1. Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia
Hospital São José

2. Centro Avançado de Oncologia
Os Trabalhos/Abstracts mais Relevantes em Terapia Biológica de Cancer de Mama Metastático
Dr Antonio C. Buzaid
Chefe Geral
Centro Avançado de Oncologia
Hospital São José

3. Índice
Estudo MA.31 (Taxano + Lapatinibe vs Taxano + Trastuzumab) Estudo CLEOPATRA (Pertuzumab + Trastuzumab + Docetaxel vs Trastuzumab + Docetaxel) Estudo HannaH (Trastuzumab SC vs EV) Estudo EMILIA (Capecitabina + Lapatinib vs TDM-1) BOLERO-2 (Exemestane vs Exemestane + Everolimo após IA na primeira linha)

4. Phase III trial comparing taxane-based chemotherapy (Tax) with lapatinib or trastuzumab as first-line therapy for women with HER2+ ABC: Interim analysis of NCIC CTG MA.31.
Taxane + Lapatinib
(L after CT)
Metastatic HER2 positive ABC
N=636
Taxane + Trastuzumab
Stratification
prior neo/adjuvant HER2 therapy,
prior neo/adjuvant Tax,
planned Tax (paclitaxel vs docetaxel),
liver metastases.
Primary endpoint: 1. PFS (ITT), 2. PFS (Central HER2+)
Non-inferiority Margin <1.25
Paclitaxel 80mg/m2 wkly or docetaxel 75mg/m2 3 wkly for 24 wks.
Lapatinib dose was 1,250 mg po daily with Tax followed by 1,500 mg daily.
Trastuzumab dose was (loading initially) 2 mg/kg wkly or 6 mg/kg 3 wkly + Tax followed by T 6 mg/kg 3 wkly.
J Clin Oncol 30, 2012 (suppl; LBA671)

5. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 Selected Patient Characteristics
L-TAX/L
(N=318)
T-TAX/T
Age
55.4
54.1
ECOG 0/1
96%
97%
Prior anti-HER2 Rx
18%
Prior Taxane
21%
22%
Stage IV at Dx
42%
43%
Liver Mets
46%
Planned Docetaxel
55%
Planned Paclitaxel
45%
J Clin Oncol 30, 2012 (suppl; LBA671)

6. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
J Clin Oncol 30, 2012 (suppl; LBA671)

7. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
J Clin Oncol 30, 2012 (suppl; LBA671)

8. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 Overall Survival
J Clin Oncol 30, 2012 (suppl; LBA671)

9. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
L Tax/L
T Tax/T
HR (95% CI; p)
PFS (ITT)
8.8 months
(95%CI, )
11.4 months
(95%CI, )
1.33; 95% CI ; p=0.01
PFS (central)*
9.0 months
13.7 months
1.48 (95% CI ; p=0.003) OS
1.1 (95% CI ; p=0.62)
*Central confirmation of HER2
Toxicity: More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001).
J Clin Oncol 30, 2012 (suppl; LBA671)

10. Take home message
Taxano + Trastuzumab aumenta TLP quando comparado com Taxano + Lapatinib
Não há aumento da SG

11. A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)
J Baselga,1 S-B Kim,2 S-A Im,3 R Hegg,4 Y-H Im,5 L Roman,6 J L Pedrini,7 J Cortés,8 A Knott,9 E Clark,9 G Ross9 and S M Swain10
1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 3Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4Hospital Pérola Byington, São Paulo, Brazil; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6Leningrad Regional Oncology Dispensary, St Petersburg, Russian Federation; 7CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8Department of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; 9Roche Products Limited, Welwyn, UK; 10Washington Cancer Institute, Washington Hospital Center, Washington D.C., USA
Baselga et al. N Engl J Med 366:109, 2012

