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


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%


Overall Survival



Toxicity:

More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001).


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

Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute.


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




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




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




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.




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)




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)




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%


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


Abstract 1̶BA

Subcutaneous Administration

A new way to deliver biologic therapy in HER2 positive breast cancer


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



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



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



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



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



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


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


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.



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


P < .0001

Pati

ents

, %

Abbreviations: CBR, clinical benefit rate; ORR, overall response rate.


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.


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

dr antonio c. buzaid chefe geral centro avançado de oncologia hospital são josé

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