitors and endometrial EGFR inhibitors and endometrial cancer: Erlotinibcancer: Erlotinib

Activity N = 32 pts

Overall Response 12.5%

Complete Response 0%

Partial Response 12.5%

Stable Disease 46.9%

Leslie et al. J Clin Oncol, 2009 abst # 6542

* Gefitinib 150mg daily

Activity N = 29 pts

Overall Response 3.8%

Complete Response 0%

Partial Response 3.8%

Stable Disease 27.0%

EGFR inhibitors and endometrial EGFR inhibitors and endometrial cancer: Gefitinibcancer: Gefitinib

Salvage Therapy: Target Salvage Therapy: Target AgentsAgentsHER-2/neu inhibitorsHER-2/neu inhibitors

HER-2 inhibitors and endometrial HER-2 inhibitors and endometrial cancercancer

Morrison et al. J Clin Oncol, 2006

HER-2 inhibitors and endometrial HER-2 inhibitors and endometrial cancercancer

Morrison et al. J Clin Oncol, 2006

HER-2 inhibitors and endometrial HER-2 inhibitors and endometrial cancer:cancer:

TrastuzumabTrastuzumab

Fleming et al. Gynecol Oncol, 2010

Activity N = 34 pts

Overall Response 0%

* Trastuzumab 6mg/kg every 3 weeks

* N = 286: Her-2 amplified: 11.5%

Santin et al. Int J Gynecol Obstet, 2008

Patient 1

HER-2 inhibitors and endometrial HER-2 inhibitors and endometrial cancer:cancer:

TrastuzumabTrastuzumab

Santin et al. Int J Gynecol Obstet, 2008

Patient 2

HER-2 inhibitors and endometrial HER-2 inhibitors and endometrial cancer:cancer:

TrastuzumabTrastuzumab

Salvage Therapy: Ongoing Salvage Therapy: Ongoing TrialsTrials

IxabepiloneIxabepilone

Paclitaxel or doxorubicinPaclitaxel or doxorubicin

RANDOMIZED

1:1

RANDOMIZED

1:1

• Progressive pretreated endometrial carcinoma patients

Patients

Microtubules inhibitors and Microtubules inhibitors and endometrial cancerendometrial cancer

Carboplatin + Paclitaxel + TemsirolimusCarboplatin + Paclitaxel + Temsirolimus

Carboplatin + Paclitaxel + BEVCarboplatin + Paclitaxel + BEV

PHASE

II

RANDOMIZED

1:1

PHASE

II

RANDOMIZED

1:1

• Progressive pretreated endometrial carcinoma patients

Patients

VEGF inhibitors and endometrial VEGF inhibitors and endometrial cancercancer

Carboplatin + Ixabepilone + BEVCarboplatin + Ixabepilone + BEV

Ongoing Clinical Trials in Ongoing Clinical Trials in Endometrial CancerEndometrial Cancer

Obrigadomaluffc@uol.com.br