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

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Presentation on theme: "Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia Hospital São José."— Presentation transcript:

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

2 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 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

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. Primary endpoint: 1. PFS (ITT), 2. PFS (Central HER2+) Non-inferiority Margin <1.25 Primary endpoint: 1. PFS (ITT), 2. PFS (Central HER2+) Non-inferiority Margin <1.25 Metastatic HER2 positive ABC N=636 Metastatic HER2 positive ABC N=636 Taxane + Lapatinib (L1250-1500 after CT) 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. Stratification 1.prior neo/adjuvant HER2 therapy, 2.prior neo/adjuvant Tax, 3.planned Tax (paclitaxel vs docetaxel), 4.liver metastases.

5 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)

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 Toxicity: More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001). J Clin Oncol 30, 2012 (suppl; LBA671) *Central confirmation of HER2

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

11 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 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 Ross 9 and S M Swain 10 1 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2 Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 3 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4 Hospital Pérola Byington, São Paulo, Brazil; 5 Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6 Leningrad Regional Oncology Dispensary, St Petersburg, Russian Federation; 7 CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8 Department of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; 9 Roche Products Limited, Welwyn, UK; 10 Washington Cancer Institute, Washington Hospital Center, Washington D.C., USA Baselga et al. N Engl J Med 366:109, 2012

12 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 12 Study design MBC, metastatic breast cancer; PD, progressive disease Patients with HER2-positive MBC (N = 808) Pertuzumab + trastuzumab + docetaxel (n = 402) Placebo + trastuzumab + docetaxel (n = 406) 1:1 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/m 2, escalating to 100 mg/m 2 if tolerated; at least 6 cycles were recommended Baselga et al. N Engl J Med 366:109, 2012

13 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 13 IRF-assessed progression-free survival D, docetaxel; IRF, independent review facility; T, trastuzumab 0510152025303540 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 n at risk 40234526713983321000Pertuzumab + T + D 406311209934217700 Placebo + T + D Time (months) Pertuzumab + T + D:median 18.5 months Placebo + T + D:median 12.4 months HR = 0.62 95% CI 0.51 ‒ 0.75 p<0.0001 ∆ = 6.1 months Baselga et al. N Engl J Med 366:109, 2012

14 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 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 6300.550.45 ‒ 0.68 1780.960.61 ‒ 1.52 nHR95% CI 0123 8080.630.52 ‒ 0.76 All 0.5 Favors placeboFavors pertuzumab 3880.720.55 ‒ 0.95 4080.550.42 ‒ 0.72 Positive Negative ER/PgR status Visceral disease Non-visceral disease Disease type 4800.620.49 ‒ 0.80 300.640.23 ‒ 1.79 2610.680.49 ‒ 0.95 370.390.13 ‒ 1.18 White Black Asian Other Race 6810.650.53 ‒ 0.80 1270.520.31 ‒ 0.86 <65 years ≥65 years Age group 3060.720.53 ‒ 0.97 1350.510.31 ‒ 0.84 1140.460.27 ‒ 0.78 2530.680.48 ‒ 0.95 Europe North America South America Asia Region 4320.630.49 ‒ 0.82 3760.610.46 ‒ 0.81 De novo (Neo)adjuvant Prior treatment 7210.600.49 ‒ 0.74 7670.640.53 ‒ 0.78 IHC 3+ FISH-positive HER2 status Baselga et al. N Engl J Med 366:109, 2012

15 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 15 Overall survival: predefined interim analysis D, docetaxel; NS, not significant; T, trastuzumab 051015202530354045 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 n at risk Pertuzumab + T + D4023873672511618731400 4063833472281436724200Placebo + T + D Time (months) Pertuzumab + T + D:69 events Placebo + 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

16 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 16 IRF-assessed objective response in 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) 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) Baselga et al. N Engl J Med 366:109, 2012

17 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 17 Adverse events grades ≥3 (≥5% incidence) Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Neutropenia182 (45.8)199 (48.9) Febrile neutropenia30 (7.6)56 (13.8) Leukopenia58 (14.6)50 (12.3) Diarrhea20 (5.0)32 (7.9) Baselga et al. N Engl J Med 366:109, 2012

18 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 18 Cardiac tolerability CRC, cardiac review committee; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Placebo + trastuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel Investigator-assessed symptomatic LVSD1.8%1.0% CRC-adjudicated symptomatic LVSD1.0% Fall in LVEF to <50% and by ≥10 percentage points from baseline 6.6%3.8% 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 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA Subcutaneous Administration A new way to deliver biologic therapy in HER2 positive breast cancer

21 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 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

22 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 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 Haller MF. 2007

23 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 23 Injection site with or without recombinant human hyaluronidase Images show left and right arms of subject 106 in the HALO-104-103 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

24 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 24 HannaH Phase III Study Objective: Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed trastuzumab C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pCR) in the breast 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/m 2 FEC 500/75/500 NeoadjuvantAdjuvant R 1:1 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 13:869, 2012

25 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 25 PK Results Trastuzumab IV n=235 Trastuzumab SC n=234 Primary endpoint Observed C trough pre-dose Cycle 8 Geometric mean (µg/mL)51.869.0 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 8232 (98.7%)227 (97.0%) AUC at Cycle 7 Geometric mean (µg/mL*day)19782108 Geometric mean ratio (90% CI) 1.07 (1.01; 1.12) Pharmacokinetic per protocol population 20 µg/mL is the therapeutic target threshold Lancet Oncol 13:869, 2012

26 Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute. 8 th European Breast Cancer Conference 21 ̶ -24 March 2012, Vienna, Austria Abstract 1BA 26 Efficacy Results Trastuzumab IV n=263 No. (%) Trastuzumab SC n=260 No. (%) Primary endpoint pCR in the breast107 (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 response6 weeks 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 T-DM1 Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T-DM1 P P P P P P HER2 Antibody: Trastuzumab Cytotoxic: DM1 Stable linker: 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.

