22 atualização tratamento sistêmico

HER2 negativo

Atualização TratamentoSistêmico

Tratamento da Doença Metastática QT Doença Metastática

Paclitaxel vs Nab-Paclitaxel vs Ixabepilona

Manutenção (?)

Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)

CALGB 40502: Bevacizumab Plus Nab-Pac, Ixabepilone, or Pac in Untreated MBC

Treatment-naive patients with locally recurrent or

metastatic breast cancer(N = 799)

Paclitaxel 90 mg/m2/wk +Bevacizumab* 10 mg/kg q2w

(n = 283)

Nab-paclitaxel 150 mg/m2/wk +Bevacizumab* 10 mg/kg q2w

(n = 271)

Ixabepilone 16 mg/m2/wk +Bevacizumab* 10 mg/kg q2w

(n = 245)

Disease progression†Stratified by receipt of adjuvant taxanes and HR status

Note: All chemotherapy given for 3 wks on, 1 wk off.*Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab.†Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone.

Rugo HS, et al. ASCO 2012. Abstract CRA1002.

Bevacizumab Plus Nab-Pac, Ixabepilone, or Paclitaxel in MBC: Interim Monitoring First interim PFS analysis (165 events)

– Ixabepilone vs paclitaxel crossed superiority futility boundary

– Accrual to ixabepilone arm closed July 2011

Second interim PFS analysis (236 events)

– Nab-paclitaxel vs paclitaxel crossed superiority futility boundary

– Study closed November 2011

Rugo HS, et al. ASCO 2012. Abstract CRA1002.

Nab-Paclitaxel vs Ixabepilone in MBC: Survival Not Improved vs Paclitaxel

PFS OS

Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

Comparison HR P Value 95% CI

Nab vs Pac 1.19 .12 0.96-1.49

Ixa vs Pac 1.53 < .0001 1.24-1.90

1

0.8

0.6

0.4

0.2

0Pro

po

rtio

n P

rog

ress

ion

Fre

e

0 10 20 30

PaclitaxelNab-paclitaxelIxabepilone

Mos

Comparison HR P Value 95% CI

Nab vs Pac 1.02 .92 0.75-1.38

Ixa vs Pac 1.28 .10 0.95-1.72

1

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n A

live

0 10 20 30


Mos

Nab-Paclitaxel vs Ixabepilone in MBC: More Discontinuation vs Paclitaxel

45% dose reductions with nab-paclitaxel by cycle 3 compared with 15% for both ixabepilone and paclitaxel


Dis

con

tin

ued

(%

)

Cycle number1 2 3 4 5

60

50

40

30

20

10

0


Nab-Paclitaxel vs Ixabepilone in MBC: Worse Toxicities vs Paclitaxel

P < .0001

P = .004

P = .0002

P = .005


90

Gra

de

≥ 3

Ad

vers

e E

ven

t (%

)

80

70

60

50

40

30

20

10

0

79

5559

51

21

12

6056

44

Nab-paclitaxel (n = 258)Paclitaxel (n = 262)Ixabepilone (n 237)

Any Hematologic Nonhematologic

Nab-Paclitaxel vs Ixabepilone vs Paclitaxel in MBC: Adverse EventsGrade 3/4 Adverse Event, % Nab-Paclitaxel

(n = 258)Paclitaxel(n = 262)

Ixabepilone(n = 237)

Leukopenia 17 (P = .0004) 7 3 (P = .042)

Neutropenia 47 (P = .0001) 18 7 (P = .0002)

Hypertension 7 8 11

Fatigue 16 (P = .010) 9 15 (P = .036)

Pain 10 (P = .010) 4 4

Neuropathy

Motor 10 (P = .0003) 2 6 (P = .021)

Sensory 25 (P = .012) 16 25 (P = .022)

• Grade 3 24 16 22

• Grade 4 1 < 1 3




Manutenção (?)

Phase III Study: Maintenance vs Obs in MBC with Response to First-line Pac/Gem

Primary endpoint: PFS from randomization Secondary endpoints: OS, toxicity, QOL, DOR

Im Y-H, et al. ASCO 2012. Abstract 1003.

Maintenance Paclitaxel and Gemcitabine*until progression

(n = 116)Patients withMBC and CR, PR, or SD

to 6 cycles first-linepaclitaxel/gemcitabine*

(N = 231) Observationuntil progression

(n = 115)

*Paclitaxel 175 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days, 1, 8 q3w

Stratified by visceral disease, prior adjuvant taxane, response (CR/PR vs SD), HR status

Maintenance vs Observation in MBC With Response to First-line Pac/Gem: Results

Maintenance(n = 116)

Observation(n = 115)

HR (95% CI) P Value

Median PFS, mos 7.5 3.8 0.73 (0.55-0.96) .026

Median OS, mos 36.8 28.0 0.65 (0.42-0.99) .048

Dose delivery, % Paclitaxel Gemcitabine

94.786.6

95.991.7

Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.

Maint vs Obs in MBC With Response to First-line Pac/Gem: Grade ≥ 3 AEs

Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.