12. Study design Placebo + trastuzumab + docetaxel (n = 406)
Patients with HER2-positive MBC
(N = 808)
1:1
Pertuzumab + trastuzumab + docetaxel (n = 402)
Randomization was stratified by geographic region and prior treatment status (neo/adjuvant therapy or de novo disease)
Study dosing was administered q3w until PD or unacceptable toxicity
− Pertuzumab: 840 mg loading dose, 420 mg maintenance dose − Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance dose − Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated; at least 6 cycles were recommended
MBC, metastatic breast cancer; PD, progressive disease
Baselga et al. N Engl J Med 366:109, 2012

13. IRF-assessed progression-free survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pertuzumab + T + D: median 18.5 months
∆ = 6.1 months
Placebo + T + D: median 12.4 months
HR = % CI 0.51‒0.75 p<0.0001 5 10 15 20 25 30 35 40
Time (months)
n at risk
Pertuzumab + T + D
402
345
267
139 83 32 10
Placebo + T + D
406
311
209 93 42 17 7
D, docetaxel; IRF, independent review facility; T, trastuzumab
Baselga et al. N Engl J Med 366:109, 2012

14. IRF-assessed PFS in predefined subgroups
Favors pertuzumab
Favors placebo
n HR 95% CI
‒0.76
All
‒ ‒0.81
De novo (Neo)adjuvant
Prior treatment
‒ ‒ ‒ ‒0.95
Europe North America South America Asia
Region
‒ ‒0.86
<65 years ≥65 years
Age group
‒ ‒ ‒ ‒1.18
White Black Asian Other
Race
Visceral disease Non-visceral disease
Disease type
‒ ‒1.52
‒ ‒0.72
Positive Negative
ER/PgR status
‒0.74
‒0.78
IHC 3+ FISH-positive
HER2 status
0.5 1 2 3
ER, estrogen receptor; IHC, immunohistochemistry; IRF, independent review facility; FISH, fluorescence in situ hybridisation; PgR, progesterone receptor; PFS, progression-free survival
Baselga et al. N Engl J Med 366:109, 2012

15. Overall survival: predefined interim analysis
1.0
0.9
0.8
0.7
HR = 0.64* 95% CI 0.47‒0.88 p = * NS
0.6
0.5
0.4
0.3
Pertuzumab + T + D: 69 events
0.2
Placebo + T + D: 96 events
0.1
0.0 5 10 15 20 25 30 35 40 45
Time (months)
n at risk
Pertuzumab + T + D
402
387
367
251
161 87 31 4
406
383
347
228
143 67 24 2
Placebo + T + D
*The interim overall survival analysis did not cross the O’Brien-Fleming stopping boundary threshold.
D, docetaxel; NS, not significant; T, trastuzumab
Baselga et al. N Engl J Med 366:109, 2012

16. IRF-assessed objective response in patients with measurable disease at baseline
Placebo + trastuzumab + docetaxel
(n = 336)
Pertuzumab + trastuzumab + docetaxel (n = 343)
Objective response rate, n (%) Complete response rate, n (%) Partial response rate, n (%)
233 (69.3) 14 (4.2) 219 (65.2)
275 (80.2) 19 (5.5) 256 (74.6)
Stable disease, n (%)
70 (20.8)
50 (14.6)
Progressive disease, n (%)
28 (8.3)
13 (3.8)
Unable to assess or no assessment, n (%)
5 (1.5)
IRF, independent review facility
Baselga et al. N Engl J Med 366:109, 2012

17. Adverse events grades ≥3 (≥5% incidence)
Adverse event, n (%)
Placebo + trastuzumab + docetaxel (n = 397)
Pertuzumab + trastuzumab + docetaxel (n = 407)
Neutropenia
182 (45.8)
199 (48.9)
Febrile neutropenia
30 (7.6)
56 (13.8)
Leukopenia
58 (14.6)
50 (12.3)
Diarrhea
20 (5.0)
32 (7.9)
Adverse events are presented in descending order with regards to the pertuzumab arm
Highlighted in yellow are adverse events with an incidence that is >2% higher in the pertuzumab arm
Highlighted in orange are adverse events with an incidence that is >2% higher in the placebo arm
Severe neutropenia: Although the difference in incidence between arms is >2%, due to the high incidence in both arms (~50%), the difference is relatively small. On the other hand, the difference in febrile neutropenia is high which might be due to associated adverse events such as mucositis.
Baselga et al. N Engl J Med 366:109, 2012

