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

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

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)

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 (L1250-1500 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)

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)

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

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

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

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

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 = 0.62 95% 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

IRF-assessed PFS in predefined subgroups Favors pertuzumab Favors placebo n HR 95% CI 808 0.63 0.52‒0.76 All 432 0.63 0.49‒0.82 376 0.61 0.46‒0.81 De novo (Neo)adjuvant Prior treatment 306 0.72 0.53‒0.97 135 0.51 0.31‒0.84 114 0.46 0.27‒0.78 253 0.68 0.48‒0.95 Europe North America South America Asia Region 681 0.65 0.53‒0.80 127 0.52 0.31‒0.86 <65 years ≥65 years Age group 480 0.62 0.49‒0.80 30 0.64 0.23‒1.79 261 0.68 0.49‒0.95 37 0.39 0.13‒1.18 White Black Asian Other Race Visceral disease Non-visceral disease Disease type 630 0.55 0.45‒0.68 178 0.96 0.61‒1.52 388 0.72 0.55‒0.95 408 0.55 0.42‒0.72 Positive Negative ER/PgR status 721 0.60 0.49‒0.74 767 0.64 0.53‒0.78 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

Overall survival: predefined interim analysis 1.0 0.9 0.8 0.7 HR = 0.64* 95% CI 0.47‒0.88 p = 0.0053* 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

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

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

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

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

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

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).

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

Injection site with or without recombinant human hyaluronidase Injection without rHuPH20 Injection with rHuPH20 2000 U/mL Before infusion Immediately post-infusion Before infusion Immediately post-infusion Images show left and right arms of subject 106 in the HALO-104-103 study Halozyme Therapeutics, Data on file 23

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

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

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

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

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.

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.

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

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

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

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 = 0.650 (95% CI, 0.55, 0.77) P < 0.0001 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).

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=0.0037 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).

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 = 0.0002 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

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

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

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 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):520-529.

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):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.

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):520-529.

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).

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).

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).

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 = 0.38 - 0.60) 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).

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):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).

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).

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

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