Presentation on theme: "Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia"— Presentation transcript:
1Dr Antonio C. Buzaid Chefe Geral Centro Avançado de Oncologia Hospital São José
2Centro Avançado de Oncologia Os Trabalhos/Abstracts mais Relevantes em Terapia Biológica de Cancer de Mama MetastáticoDr Antonio C. BuzaidChefe GeralCentro Avançado de OncologiaHospital São José
3ÍndiceEstudo 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)
4Phase III trial comparing taxane-based chemotherapy (Tax) with lapatinib or trastuzumab as first-line therapy for women with HER2+ ABC: Interim analysis of NCIC CTG MA.31.Taxane + Lapatinib(L after CT)Metastatic HER2 positive ABCN=636Taxane + TrastuzumabStratificationprior 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 <1.25Paclitaxel 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)
5Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 Selected Patient CharacteristicsL-TAX/L(N=318)T-TAX/TAge55.454.1ECOG 0/196%97%Prior anti-HER2 Rx18%Prior Taxane21%22%Stage IV at Dx42%43%Liver Mets46%Planned Docetaxel55%Planned Paclitaxel45%J Clin Oncol 30, 2012 (suppl; LBA671)
6Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 J Clin Oncol 30, 2012 (suppl; LBA671)
7Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 J Clin Oncol 30, 2012 (suppl; LBA671)
8Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 Overall SurvivalJ Clin Oncol 30, 2012 (suppl; LBA671)
9Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 L Tax/LT Tax/THR (95% CI; p)PFS (ITT)8.8 months(95%CI, )11.4 months(95%CI, )1.33; 95% CI ; p=0.01PFS (central)*9.0 months13.7 months1.48 (95% CI ; p=0.003)OS1.1 (95% CI ; p=0.62)*Central confirmation of HER2Toxicity: More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001).J Clin Oncol 30, 2012 (suppl; LBA671)
10Take home messageTaxano + Trastuzumab aumenta TLP quando comparado com Taxano + LapatinibNão há aumento da SG
11A 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 Swain101Massachusetts 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., USABaselga et al. N Engl J Med 366:109, 2012
12Study design Placebo + trastuzumab + docetaxel (n = 406) Patients with HER2-positive MBC(N = 808)1:1Pertuzumab + 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 recommendedMBC, metastatic breast cancer; PD, progressive diseaseBaselga et al. N Engl J Med 366:109, 2012
13IRF-assessed progression-free survival 0.00.10.20.18.104.22.168.22.214.171.124Pertuzumab + T + D: median 18.5 months∆ = 6.1 monthsPlacebo + T + D: median 12.4 monthsHR = % CI 0.51‒0.75 p<0.0001510152025303540Time (months)n at riskPertuzumab + T + D402345267139833210Placebo + T + D4063112099342177D, docetaxel; IRF, independent review facility; T, trastuzumabBaselga et al. N Engl J Med 366:109, 2012
14IRF-assessed PFS in predefined subgroups Favors pertuzumabFavors placebon HR 95% CI‒0.76All‒ ‒0.81De novo (Neo)adjuvantPrior treatment‒ ‒ ‒ ‒0.95Europe North America South America AsiaRegion‒ ‒0.86<65 years ≥65 yearsAge group‒ ‒ ‒ ‒1.18White Black Asian OtherRaceVisceral disease Non-visceral diseaseDisease type‒ ‒1.52‒ ‒0.72Positive NegativeER/PgR status‒0.74‒0.78IHC 3+ FISH-positiveHER2 status0.5123ER, estrogen receptor; IHC, immunohistochemistry; IRF, independent review facility; FISH, fluorescence in situ hybridisation; PgR, progesterone receptor; PFS, progression-free survivalBaselga et al. N Engl J Med 366:109, 2012
15Overall survival: predefined interim analysis 1.00.90.80.7HR = 0.64* 95% CI 0.47‒0.88 p = * NS0.60.50.40.3Pertuzumab + T + D: 69 events0.2Placebo + T + D: 96 events0.10.051015202530354045Time (months)n at riskPertuzumab + T + D4023873672511618731440638334722814367242Placebo + T + D*The interim overall survival analysis did not cross the O’Brien-Fleming stopping boundary threshold.D, docetaxel; NS, not significant; T, trastuzumabBaselga et al. N Engl J Med 366:109, 2012
16IRF-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 facilityBaselga et al. N Engl J Med 366:109, 2012
17Adverse 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)Adverse events are presented in descending order with regards to the pertuzumab armHighlighted in yellow are adverse events with an incidence that is >2% higher in the pertuzumab armHighlighted in orange are adverse events with an incidence that is >2% higher in the placebo armSevere 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