18. Placebo + trastuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel
Cardiac tolerability
Placebo + trastuzumab + docetaxel
Pertuzumab + trastuzumab + docetaxel
Investigator-assessed symptomatic LVSD
1.8%
1.0%
CRC-adjudicated symptomatic LVSD
Fall in LVEF to <50% and by ≥10 percentage points from baseline
6.6%
3.8%
CRC, cardiac review committee; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
Baselga et al. N Engl J Med 366:109, 2012

19. Take home message
A adição de Pertuzumab à Docetaxel + Trastuzumab aumenta a RG, TLP e resulta em forte tendencia para aumento da SG.
Há um aumento da incidencia de diarreia e neutropenia febril com bloqueio duplo

20. Subcutaneous Administration
A new way to deliver biologic therapy in HER2 positive breast cancer

21. Subcutaneous administration of trastuzumab in patients with HER2-positive early breast cancer: Results from the Phase III randomised, open-label, multi-centre (neo)adjuvant HannaH study
Ismael G, Hegg, R, Muehlbauer S, et al. Lancet Oncol 13:869, 2012
Este estudo fase III contou com a participação de 9 centros brasileiros e um total de 52 pacientes (10% da amostra total).
Destaque para Dr Gustavo Ismael que é co-autor da apresentação realizada no “European Breast Cancer Conference”, em Viena, no mês passado (março de 2012).

22. Development of a subcutaneous formulation of Herceptin
Subcutaneous administration of large volumes is restricted by the structure and physiology of the subcutaneous layer
Contains a matrix of hyaluronan fibres and collagen fibres, which limits subcutaneous administration to <1 mL
Hyaluronan is broken down by the naturally occurring enzyme, hyaluronidase, on a daily basis
Recombinant human hyaluronidase (rHuPH20) causes temporary and local degradation of hyaluronan
Results in a temporary increase in the local subcutaneous dispersion area, enabling large volumes of fluids to be administered
After subcutaneous administration, skin returns to normal
Reference
Haller MF. Converting intravenous dosing to subcutaneous dosing with recombinant human hyaluronidase. Pharm Tech 2007; 10:861864.
Haller MF. 2007

23. Injection site with or without recombinant human hyaluronidase
Injection without rHuPH20
Injection with rHuPH U/mL
Before infusion
Immediately post-infusion
Before infusion
Immediately post-infusion
Images show left and right arms of subject 106 in the HALO study
Halozyme Therapeutics, Data on file 23

24. HER2-positive EBC (N=596)*
HannaH Phase III Study
HER2-positive EBC (N=596)*
SC trastuzumab
IV trastuzumab
Surgery
Follow-up: 24 mo
pCR
18 cycles/ 1 year
Trastuzumab SC 600 mg/5 mL q3w (fixed dose)
Trastuzumab IV 6 mg/kg q3w (8 mg/kg loading dose)
Docetaxel 75 mg/m2
FEC 500/75/500
Neoadjuvant
Adjuvant R
1:1
Clinical stage Ic to IIIc including IBC
O estudo fase III tem 2 desfechos primários, que se atingidos demonstram a não inferioridade de trastuzumabe SC em relação ao trastuzumabe convencional (IV): 1. farmacocinética : medida da concentração de trastuzumabe sc antes da cirurgia; 2. eficácia : resposta patológica completa (na mama).
A administração sc é feita na coxa e demora menos de 5 minutos, sendo feita com uma seringa hipodérmica (~insulina), sem ajuste dose de ataque e sem ajuste de dose por peso vs infusão padrão IV.
Objective:
Show non-inferiority of SC vs. IV based on co-primary endpoints
PK: observed trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)
Efficacy: pathological complete response (pCR) in the breast
IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide
* Central HER2 testing was carried out by TARGOS Molecular Pathology GmbH
Lancet Oncol 13:869, 2012