Grade 3/4 AE, n (%)

Cycles 1-6 Cycle 7 and Beyond

Maint(n = 116)

Obs(n = 115)

P ValueMaint

(n = 116)Obs

(n = 115)P Value

Neutropenia 80 (69.0) 78 (67.8) .57 71 (61.2) 1 (0.9) < .0001

Thrombocytopenia 0 1 (0.9) .50 1 (0.9) 0 .50

Anemia 3 (2.6) 6 (5.2) .33 1 (0.9) 0 .50

Azotemia 0 0 NS 5 (4.3) 0 .06

AST ↑ 0 0 NS 1 (0.9) 1 (0.9) .10

ALT ↑ 4 (3.4) 2 (1.7) .68 0 0 NS

Febrile neutropenia 0 3 (2.6) .12 0 0 NS

Diarrhea 0 2 (1.7) .25 1 (0.9) 1 (0.9) .10

Grade 3 neuropathy 4 (3.4) 1 (1.7) .68 4 (3.4) 2 (1.7) .68

Grade 2/3 neuropathy 32 (27.6) 39 (33.9) .30 49 (42.2) 18 (15.7) < .0001

Maint vs Obs in MBC With Response to First-line Pac/Gem: Expert Perspectives Maintenance paclitaxel/gemcitabine in responding patients with MBC

substantially prolonged PFS vs observation

– 3.8 vs 7.5 mos (HR: 0.73; 95% CI: 0.55-0.96; P = .026)

OS significantly prolonged in maintenance arm

Maintenance therapy was tolerable and feasible

No negative effect on QoL with maintenance

Maintenance paclitaxel/gemcitabine after 6 cycles should be considered for selected patients

– Hormone receptor negative

– Visceral disease

– High tumor burden

– 50 yrs of age or younger

– Premenopausal

Im Y-H, et al. ASCO 2012. Abstract 1003.



Manutenção (?)

Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)

Clinical scenario

“Virgem” de Tratamento

Tamoxifen sensível (TAM sens.)

Tamoxifen resistente (TAM resist.)

IA resistente (IA resist.)

⌫

⌫

⌫

⌫

‘Virgem’ Tratamento &Sensível ao TAM

Imagem do cristal de ESTRADIOL por microscopia de luz polarizada

Opções

Tamoxifeno (TAM)

Inibidor da Aromatase (IA)

Fulvestranto (Fulv)

Tamoxifenoversus

Inibidor da Aromatase

Imagem do cristal de TAMOXIFENO por microscopia de varredura

Resposta Objetiva (%)

ANAST ANAST LETRO EXEMEST10

20

30

40

50

60

70

80

17

32.6

21

31.2

21.1

32.9 32

45.6

TAM IA


20

30

40

50

60

70

80

45.6

55.5

3841.7

59.156.2

50

66.2

TAM IA

Benefício Clínico (%)


2

4

6

8

10

12

5.6

8.2

6 5.8

11.1

8.2

9.49.9

TAM IA

Tempo até Progressão (meses)

Time-to-Chemotherapy

Tamoxifenoversus

Fulvestranto

Imagem do cristal de ESTRADIOL por microscopia de varredura

Resposta Objetiva &Benefício Clínico (%)

RO BC10

20

30

40

50

60

70

80

31.6

62

33.9

54.3

TAM FULV

TAP0

2

4

6

8

10

12

8.3

6.8

TAM FULV


Clinical scenario

“Virgem” de Tratamento

Tamoxifen sensível (TAM sens.)

Tamoxifen resistente (TAM resist.)

IA resistente (IA resist.)

⌫

⌫

⌫

⌫

Resistente ao TAM

Imagem do cristal de ESTRADIOL por microscopia de luz polarizada

Opções

Inibidor da Aromatase (IA)

Fulvestranto (Fulv)

Anastrozolversus

Fulvestranto

Imagem do cristal de ESTRONA por microscopia de luz polarizada

TAM resistente

Estudo Americano

Estudo Europeu

TAM resistente

Fulvestranto dose

Fulvestrant dose

Fulvestranto dose

CONFIRM loading and high dose

RR (%)

CB (%)

TTP* (m)

DOCB (m)

OS(m)

FULVESTRANT

250 mg 9.1% 39.6%

5.5 16.6 22.8

500 mg 10.2%

45.6%

6.5 13.9 22,8*HR=0.80; p=0.006

CONFIRM loading and high dose

FIRST 500 mg vs ANA 1 mg

RR (%)

CB (%)

TTP (m)

FULVESTRANT

14% 41.2%

23,4

ANASTROZOLE

8.8% 42% 13.1

FIRST 500 mg vs ANA 1 mg

Imagem do cristal de PROGESTERONA por microscopia de luz polarizada

Resistente aoIA não-esteroidal

Opções

Exemestano

Exemestano + Everolimus

Exemestanoversus

Fulvestranto

Imagem do cristal de Testosterona por microscopia de varredura

RO BC0

10

20

30

40

50

60

70

6.7

32.2

7.4

31.5

EXEMEST FULV

Resposta Objetiva &Benefício Clínico (%)

Exemestane & Fulvestrant3,7 months


IA (non-steroidal) resistant


Placebo PO dailyExemestane 25 mg PO daily (N=239)

Everolimus 10 mg PO dailyExemestane 25 mg PO daily

(N=485)Postmenopausal ER+, Her2-, unresectable locally advanced or metastatic breast cancer refractory to letrozole or anastrozole

R

N = 7242:1

(everolimus:placebo)

PFS

OSORR

Bone MarkersSafety

PK

Stratification:1. Sensitivity to prior hormonal therapy2. Presence of visceral disease

No cross-over


RR (%)

CB (%)

TTP (m)

EXEMESTANE 0,4% - 4.1

EXE + Everolimus

9.0% - 10,6

BOLERO2 study


Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months

Log rank P value = 3.3 x 10 -15

0 126 18 24 30 36 48 6042 54 7266 78

80

60

40

20

100

0

Pro

babili

ty o

f Event

(%)

Everolimus + Exemestane (E/N=114/485)Placebo + Exemestane (E/N=104/239)


P < 0.0001

P < 0.0001

TAM

IA

FULV

IA

FULV

EXEM

FULV

BOLERO2

0 5 10 15 20 25

6

23,4

5

5

4

10

10Naive/TAM sens.

TAM resist.

AI resist.

500 mg

5

22 atualização tratamento sistêmico

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