18Placebo + trastuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel Cardiac tolerabilityPlacebo + trastuzumab + docetaxelPertuzumab + trastuzumab + docetaxelInvestigator-assessed symptomatic LVSD1.8%1.0%CRC-adjudicated symptomatic LVSDFall in LVEF to <50% and by ≥10 percentage points from baseline6.6%3.8%CRC, cardiac review committee; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunctionBaselga et al. N Engl J Med 366:109, 2012
19Take home messageA 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
20Subcutaneous Administration A new way to deliver biologic therapy in HER2 positive breast cancer
21Subcutaneous administration of trastuzumab in patients with HER2-positive early breast cancer: Results from the Phase III randomised, open-label, multi-centre (neo)adjuvant HannaH studyIsmael G, Hegg, R, Muehlbauer S, et al. Lancet Oncol 13:869, 2012Este 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).
22Development of a subcutaneous formulation of Herceptin Subcutaneous administration of large volumes is restricted by the structure and physiology of the subcutaneous layerContains a matrix of hyaluronan fibres and collagen fibres, which limits subcutaneous administration to <1 mLHyaluronan is broken down by the naturally occurring enzyme, hyaluronidase, on a daily basisRecombinant human hyaluronidase (rHuPH20) causes temporary and local degradation of hyaluronanResults in a temporary increase in the local subcutaneous dispersion area, enabling large volumes of fluids to be administeredAfter subcutaneous administration, skin returns to normalReferenceHaller MF. Converting intravenous dosing to subcutaneous dosing with recombinant human hyaluronidase. Pharm Tech 2007; 10:861864.Haller MF. 2007
23Injection site with or without recombinant human hyaluronidase Injection without rHuPH20Injection with rHuPH U/mLBefore infusionImmediately post-infusionBefore infusionImmediately post-infusionImages show left and right arms of subject 106 in the HALO studyHalozyme Therapeutics, Data on file23
24HER2-positive EBC (N=596)* HannaH Phase III StudyHER2-positive EBC (N=596)*SC trastuzumabIV trastuzumabSurgeryFollow-up: 24 mopCR18 cycles/ 1 yearTrastuzumab SC 600 mg/5 mL q3w (fixed dose)Trastuzumab IV 6 mg/kg q3w (8 mg/kg loading dose)Docetaxel 75 mg/m2FEC 500/75/500NeoadjuvantAdjuvantR1:1Clinical stage Ic to IIIc including IBCO 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 endpointsPK: observed trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)Efficacy: pathological complete response (pCR) in the breastIBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide* Central HER2 testing was carried out by TARGOS Molecular Pathology GmbHLancet Oncol 13:869, 2012
25Geometric mean (µg/mL) PK ResultsTrastuzumab IVn=235Trastuzumab SCn=234Primary endpointObserved Ctrough pre-dose Cycle 8Geometric mean (µg/mL)51.869.0Geometric 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 0.8Secondary endpointsPatients >20 µg/mL pre-dose Cycle 8232 (98.7%)227 (97.0%)AUC at Cycle 7Geometric mean (µg/mL*day)19782108Geometric 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 SCPharmacokinetic per protocol population20 µg/mL is the therapeutic target thresholdLancet Oncol 13:869, 2012
26Efficacy Results Trastuzumab IV n=263 No. (%) Trastuzumab SC n=260 Primary endpointpCR 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 endpointspCR 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 weeksO 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 pCRLancet Oncol 13:869, 2012
27Take home messageTrastuzumab administrado por via SC tem eficácia e toxicidade semelhante à administrada por via EVGrande conveniência para a adjuvância
28Trastuzumab emtansine for HER2-positive advanced breast cancer (EMILIA) Verma et al. N Engl J Med 367:1783, 2012
29Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T-DM1Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, and T-DM1Antibody: TrastuzumabHER2Cytotoxic:DM1Stablelinker:MCCEmtansinePPPPPTrastuzumabLapatinibPT-DM1NucleusSpector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006;Lewis Philips GD, et al. Cancer Res 2008.