25. Geometric mean (µg/mL)
PK Results
Trastuzumab IV
n=235
Trastuzumab SC
n=234
Primary endpoint
Observed Ctrough pre-dose Cycle 8
Geometric mean (µg/mL)
51.8
69.0
Geometric mean ratio (90% CI)
1.33 (1.24; 1.44)
Non-inferiority of SC vs IV demonstrated as lower bound of 90% CI > pre-specified non-inferiority margin of 0.8
Secondary endpoints
Patients >20 µg/mL pre-dose Cycle 8
232 (98.7%)
227 (97.0%)
AUC at Cycle 7
Geometric mean (µg/mL*day)
1978
2108
Geometric mean ratio (90% CI)
1.07 (1.01; 1.12)
A farmacocinética da droga sc é avaliada através do endpoint de concentração da droga SC vs IV.
A concentração da droga SC não é inferior ao IV, isto é a droga está em concentração terapêutica quando administrada por via SC
Pharmacokinetic per protocol population
20 µg/mL is the therapeutic target threshold
Lancet Oncol 13:869, 2012

26. Efficacy Results Trastuzumab IV n=263 No. (%) Trastuzumab SC n=260
Primary endpoint
pCR in the breast
107 (40.7%)
118 (45.4%)
Difference in pCR rates (95% CI)
4.7% (-4.0%; 13.4%)
Non-inferiority of SC vs IV demonstrated as lower bound of 95% CI > pre-specified non-inferiority margin -12.5%
Secondary endpoints
pCR in breast and axilla (tpCR)
90 (34.2%)
102 (39.2%)
Difference in tpCR (95% CI)
5.0% (-3.5%; 13.5%)
Overall response rate
 231 (88.8%)
225 (87.2%) 
Median time to response
6 weeks
O segundo endpoint primário confirma que a resposta patológica completa com trastuzumabe sc não é inferior ao IV, o que significa que a eficácia de ambas as vias é similar.
Os endpoints secundários são positivos e confirmam que a pCR na mama e axila são equivalentes a obtida com IV, o mesmo ocorrendo com a taxa de resposta global e tempo de resposta.
Efficacy per protocol population Pathological tumor response was assessed locally. Difference in pCR/tpCR calculated as SC-IV pCR defined as absence of invasive neoplastic cells in the breast Residual ductal carcinoma in situ (DCIS) is acceptable for pCR
Lancet Oncol 13:869, 2012

27. Take home message
Trastuzumab administrado por via SC tem eficácia e toxicidade semelhante à administrada por via EV
Grande conveniência para a adjuvância

28. Trastuzumab emtansine for HER2-positive advanced breast cancer (EMILIA)
Verma et al. N Engl J Med 367:1783, 2012

29. Targeted Therapies for HER2+ Breast Cancer:
Trastuzumab, Lapatinib, and T-DM1
Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T-DM1
Antibody: Trastuzumab
HER2
Cytotoxic:
DM1
Stable
linker:
MCC
Emtansine P P P P P
Trastuzumab
Lapatinib P
T-DM1
Nucleus
Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006;
Lewis Philips GD, et al. Cancer Res 2008.

30. T-DM1: Mechanism of Action
HER2
T-DM1
Emtansine
release P
Inhibition of
microtubule
polymerization P P
Lysosome
Internalization
Nucleus
Nucleus
Clin Cancer Res
2011.