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

31 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

32 EMILIA 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 Capecitabine 1000 mg/m 2 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

33 Patient Disposition Cap + LapT-DM1 Randomized, n496495 Treated, n488490 On treatment at data cutoff date125182 Median follow-up, mos (range)*12.4 (0-35)12.9 (0-34) Median follow-up for OS19 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

34 Progression-Free Survival by Independent Review Unstratified HR=0.66 (P=0.0001). Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 024681012141618202224262830 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 5959 1313 0101 0000 Time (mos) Median (mos)No. Events Cap + Lap6.4304 T-DM19.6265 Stratified HR = 0.650 (95% CI, 0.55, 0.77) P < 0.0001

35 35 www.esmo2012.org Overall Survival: Confirmatory Analysis 496471453435403368297240204159133110866345271774 49548547445743941834929324219716413611186623828135 Cap + Lap T-DM1 No. at risk: Time (months) 78.4% 64.7% 51.8% 85.2% 024681012141618202224262830323436 0.0 0.2 0.4 0.6 0.8 1.0 Proportion surviving Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). Median (months)No. of events Cap + Lap25.1182 T-DM130.9 149 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006 Efficacy stopping boundary P=0.0037 or HR=0.727

36 Objective Response Rate (ORR) ad Duration of Response (DOR) in Patients with Measurale Diasease ORR Difference: 12.7% (95% CI, 6.0, 19.4) p = 0.0002 50 40 30 20 10 0 Percent Cap + Lap 30.8% 43.6% 120/389173/397 T-DM1 1.0 0.8 0.6 0.4 0.2 0.0 proportion progression-free 024681012141618202224262830323436 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 1818 0202 0000 0000 0000 0000 0000 0000 Median (mos) (95% CI Cap + Lap6.5 (5.5, 7.2 T-DM112.6 (8.4, 20.8) DOR

37 Non-Hematologogic Adverse Events Grade ≥ 3 AEs with Incidence ≥ 2% Cap + LapT-DM1 Adverse EventAll Grades, %Grade ≥ 3, %All Grades, %Grade ≥ 3, % Diarrhea79.720.723.31.6 Hand-foot syndrome58.016.41.20.0 Vomiting29.34.519.00.8 Hypokalemia8.64.18.62.2 Fatigue27.93.535.12.4 Nausea44.72.539.20.8 Mucosal inflammation19.12.36.70.2 Increased AST9.40.822.44.3 Increased ALT8.81.416.92.9 ALT, alnine aminotransferase; AST, aspartate aminotransferase

38 Hematologogic Adverse Events Cap + LapT-DM1 Adverse Event All Grade, % Grade 3, % Grade 4, % All Grade, % Grade 3, % Grade 4, % Neutropenia8.63.50.85.91.60.4 Febrile neutropenia1.00.40.60.0 Anemia8.01.60.010.42.70.0 Thrombocytopenia2.50.00.228.010.42.4

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 Stratification Sensitivity to prior hormonal therapy Presence 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 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) Everolimus 10 mg/d + Exemestane 25 mg/d (n = 485) Placebo + Exemestane 25 mg/d (n = 239) Placebo + Exemestane 25 mg/d (n = 239) Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers

41 Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition mTORC1 activates ER in a ligand-independent fashion 1 Estradiol suppresses the apoptosis induced by PI3K/AKT/mTOR blockade 2 Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells 3 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.

42 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 therapy84 Previous treatment with letrozole / anastrozole100 Last non-steroidal aromatase inhibitor treatment setting Adjuvant Metastatic 21 79 16 84 Prior tamoxifen4749 Prior fulvestrant1716 Prior chemotherapy for metastatic breast cancer2624 Number of prior therapies: ≥ 3 a 5453

43 BOLERO-2: Primary Endpoint, PFS (Local Assessment) Everolimus + Exemestane Placebo + Exemestane Number of patients still at risk 0 20 40 60 80 100 Time, wk 06121824303642485460667278849096102108114120 48543636630425722118515812491665035242213108210 23919013296675039302115108531110000 Probability (%) 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

44 BOLERO-2: Primary Endpoint, PFS (Central Assessment) 06121824303642485460667278849096102108 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 0 11 0 10 0 5050 0000 0 20 40 60 80 100 Probability (%) 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 + Exemestane Placebo + Exemestane Number of patients still at risk

45 BOLERO-2: Overall Response Rate and Clinical Benefit Rate (Local Assessment) P <.0001 Patients, % Abbreviations: CBR, clinical benefit rate; ORR, overall response rate. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster). P <.0001

46 BOLERO-2: PFS in Prespecified Subgroups 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 metastasis No 318 Yes 406 Baseline ECOG performance status 0 435 1, 2 274 Prior chemotherapy No 231 Yes 493 Number of prior therapies 1 118 2 217 ≥ 3 389 Prior use of hormonal therapy other than NSAI No 326 Yes 398 PgR status Negative 184 Positive 523

47 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 date11 Feb 20118 Jul 201115 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 events2.3%5.4%6.8%

48 BOLERO-2: Most Common Adverse Events 48 a 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), % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Stomatitis598012< 10 Rash3910700 Fatigue374< 12710 Diarrhea342< 119< 10 Appetite decreased31101310 Nausea31< 1 2910 Noninfectious pneumonitis a 1630000 Hyperglycemia a 145< 12 0

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

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