This document summarizes results from several clinical trials testing different treatments for HER2-negative metastatic breast cancer. Key findings include: 1) A phase III study found that maintenance treatment with paclitaxel and gemcitabine after first-line paclitaxel/gemcitabine significantly prolonged progression-free survival compared to observation alone. Overall survival was also significantly prolonged with maintenance therapy. 2) Another study found fulvestrant 500 mg was superior to anastrozole in patients with advanced breast cancer who had relapsed or progressed on prior tamoxifen therapy. Progression-free survival was longer with fulvestrant. 3) The BOLERO-2 trial

1. HER2 negativo
Atualização Tratamento
Sistêmico

2. Tratamento da Doença Metastática
 QT Doença Metastática
 Paclitaxel vs Nab-Paclitaxel vs
Ixabepilona
 Manutenção (?)
 Hormonioterapia
 Faslodex na primeira linha
 Everolimus
 Duplo bloqueio hormonal (?)

3. Tratamento da Doença Metastática
 QT Doença Metastática
 Paclitaxel vs Nab-Paclitaxel vs
Ixabepilona

4. CALGB 40502: Bevacizumab Plus Nab-
Pac, Ixabepilone, or Pac in Untreated MBC
Stratified by receipt of adjuvant taxanes Disease progression†
and HR status
Paclitaxel 90 mg/m2/wk +
Bevacizumab* 10 mg/kg q2w
(n = 283)
Treatment-naive patients Nab-paclitaxel 150 mg/m2/wk +
with locally recurrent or Bevacizumab* 10 mg/kg q2w
metastatic breast cancer (n = 271)
(N = 799)
Ixabepilone 16 mg/m2/wk +
Bevacizumab* 10 mg/kg q2w
(n = 245)
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approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab.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.

5. 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.

6. Nab-Paclitaxel vs Ixabepilone in MBC:
Survival Not Improved vs Paclitaxel
PFS OS
Comparison HR P Value 95% CI Comparison HR P Value 95% CI
Nab vs Pac 1.19 .12 0.96-1.49 Nab vs Pac 1.02 .92 0.75-1.38
Ixa vs Pac 1.53 < .0001 1.24-1.90 Ixa vs Pac 1.28 .10 0.95-1.72
1 1
Proportion Progression Free
0.8 0.8
Proportion Alive
Paclitaxel
Nab-paclitaxel
0.6 0.6
Ixabepilone
0.4 0.4
Paclitaxel
Nab-paclitaxel
0.2 0.2
Ixabepilone
0 0
0 10 20 30 0 10 20 30
Mos Mos
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

7. Nab-Paclitaxel vs Ixabepilone in MBC:
More Discontinuation vs Paclitaxel
60
50 Paclitaxel
Discontinued (%)
Nab-paclitaxel
40 Ixabepilone
30
20
10
0
1 2 3 4 5
Cycle number
 45% dose reductions with nab-paclitaxel by cycle 3
compared with 15% for both ixabepilone and paclitaxel
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

8. Nab-Paclitaxel vs Ixabepilone in MBC:
Worse Toxicities vs Paclitaxel
P = .004 P = .005
90 P < .0001
P = .0002 Nab-paclitaxel (n = 258)
79
Grade ≥ 3 Adverse Event (%)
80 Paclitaxel (n = 262)
70 Ixabepilone (n 237)
59 60
60 55 56
51
50 44
40
30
21
20
12
10
0
Any Hematologic Nonhematologic
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

9. Nab-Paclitaxel vs Ixabepilone vs Paclitaxel
in MBC: Adverse Events
Grade 3/4 Adverse Event, % Nab-Paclitaxel Paclitaxel Ixabepilone
(n = 258) (n = 262) (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
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

10. Tratamento da Doença Metastática
 QT Doença Metastática
 Paclitaxel vs Nab-Paclitaxel vs
Ixabepilona
 Manutenção (?)

11. Phase III Study: Maintenance vs Obs in
MBC with Response to First-line Pac/Gem
Stratified by visceral disease, prior adjuvant taxane,
response (CR/PR vs SD), HR status
Maintenance Paclitaxel and Gemcitabine*
until progression
Patients with (n = 116)
MBC and CR, PR, or SD
to 6 cycles first-line
paclitaxel/gemcitabine*
(N = 231) Observation
until progression
(n = 115)
*Paclitaxel 175 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days, 1, 8 q3w
 Primary endpoint: PFS from randomization
 Secondary endpoints: OS, toxicity, QOL, DOR
Im Y-H, et al. ASCO 2012. Abstract 1003.