31. TDM-1 is highly selective and releases the toxic agend inside the cell
T-DM1 binds to the HER-2 receptor
Receptor-T-DM1 complex is internalized into HER2-positive cancer cell
Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

32. EMILIA Study Design EMILIA Study Design HER2+ (central) LABC or MBC
T-DM1
3.6 mg/kg q3w IV PD
Prior taxane and trastuzumab
Progression on metastatic tx or within 6 mos of adjuvant tx
1:1
Capecitabine
1000 mg/m2 orally, days 1-14, q3w +
Lapatinib
1250 mg/day orally qd PD
Primary end points: PFS by independent review, OS, and safety
Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression
Verma et al. N Engl J Med 367:1783, 2012

33. Patient Disposition Patient Disposition Cap + Lap T-DM1 Randomized, n
496
495
Treated, n
488
490
On treatment at data cutoff date
125
182
Median follow-up, mos (range)*
12.4 (0-35)
12.9 (0-34)
Median follow-up for OS 19
Except for OS, all analysis were done with a median fu of approximately 1 year
Verma et al. N Engl J Med 367:1783, 2012

34. Progression-Free Survival by Independent Review
1.0
Median (mos)
No. Events
Cap + Lap
6.4
304
T-DM1
9.6
265
0.8
0.6
Stratified HR = (95% CI, 0.55, 0.77)
P <
Proportion progression-free
0.4
0.2
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (mos)
No. at risk by independent review:
Cap + Lap
T-DM1
496
495
404
419
310
341
176
236
129
183 73
130 53
101 35 72 25 54 14 44 9 30 8 18 5 9 1 3 1
Unstratified HR=0.66 (P=0.0001).

35. Overall Survival: Confirmatory Analysis
Median (months)
No. of events
Cap + Lap
25.1
182
T-DM1
30.9
149
Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
Efficacy stopping boundary P= or HR=0.727
1.0
85.2%
0.8
78.4%
64.7%
0.6
Proportion surviving
51.8%
0.4
0.2
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
496
471
453
435
403
368
297
240
204
159
133
110 86 63 45 27 17 7 4
495
485
474
457
439
418
349
293
242
197
164
136
111 62 38 28 13 5
Cap + Lap
T-DM1
No. at risk:
Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

36. Objective Response Rate (ORR) ad Duration of Response (DOR) in Patients with Measurale Diasease
Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease
ORR
DOR
Difference: 12.7% (95% CI, 6.0, 19.4)
p =
Median (mos) (95% CI
Cap + Lap
6.5 (5.5, 7.2
T-DM1
12.6 (8.4, 20.8)
43.6% 50 40 30 20 10
1.0
0.8
0.6
0.4
0.2
0.0
30.8%
Percent
proportion progression-free
120/389
173/397
Cap + Lap
T-DM1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. at risk
Cap + Lap
T-DM1
120
173
105
159 77
126 48 84 32 65 14 47 9 42 8 33 3 27 3 19 1 12 1 8 2

37. Non-Hematologic Adverse Events Grade ≥3 AEs With Incidence ≥2%
Non-Hematologogic Adverse Events
Grade ≥ 3 AEs with Incidence ≥ 2%
Cap + Lap
T-DM1
Adverse Event
All Grades, %
Grade ≥ 3, %
Diarrhea
79.7
20.7
23.3
1.6
Hand-foot syndrome
58.0
16.4
1.2
0.0
Vomiting
29.3
4.5
19.0
0.8
Hypokalemia
8.6
4.1
2.2
Fatigue
27.9
3.5
35.1
2.4
Nausea
44.7
2.5
39.2
Mucosal inflammation
19.1
2.3
6.7
0.2
Increased AST
9.4
22.4
4.3
Increased ALT
8.8
1.4
16.9
2.9
ALT, alnine aminotransferase; AST, aspartate aminotransferase

38. Hematologic Adverse Events
Hematologogic Adverse Events
Hematologic Adverse Events
Cap + Lap
T-DM1
Adverse Event
All Grade, %
Grade 3,
Grade 4,
Neutropenia
8.6
3.5
0.8
5.9
1.6
0.4
Febrile neutropenia
1.0
0.6
0.0
Anemia
8.0
10.4
2.7
Thrombocytopenia
2.5
0.2
28.0
2.4

