Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia Hospital São José.
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Transcript of Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia Hospital São José.
Dr Antonio C. BuzaidChefe GeralCentro Avançado de OncologiaHospital São José
Os Trabalhos/Abstracts mais Relevantes em Terapia Biológica
de Cancer de Mama Metastático
Dr Antonio C. BuzaidChefe Geral
Centro Avançado de OncologiaHospital São José
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)
Índice
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.
Primary endpoint: 1. PFS (ITT), 2. PFS (Central HER2+)
Non-inferiority Margin <1.25
Metastatic HER2 positive ABC
N=636
Taxane + Lapatinib(L1250-1500 after CT)
Taxane + Trastuzumab
J Clin Oncol 30, 2012 (suppl; LBA671)
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.
Stratification 1. prior neo/adjuvant HER2 therapy, 2. prior neo/adjuvant Tax, 3. planned Tax (paclitaxel vs docetaxel), 4. liver metastases.
Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
Selected Patient Characteristics
J Clin Oncol 30, 2012 (suppl; LBA671)
L-TAX/L (N=318)
T-TAX/T(N=318)
Age 55.4 54.1
ECOG 0/1 96% 97%
Prior anti-HER2 Rx 18% 18%
Prior Taxane 21% 22%
Stage IV at Dx 42% 43%
Liver Mets 46% 46%
Planned Docetaxel 55% 55%
Planned Paclitaxel 45% 45%
Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
J Clin Oncol 30, 2012 (suppl; LBA671)
Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
J Clin Oncol 30, 2012 (suppl; LBA671)
Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
Overall Survival
J Clin Oncol 30, 2012 (suppl; LBA671)
Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31
Toxicity:
More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001).
J Clin Oncol 30, 2012 (suppl; LBA671)
L Tax/L T Tax/T HR (95% CI; p)
PFS (ITT) 8.8 months(95%CI, 8.3-
19.6)
11.4 months(95%CI, 10.8-
13.7)
1.33; 95% CI 1.06-1.67; p=0.01
PFS (central)* 9.0 months 13.7 months 1.48 (95% CI 1.15-1.92; p=0.003)
OS 1.1 (95% CI 0.75-1.61; p=0.62)
*Central confirmation of HER2
Take home message
• Taxano + Trastuzumab aumenta TLP quando comparado com Taxano + Lapatinib
• Não há aumento da SG
8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs.Pertuzumab + Trastuzumab + Docetaxelin 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
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
12
Study design
MBC, metastatic breast cancer; PD, progressive disease
Patients withHER2-positive MBC
(N = 808)Pertuzumab + trastuzumab + docetaxel
(n = 402)
Placebo + trastuzumab + docetaxel(n = 406)
1̶:1̶
• 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 1̶00 mg/m2 if tolerated; at least 6 cycles were recommended
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
13
IRF-assessed progression-free survival
D, docetaxel; IRF, independent review facility; T, trastuzumab
0 5 1̶0 1̶5 20 25 30 35 40
0.0
0.1̶
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1̶.0
n at risk
402 345 267 1̶39 83 32 1̶0 0 0Pertuzumab + T + D
406 31̶1̶ 209 93 42 1̶7 7 0 0Placebo + T + D
Time (months)
Pertuzumab + T + D: median 1̶8.5 monthsPlacebo + T + D: median 1̶2.4 months
HR = 0.6295% CI 0.51̶‒0.75
p<0.0001̶
∆ = 6.1̶ months
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
14
IRF-assessed PFS in predefined subgroups
ER, estrogen receptor; IHC, immunohistochemistry; IRF, independent review facility; FISH, fluorescence in situ hybridisation;PgR, progesterone receptor; PFS, progression-free survival