12. Maintenance vs Observation in MBC With
Response to First-line Pac/Gem: Results
Maintenance Observation HR (95% CI) P Value
(n = 116) (n = 115)
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 94.7 95.9
 Gemcitabine 86.6 91.7
Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.

13. Maint vs Obs in MBC With Response to
First-line Pac/Gem: Grade ≥ 3 AEs
Cycles 1-6 Cycle 7 and Beyond
Grade 3/4 AE, n (%) Maint Obs Maint Obs
P Value P Value
(n = 116) (n = 115) (n = 116) (n = 115)
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
Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.

14. 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 – 50 yrs of age or younger
– Visceral disease – Premenopausal
– High tumor burden
Im Y-H, et al. ASCO 2012. Abstract 1003.

15. Tratamento da Doença Metastática
 QT Doença Metastática
 Paclitaxel vs Nab-Paclitaxel vs
Ixabepilona
 Manutenção (?)
 Hormonioterapia
 Faslodex na primeira linha
 Everolimus
 Duplo bloqueio hormonal (?)

16. ⌫
“Virgem” de Tratamento
⌫
Tamoxifen sensível (TAM sens.)
⌫
Tamoxifen resistente (TAM resist.)
⌫
IA resistente (IA resist.)

18. Tamoxifeno (TAM)
Inibidor da Aromatase (IA)
Fulvestranto (Fulv)

20. 80
70
60
50 45.6
40
32.6 32.9 32 31.2
30
21.1 21
20 17
10
ANAST ANAST LETRO EXEMEST
TAM IA

21. 80
70 66.2
59.1
60 55.5 56.2
50
50 45.6
41.7
40 38
30
20
10
ANAST ANAST LETRO EXEMEST
TAM IA

22. 12 11.1
9.9
10 9.4
8.2 8.2
8
5.6 6 5.8
6
4
2
0
ANAST ANAST LETRO EXEMEST
TAM IA

25. 80
70
62
60 54.3
50
40
31.6 33.9
30
20
10
RO BC
TAM FULV

26. 12
10
8.3
8
6.8
6
4
2
0
TAP
TAM FULV

27. ⌫
“Virgem” de Tratamento
⌫
Tamoxifen sensível (TAM sens.)
⌫
Tamoxifen resistente (TAM resist.)
⌫
IA resistente (IA resist.)

29. Inibidor da Aromatase (IA)
Fulvestranto (Fulv)

31. Estudo Americano

32. Estudo Europeu

38. RR CB TTP* DOCB OS
(%) (%) (m) (m) (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

40. RR CB (%) TTP
(%) (m)
FULVESTRANT 14% 41.2% 23,4
ANASTROZOLE 8.8% 42% 13.1

43. Exemestano
Exemestano + Everolimus

45. 70
60
50
40
32.2 31.5
30
20
10 6.7 7.4
0
RO BC
EXEMEST FULV

46. Exemestane & Fulvestrant
3,7 months

47. IGF-1R, EGFR
ER RAS
PI3K
E ER AKT RAF
TSC2 TSC1
MEK
mTOR
ERK
E ER
Cell Proliferation

48. Everolimus 10 mg PO daily
PFS
Exemestane 25 mg PO daily
Postmenopausal
(N=485)
ER+, Her2- OS
, unresectable locally ORR
advanced or metastatic R Bone Markers
breast cancer refractory Placebo PO daily Safety
to letrozole or
Exemestane 25 mg PO daily PK
anastrozole
N = 724 (N=239)
2:1
(everolimus:placebo)
 Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
 No cross-over

49. BOLERO2 study
RR CB (%) TTP
(%) (m)
EXEMESTANE 0,4% - 4.1
EXE + Everolimus 9.0% - 10,6

50. HR = 0.36 (95% CI: 0.27–0.47)
100 Log rank P value = 3.3 x 10 -15
Probability of Event (%)
80 EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
60
40
20
Everolimus + Exemestane (E/N=114/485)
Placebo + Exemestane (E/N=104/239)
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Time (weeks)

51. 40
Everolimus + Exemestane
35 33,4%
Placebo + Exemestane
30
P < 0.0001
25
20 18,0%
P < 0.0001
15
9,5%
10
5
0,4%
0
Response Clinical Benefit

52. BOLERO2 10 AI resist.
FULV
EXEM 4 TAM resist.
FULV 5 5
IA 5
500 mg
FULV 23,4
Naive/
IA TAM sens.
10
TAM
6
0 5 10 15 20 25