39. Take home message
Quando comparado com Capecitabina + Lapatinibe na segunda linha, TDM-1 demonstra aumendo da RG, TLP e SG e com menor toxicidade

40. BOLERO-2: Exemestane ± Everolimus in Non-Steroidal Aromatase Inhibitor-Refractory Advanced Breast Cancer
Phase 3 study; N = 724
Postmenopausal women with ER+ HER2– advanced breast cancer refractory to letrozole or anastrozole
Recurrence during or within 12 mo after end of adjuvant treatment or progression during or within 1 mo after end of treatment for advanced disease
Everolimus 10 mg/d +
Exemestane 25 mg/d
(n = 485)
Primary endpoint:
PFS
Secondary endpoints:
OS, ORR, CBR, safety, QoL, bone markers
Placebo +
Exemestane 25 mg/d
(n = 239)
BOLERO-2 was an international, multicenter, randomized, pivotal phase 3 study evaluating everolimus in combination with exemestane in postmenopausal women with ER+ HER2− advanced breast cancer who had recurrence or progression following prior therapy with the nonsteroidal aromatase inhibitors, letrozole or anastrozole.
Seven hundred twenty four (724) patients were randomized in a 2:1 ratio to receive everolimus (10 mg/day) or matching placebo in combination with open-label exemestane (25 mg/day). Randomization was stratified by documented sensitivity to prior hormonal therapy (yes versus no) and by the presence of visceral metastasis (yes versus no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease [SD] for 24 or more weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. No cross-over after disease progression was allowed.
The primary endpoint was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors) and based on the investigators (local radiology) assessment. Supportive PFS analyses were based on an independent central radiology review. Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), safety, and change in quality of life (QoL). Additional endpoints included changes in bone turnover markers at 6 and 12 weeks.
Stratification
Sensitivity to prior hormonal therapy
Presence of visceral disease
No crossover
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):

41. Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition
mTORC1 activates ER in a ligand-independent fashion1
Estradiol suppresses the apoptosis induced by PI3K/AKT/mTOR blockade2
Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells3
mTOR is a rational target to enhance the efficacy of endocrine therapy
Resistance to endocrine therapy is currently a major limitation in the treatment of women with ER+ advanced breast cancer.
Research has demonstrated that there is crosstalk between ER and other growth factor receptor mediated signaling pathways. For example, there is growing evidence supporting a close interaction between ER signaling and PI3K/Akt/mTOR signaling. The mTOR pathway is a key central regulator of cell growth and proliferation. mTOR forms 2 different protein complexes, mTORC1 and mTORC2. mTORC1 is responsible for ligand-independent activation of ER. Additionally, estradiol can suppress the apoptosis induced by inhibition of PI3K/Akt/mTOR signaling.
Hyperactivation of the PI3K/Akt/mTOR signaling pathway is an important mediator of endocrine resistance in ER+ breast cancer cells. Therefore, inhibition of mTOR is a rational approach to enhance the efficacy of endocrine therapy.
Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36.
Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; ER, endocrine receptor; ERE, endocrine response element; HER2, human epidermal growth factor receptor-2; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin.
1. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 2. Crowder RJ, et al. Cancer Res. 2009;69(9): ; 3. Miller TW, et al. J Clin Invest. 2010;120(7):