630 0.55 0.45‒0.681̶78 0.96 0.61̶‒1̶.52
n HR 95% CI
0 1̶ 2 3
808 0.63 0.52‒0.76All
0.5
Favors placeboFavors pertuzumab
388 0.72 0.55‒0.95408 0.55 0.42‒0.72
PositiveNegativeER/PgR status
Visceral diseaseNon-visceral diseaseDisease type
480 0.62 0.49‒0.8030 0.64 0.23‒1̶.79261̶ 0.68 0.49‒0.9537 0.39 0.1̶3‒1̶.1̶8
WhiteBlackAsianOther
Race
681̶ 0.65 0.53‒0.801̶27 0.52 0.31̶‒0.86
<65 years≥65 years
Age group
306 0.72 0.53‒0.971̶35 0.51̶ 0.31̶‒0.841̶1̶4 0.46 0.27‒0.78253 0.68 0.48‒0.95
EuropeNorth AmericaSouth America
Asia
Region
432 0.63 0.49‒0.82376 0.61̶ 0.46‒0.81̶
De novo(Neo)adjuvant Prior treatment
721̶ 0.60 0.49‒0.74767 0.64 0.53‒0.78
IHC 3+FISH-positiveHER2 status
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
15
Overall survival: predefined interim analysis
D, docetaxel; NS, not significant; T, trastuzumab
0 5 1̶0 1̶5 20 25 30 35 40 45
0.0
0.1̶
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1̶.0
n at risk
Pertuzumab + T + D 402 387 367 251̶ 1̶61̶ 87 31̶ 4 0 0
406 383 347 228 1̶43 67 24 2 0 0Placebo + T + D
Time (months)
Pertuzumab + T + D: 69 eventsPlacebo + T + D: 96 events
HR = 0.64*95% CI 0.47‒0.88
p = 0.0053* NS
*The interim overall survival analysis did not cross the O’Brien-Fleming stopping boundary threshold.
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
16
IRF-assessed objective responsein patients with measurable disease at baseline
IRF, independent review facility
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)
1̶4 (4.2)
21̶9 (65.2)
275 (80.2)
1̶9 (5.5)
256 (74.6)
Stable disease, n (%) 70 (20.8) 50 (1̶4.6)
Progressive disease, n (%) 28 (8.3) 1̶3 (3.8)
Unable to assess or no assessment, n (%)
5 (1̶.5) 5 (1̶.5)
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
17
Adverse events grades ≥3 (≥5% incidence)
Adverse event, n (%)
Placebo+ trastuzumab + docetaxel
(n = 397)
Pertuzumab+ trastuzumab + docetaxel
(n = 407)
Neutropenia 1̶82 (45.8) 1̶99 (48.9)
Febrile neutropenia 30 (7.6) 56 (1̶3.8)
Leukopenia 58 (1̶4.6) 50 (1̶2.3)
Diarrhea 20 (5.0) 32 (7.9)
•Baselga et al. N Engl J Med 366:109, 2012
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
18
Cardiac tolerability
CRC, cardiac review committee; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
Placebo
+ trastuzumab + docetaxelPertuzumab
+ trastuzumab + docetaxel
Investigator-assessed symptomatic LVSD 1̶.8% 1̶.0%
CRC-adjudicated symptomatic LVSD 1̶.0% 1̶.0%
Fall in LVEF to <50% and by ≥1̶0 percentage points from baseline
6.6% 3.8%
•Baselga et al. N Engl J Med 366:109, 2012
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
8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
Subcutaneous Administration
A new way to deliver biologic therapy in HER2 positive breast cancer
8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
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 1̶3:869, 201̶2
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
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 administrationto <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
Haller MF. 2007
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
23
Injection site with or without recombinant human hyaluronidase
Images show left and right arms of subject 1̶06 in the HALO-1̶04-1̶03 study
Before infusion
Immediately post-infusion
Before infusion
Immediately post-infusion
Injection without rHuPH20
Injection with rHuPH20 2000 U/mL
Halozyme Therapeutics, Data on file