42. BOLERO-2: Prior Therapy
Everolimus +
Exemestane
(n = 485), %
Placebo +
(n = 239), %
Sensitivity to prior hormonal therapy 84
Previous treatment with letrozole / anastrozole
100
Last non-steroidal aromatase inhibitor treatment setting Adjuvant Metastatic
21 79
16 84
Prior tamoxifen 47 49
Prior fulvestrant 17 16
Prior chemotherapy for metastatic breast cancer 26 24
Number of prior therapies: ≥ 3a 54 53
This slide shows prior breast cancer therapies received by patients enrolled in the BOLERO-2 study.
By protocol definition, 84% of patients had previous sensitivity to hormonal therapy, defined as response or long stabilization in the metastatic setting or at least 2 years of adjuvant therapy.
All patients, per the inclusion criteria, received letrozole or anastrozole.
Additionally, 48% of patients previously received tamoxifen and 16% previously received fulvestrant. One prior chemotherapy regimen for metastatic breast cancer was given to 25% of patients. Approximately, 53% of patients had at least 3 previous systemic therapies.
a Each prior therapy counts as one line of treatment.
Baselga J, et al. N Engl J Med. 2012;366(6):

43. BOLERO-2: Primary Endpoint, PFS (Local Assessment)
HR = 0.45 (95% CI = 0.38, 0.54)
100
Log-rank P value: < .0001
Everolimus + Exemestane: 7.8 mo (E/N = 310/485) 80
Placebo + Exemestane: 3.2 mo (E/N = 200/239) 60
Probability (%) of Event 40 20
The study met its primary endpoint.
The primary efficacy analysis resulted in an estimated 55% risk reduction for PFS events as per investigator assessment (HR = 0.45). This corresponded to a clinically meaningful 4.6-month prolongation in median PFS for the everolimus plus exemestane arm (7.8 months) compared with the exemestane arm alone (3.2 months).
The percentage of patients in the exemestane alone arm who were progressing at the first assessment is similar to that seen in the EFECT trial. Adding everolimus to exemestane resulted in a clear disease control early after initiating therapy. This early separation of the Kaplan-Meier curves at 6 weeks was maintained later on. 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
102
108
114
120
Time, wk
Number of patients still at risk
Everolimus + Exemestane
485
436
366
304
257
221
185
158
124 91 66 50 35 24 22 13 10 8 2 1
Placebo + Exemestane
239
190
132 96 67 50 39 30 21 15 10 8 5 3 1 1 1
Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

44. BOLERO-2: Primary Endpoint, PFS (Central Assessment)
HR = 0.38 (95% CI = 0.31, 0.48)
100
Log-rank P value: < .0001
Everolimus + Exemestane: 11.0 mo (E/N = 188/485) 80
Placebo + Exemestane: 4.1 mo (E/N = 132/239) 60
Probability (%) of Event 40 20
The analysis of PFS based on independent central radiological assessment was very consistent with that seen by local assessment.
Based on central assessment, there was a 2.6-fold prolongation in median PFS for everolimus plus exemestane (11.0 months) compared with exemestane alone (4.1 months), resulting in a 62% risk reduction of progression or death (HR = 0.38). 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
102
108
Time, wk
Number of patients still at risk
Everolimus + Exemestane
485
239
427
179
359
114
292 76
239 56
211 39
166 31
140 27
108 16 77 13 62 9 48 6 32 4 21 1 18 11 10 5
Placebo + Exemestane
Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

45. BOLERO-2: Overall Response Rate and Clinical Benefit Rate (Local Assessment)
Patients, %
P < .0001
Overall response rates (ORR) per local assessment were statistically significantly higher for the everolimus plus exemestane arm compared with the exemestane alone arm (12.6% versus 1.7%; P < .0001). This represents a 7.4-fold increase in ORR between treatment arms.
The efficacy of everolimus plus exemestane was also confirmed by a statistically superior clinical benefit rate (CBR) compared with exemestane alone (51.3% versus 26.4%; P < .0001). This represents a 2-fold increase in CBR between treatment arms.
Central assessment showed consistent results for both ORR and CBR.
Abbreviations: CBR, clinical benefit rate; ORR, overall response rate.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