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
24
HannaH Phase III Study
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
HER2-positive
EBC (N=596)*
SC trastuzumab
IV trastuzumab
Su
rger
y
Fo
llo
w-u
p:
24
mo
pCR
1̶8 c
ycle
s/
1̶ ye
ar
Trastuzumab SC 600 mg/5 mL q3w (fixed dose)
Trastuzumab IV 6 mg/kg q3w
(8 mg/kg loading dose)
Docetaxel75 mg/m2
FEC500/75/500
Neoadjuvant Adjuvant
R1̶:1̶
Clinical stage Ic to IIIc including IBC
IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide* Central HER2 testing was carried out by TARGOS Molecular Pathology GmbH Lancet Oncol 1̶3:869, 201̶2
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
25
PK Results
Trastuzumab IVn=235
Trastuzumab SCn=234
Primary endpoint
Observed Ctrough pre-dose Cycle 8
Geometric mean (µg/mL) 51̶.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) 1̶978 21̶08
Geometric mean ratio (90% CI)
1.07 (1.01; 1.12)
Pharmacokinetic per protocol population20 µg/mL is the therapeutic target threshold Lancet Oncol 1̶3:869, 201̶2
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8th European Breast Cancer Conference21̶�-24 March 201̶2, Vienna, Austria
Abstract 1̶BA
26
Efficacy Results
Trastuzumab IVn=263
No. (%)
Trastuzumab SCn=260
No. (%)
Primary endpoint
pCR in the breast 1̶07 (40.7%) 1̶1̶8 (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%) 1̶02 (39.2%)
Difference in tpCR (95% CI) 5.0% (-3.5%; 13.5%)
Overall response rate 231̶ (88.8%) 225 (87.2%)
Median time to response 6 weeks 6 weeks
Efficacy per protocol populationPathological tumor response was assessed locally. Difference in pCR/tpCR calculated as SC-IVpCR defined as absence of invasive neoplastic cells in the breastResidual ductal carcinoma in situ (DCIS) is acceptable for pCR Lancet Oncol 1̶3:869, 201̶2
Take home message
• Trastuzumab administrado por via SC tem eficácia e toxicidade semelhante à administrada por via EV
• Grande conveniência para a adjuvância
Trastuzumab emtansine for HER2-positive advanced breast cancer (EMILIA)
Verma et al. N Engl J Med 367:1783, 2012
T-DM1
Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T-DM1
Targeted Therapies for HER2+ Breast Cancer:Trastuzumab, Lapatinib, and T-DM1
PP
P
PP
P
HER2
Antibody: Trastuzumab
Cytotoxic:DM1
Stablelinker:MCC
Trastuzumab
Lapatinib
Nucleus
Emtansine
Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006;Lewis Philips GD, et al. Cancer Res 2008.
T-DM1: Mechanism of ActionT-DM1: Mechanism of Action
PP
P
T-DM1
HER2
Emtansinerelease
Internalization
Lysosome
Nucleus
Inhibition ofmicrotubule
polymerization
TDM-1 is highly selective and releases the toxic agend inside the
cell
Receptor-T-DM1 complex is internalized into HER2-
positive cancer cell
Potent antimicrotubule agent is released once
inside the HER2-positive
tumor cell
T-DM1 binds to the HER-2 receptor
EMILIA Study DesignEMILIA Study Design
HER2+ (central)LABC or MBC
(N=980)
• Prior taxane and trastuzumab
• Progression on metastatic tx or within 6 mos of adjuvant tx
T-DM1 3.6 mg/kg q3w IV
Capecitabine1000 mg/m2 orally, days 1-14, q3w
+Lapatinib
1250 mg/day orally qd
PD
1:1
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
Patient DispositionPatient 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 19
Verma et al. N Engl J Med 367:1783, 2012
Except for OS, all analysis were done with a median fu of approximately 1 year
Progression-Free Survival by Independent Review
Unstratified HR=0.66 (P=0.0001).