46. BOLERO-2: PFS in Prespecified Subgroups
All
N = 724
Age group
< 65
449
≥ 65
275
Presence of visceral metastasis No
318
Yes
406
Baseline ECOG performance status
435
1, 2
274
Prior chemotherapy
231
493
Number of prior therapies 1
118 2
217
≥ 3
389
Prior use of hormonal therapy other than NSAI
326
398
PgR status
Negative
184
Positive
523
This forest plot demonstrates that the benefit of everolimus in combination with exemestane compared with exemestane alone was substantial and consistent (HR = ) across all prospectively defined subgroups. These included age, visceral metastases, baseline performance status (PS), prior therapies, and progesterone receptor (PgR) status.
Favors Everolimus + Exemestane
Favors Placebo + Exemestane
Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSAI, nonsteroidal aromatase inhibitor; PgR, progesterone receptor.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

47. BOLERO-2: Overall Survival
Interim Analysis
(7-mo follow-up)1
Updated Analysis (12.5-mo follow-up)2
Final PFS Analysis (18-mo follow-up)3
Cutoff date
11 Feb 2011
8 Jul 2011
15 Dec 2011
OS events
(Everolimus vs Placebo) 83
(10.7% vs 13.0%)
137
(17.3% vs 22.7%)
200 (25.4% vs 32.2%)
Δ OS events
2.3%
5.4%
6.8%
Overall survival (OS) data were immature at the time of this analysis; 200 events had been recorded at the time of database lock (25.4% in the everolimus plus exemestane arm versus 32.2% in the exemestane alone arm). Mature OS results are awaited.
Abbreviations: OS, overall survival; PFS, progression free survival.
1. Baselga J, et al. N Engl J Med. 2012;366(6): ; 2. Hortobagyi G, et al. SABCS 2011; abstract S3-7 (oral); 3. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

48. BOLERO-2: Most Common Adverse Events
Everolimus + Exemestane (n = 482), %
Placebo + Exemestane
(n = 238), %
All Grades
Grade 3 4
Stomatitis 59 8 12
< 1
Rash 39 1 7
Fatigue 37 27
Diarrhea 34 2 19
Appetite decreased 31 13
Nausea 29
Noninfectious pneumonitisa 16
Hyperglycemiaa 14 5
The adverse events (AEs) observed in the BOLERO-2 study are consistent with the known safety profile of everolimus.
The most common AEs in the everolimus plus exemestane arm included stomatitis, rash, and fatigue. Noninfectious pneumonitis and hyperglycemia were AEs of special interest that occurred more frequently in the everolimus plus exemestane arm compared with the exemestane alone arm.
The most frequently reported grade 3 or 4 AEs, irrespective of relationship to study drug, in the everolimus plus exemestane arm versus the exemestane alone arm were: stomatitis (8% versus less than 1%), anemia (7% versus less than 1%), hyperglycemia (5% versus less than 1%), dyspnea (4% versus 1%), fatigue (4% versus 1%), and noninfectious pneumonitis (3% versus 0%).
a Adverse events of special interest.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).

49. Take home message
A adição de everolimo à exemestane resulta em importante redução do risco de progressão e aumento do benefício clínico
Everolimo tem efeitos colaterais como hiperglicemia, pneumonite e mucosite que demandam atenção

50. Take home message
Estudo MA.31 (Taxano + Lapatinibe vs Taxano + Trastuzumab) Trastuzumab + Taxano é superior a Lapatinibe + Taxano Estudo CLEOPATRA (Pertuzumab + Trastuzumab + Docetaxel vs Trastuzumab + Docetaxel) Bloqueio duplo aumenta RG, SLP e trend para SG Estudo HannaH (Trastuzumab SC vs EV) SC tem eficácia igual a EV Estudo EMILIA (Capecitabina + Lapatinib vs TDM-1) TDM-1 tem eficácia maior e é menos tóxico que capecitabina + lapatinib BOLERO-2 (Exemestane vs Exemestane + Everolimo após IA na primeira linha) Adição de Everolimo aumenta eficácia do Exemestano

51. Obrigado