Pro
port
ion p
rogre
ssio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
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
0
1
0
0
Time (mos)
Median (mos) No. Events
Cap + Lap
6.4 304
T-DM1 9.6 265Stratified HR = 0.650 (95% CI, 0.55, 0.77)
P < 0.0001
35www.esmo201̶2.org
Overall Survival: Confirmatory Analysis
496 471̶ 453 435 403 368 297 240 204 1̶59 1̶33 1̶1̶0 86 63 45 27 1̶7 7 4
495 485 474 457 439 41̶8 349 293 242 1̶97 1̶64 1̶36 1̶1̶1̶ 86 62 38 28 1̶3 5
Cap + LapT-DM1̶
No. at risk: Time (months)
78.4% 64.7%
51̶.8%
85.2%
0 2 4 6 8 1̶0 1̶2 1̶4 1̶6 1̶8 20 22 24 26 28 30 32 34 360.0
0.2
0.4
0.6
0.8
1̶.0
Pro
po
rtio
n s
urv
ivin
g
Data cut-off July 31̶, 201̶2; Unstratified HR=0.70 (P=0.0012).
Median (months) No. of events
Cap + Lap 25.1̶ 1̶82
T-DM1̶ 30.9 1̶49
Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
Efficacy stopping boundary P=0.0037 or HR=0.727
Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease
Objective Response Rate (ORR) ad Duration of Response (DOR) in Patients with Measurale
Diasease
ORRDifference: 12.7% (95% CI, 6.0, 19.4)
p = 0.0002
50
40
30
20
10
0
Perc
ent
Cap + Lap
30.8%
43.6%
120/389 173/397
T-DM1
1.0
0.8
0.6
0.4
0.2
0.0
pro
port
ion
pro
gre
ssio
n-f
ree
0 2 4 6 8 101214161820 2224 262830 32 34 36No. at riskCap + LapT-DM1
120173
105159
77126
4884
3265
1447
942
833
327
319
112
18
02
00
00
00
00
00
00
Median (mos) (95% CI
Cap + Lap
6.5 (5.5, 7.2
T-DM1 12.6 (8.4, 20.8)
DOR
Non-Hematologic Adverse EventsGrade ≥3 AEs With Incidence ≥2%
Non-Hematologogic Adverse EventsGrade ≥ 3 AEs with Incidence ≥ 2%
Cap + Lap T-DM1
Adverse EventAll Grades,
%Grade ≥ 3,
%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 8.6 2.2
Fatigue 27.9 3.5 35.1 2.4
Nausea 44.7 2.5 39.2 0.8
Mucosal inflammation
19.1 2.3 6.7 0.2
Increased AST 9.4 0.8 22.4 4.3
Increased ALT 8.8 1.4 16.9 2.9ALT, alnine aminotransferase; AST, aspartate aminotransferase
Hematologic Adverse EventsHematologogic Adverse Events
Cap + Lap T-DM1
Adverse EventAll Grade,
%
Grade 3,%
Grade 4,%
All Grade,
%
Grade 3,%
Grade 4,%
Neutropenia 8.6 3.5 0.8 5.9 1.6 0.4
Febrile neutropenia
1.0 0.4 0.6 0.0 0.0 0.0
Anemia 8.0 1.6 0.0 10.4 2.7 0.0
Thrombocytopenia
2.5 0.0 0.2 28.0 10.4 2.4
Take home message
• Quando comparado com Capecitabina + Lapatinibe na segunda linha, TDM-1 demonstra aumendo da RG, TLP e SG e com menor toxicidade
BOLERO-2: Exemestane ± Everolimus in Non-Steroidal Aromatase Inhibitor-Refractory
Advanced Breast Cancer
• StratificationSensitivity to prior hormonal
therapyPresence of visceral disease
• No crossover
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
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):520-529.
Everolimus 10 mg/d +Exemestane 25 mg/d (n = 485)
Placebo +Exemestane 25 mg/d (n = 239)
Primary endpoint:PFS
Secondary endpoints:OS, ORR, CBR, safety, QoL, bone markers
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
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):6361-6369; 2. Crowder RJ, et al. Cancer Res. 2009;69(9):3955-3962; 3. Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413.
Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36.
BOLERO-2: Prior Therapy
a Each prior therapy counts as one line of treatment.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
Therapy
Everolimus + Exemestane(n = 485), %
Placebo + Exemestane(n = 239), %
Sensitivity to prior hormonal therapy 84 84
Previous treatment with letrozole / anastrozole
100 100
Last non-steroidal aromatase inhibitor treatment setting Adjuvant Metastatic
2179
1684
Prior tamoxifen 47 49
Prior fulvestrant 17 16
Prior chemotherapy for metastatic breast cancer
26 24
Number of prior therapies: ≥ 3a 54 53
BOLERO-2: Primary Endpoint, PFS(Local Assessment)
Everolimus + ExemestanePlacebo + Exemestane
Number of patients still at risk
0
20
40
60
80
100
Time, wk
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0
Pro
babili
ty (
%)
of
Event
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).
HR = 0.45 (95% CI = 0.38, 0.54)
Everolimus + Exemestane: 7.8 mo(E/N = 310/485)Placebo + Exemestane: 3.2 mo(E/N = 200/239)
Log-rank P value: < .0001
BOLERO-2: Primary Endpoint, PFS(Central Assessment)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
485239
427179
359114
29276
23956
21139
16631
14027
10816
7713
629
486
324
211
180
110
100
50
00
0
20
40
60
80
100
Pro
babili
ty (
%)
of
Event
Time, wk
HR = 0.38 (95% CI = 0.31, 0.48)
Everolimus + Exemestane: 11.0 mo(E/N = 188/485)Placebo + Exemestane: 4.1 mo(E/N = 132/239)
Log-rank P value: < .0001
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).
Everolimus + ExemestanePlacebo + Exemestane
Number of patients still at risk
BOLERO-2: Overall Response Rate and Clinical Benefit Rate (Local
Assessment)
12,6%
51,3%
1,7%
26,4%
0
10
20
30
40
50
60
ORR CBR
Everolimus + ExemestanePlacebo + Exemestane
P < .0001
Pati
ents
, %
Abbreviations: CBR, clinical benefit rate; ORR, overall response rate.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).
P < .0001
BOLERO-2: PFS in Prespecified Subgroups
0 0,2 0,4 0,6 0,8 1 1,2 1,4Hazard Ratio
Favors Placebo + ExemestaneFavors Everolimus + 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).
All N = 724
Age group< 65 449≥ 65 275
Presence of visceral metastasisNo 318Yes 406
Baseline ECOG performance status0 4351, 2 274
Prior chemotherapyNo 231Yes 493
Number of prior therapies1 1182 217≥ 3 389
Prior use of hormonal therapy other than NSAI
No 326Yes 398
PgR statusNegative 184Positive 523
BOLERO-2: Overall Survival
Abbreviations: OS, overall survival; PFS, progression free survival.
1. Baselga J, et al. N Engl J Med. 2012;366(6):520-529; 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).
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%
BOLERO-2: Most Common Adverse Events
48a Adverse events of special interest.
Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).
Everolimus + Exemestane(n = 482), %
Placebo + Exemestane(n = 238), %
AllGrade
sGrade
3Grade
4All
GradesGrade
3Grade
4
Stomatitis 59 8 0 12 < 1 0
Rash 39 1 0 7 0 0
Fatigue 37 4 < 1 27 1 0
Diarrhea 34 2 < 1 19 < 1 0
Appetite decreased 31 1 0 13 1 0
Nausea 31 < 1 < 1 29 1 0
Noninfectious pneumonitisa 16 3 0 0 0 0
Hyperglycemiaa 14 5 < 1 2 < 1 0
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
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
Obrigado