30T-DM1: Mechanism of Action HER2T-DM1EmtansinereleasePInhibition ofmicrotubulepolymerizationPPLysosomeInternalizationNucleusNucleusClin Cancer Res2011.
31TDM-1 is highly selective and releases the toxic agend inside the cell T-DM1 binds to the HER-2 receptorReceptor-T-DM1 complex is internalized into HER2-positive cancer cellPotent antimicrotubule agent is released once inside the HER2-positive tumor cell
32EMILIA Study Design EMILIA Study Design HER2+ (central) LABC or MBC T-DM13.6 mg/kg q3w IVPDPrior taxane and trastuzumabProgression on metastatic tx or within 6 mos of adjuvant tx1:1Capecitabine1000 mg/m2 orally, days 1-14, q3w+Lapatinib1250 mg/day orally qdPDPrimary end points: PFS by independent review, OS, and safetyKey secondary end points: PFS by investigator, ORR, duration of response, time to symptom progressionVerma et al. N Engl J Med 367:1783, 2012
33Patient Disposition Patient Disposition Cap + Lap T-DM1 Randomized, n 496495Treated, n488490On treatment at data cutoff date125182Median follow-up, mos (range)*12.4 (0-35)12.9 (0-34)Median follow-up for OS19Except for OS, all analysis were done with a median fu of approximately 1 yearVerma et al. N Engl J Med 367:1783, 2012
34Progression-Free Survival by Independent Review 1.0Median (mos)No. EventsCap + Lap6.4304T-DM19.62650.80.6Stratified HR = (95% CI, 0.55, 0.77)P <Proportion progression-free0.40.20.024681012141618202224262830Time (mos)No. at risk by independent review:Cap + LapT-DM1496495404419310341176236129183731305310135722554144493081859131Unstratified HR=0.66 (P=0.0001).
35Overall Survival: Confirmatory Analysis Median (months)No. of eventsCap + Lap25.1182T-DM130.9149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006Efficacy stopping boundary P= or HR=0.7271.085.2%0.878.4%64.7%0.6Proportion surviving51.8%0.40.20.024681012141618202224262830323436Time (months)496471453435403368297240204159133110866345271774495485474457439418349293242197164136111623828135Cap + LapT-DM1No. at risk:Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
36Objective 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 DiseaseORRDORDifference: 12.7% (95% CI, 6.0, 19.4)p =Median (mos) (95% CICap + Lap6.5 (5.5, 7.2T-DM112.6 (8.4, 20.8)43.6%50403020101.00.80.60.40.20.030.8%Percentproportion progression-free120/389173/397Cap + LapT-DM124681012141618202224262830323436No. at riskCap + LapT-DM112017310515977126488432651447942833327319112182
39Take home messageQuando comparado com Capecitabina + Lapatinibe na segunda linha, TDM-1 demonstra aumendo da RG, TLP e SG e com menor toxicidade
40BOLERO-2: Exemestane ± Everolimus in Non-Steroidal Aromatase Inhibitor-Refractory Advanced Breast CancerPhase 3 study; N = 724Postmenopausal women with ER+ HER2– advanced breast cancer refractory to letrozole or anastrozoleRecurrence during or within 12 mo after end of adjuvant treatment or progression during or within 1 mo after end of treatment for advanced diseaseEverolimus 10 mg/d +Exemestane 25 mg/d(n = 485)Primary endpoint:PFSSecondary endpoints:OS, ORR, CBR, safety, QoL, bone markersPlacebo +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.StratificationSensitivity to prior hormonal therapyPresence of visceral diseaseNo crossoverAbbreviations: 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):
41Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition mTORC1 activates ER in a ligand-independent fashion1Estradiol suppresses the apoptosis induced by PI3K/AKT/mTOR blockade2Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells3mTOR is a rational target to enhance the efficacy of endocrine therapyResistance to endocrine therapy is currently a major limitation in the treatment of women with ER+ advanced breast cancer.Research has demonstrated that there is crosstalk between ER and other growth factor receptor mediated signaling pathways. For example, there is growing evidence supporting a close interaction between ER signaling and PI3K/Akt/mTOR signaling. The mTOR pathway is a key central regulator of cell growth and proliferation. mTOR forms 2 different protein complexes, mTORC1 and mTORC2. mTORC1 is responsible for ligand-independent activation of ER. Additionally, estradiol can suppress the apoptosis induced by inhibition of PI3K/Akt/mTOR signaling.Hyperactivation of the PI3K/Akt/mTOR signaling pathway is an important mediator of endocrine resistance in ER+ breast cancer cells. Therefore, inhibition of mTOR is a rational approach to enhance the efficacy of endocrine therapy.Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36.Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; ER, endocrine receptor; ERE, endocrine response element; HER2, human epidermal growth factor receptor-2; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin.1. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 2. Crowder RJ, et al. Cancer Res. 2009;69(9): ; 3. Miller TW, et al. J Clin Invest. 2010;120(7):
42BOLERO-2: Prior Therapy Everolimus +Exemestane(n = 485), %Placebo +(n = 239), %Sensitivity to prior hormonal therapy84Previous treatment with letrozole / anastrozole100Last non-steroidal aromatase inhibitor treatment setting Adjuvant Metastatic21 7916 84Prior tamoxifen4749Prior fulvestrant1716Prior chemotherapy for metastatic breast cancer2624Number of prior therapies: ≥ 3a5453This 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):
43BOLERO-2: Primary Endpoint, PFS (Local Assessment) HR = 0.45 (95% CI = 0.38, 0.54)100Log-rank P value: < .0001Everolimus + Exemestane: 7.8 mo (E/N = 310/485)80Placebo + Exemestane: 3.2 mo (E/N = 200/239)60Probability (%) of Event4020The 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.6121824303642485460667278849096102108114120Time, wkNumber of patients still at riskEverolimus + Exemestane4854363663042572211851581249166503524221310821Placebo + Exemestane2391901329667503930211510853111Abbreviations: 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).
44BOLERO-2: Primary Endpoint, PFS (Central Assessment) HR = 0.38 (95% CI = 0.31, 0.48)100Log-rank P value: < .0001Everolimus + Exemestane: 11.0 mo (E/N = 188/485)80Placebo + Exemestane: 4.1 mo (E/N = 132/239)60Probability (%) of Event4020The 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).6121824303642485460667278849096102108Time, wkNumber of patients still at riskEverolimus + Exemestane48523942717935911429276239562113916631140271081677136294863242111811105Placebo + ExemestaneAbbreviations: 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).
45BOLERO-2: Overall Response Rate and Clinical Benefit Rate (Local Assessment) Patients, %P < .0001Overall 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).
46BOLERO-2: PFS in Prespecified Subgroups AllN = 724Age group< 65449≥ 65275Presence of visceral metastasisNo318Yes406Baseline ECOG performance status4351, 2274Prior chemotherapy231493Number of prior therapies11182217≥ 3389Prior use of hormonal therapy other than NSAI326398PgR statusNegative184Positive523This forest plot demonstrates that the benefit of everolimus in combination with exemestane compared with exemestane alone was substantial and consistent (HR = ) across all prospectively defined subgroups. These included age, visceral metastases, baseline performance status (PS), prior therapies, and progesterone receptor (PgR) status.Favors Everolimus + ExemestaneFavors Placebo + ExemestaneAbbreviations: 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).
47BOLERO-2: Overall Survival Interim Analysis(7-mo follow-up)1Updated Analysis (12.5-mo follow-up)2Final PFS Analysis (18-mo follow-up)3Cutoff date11 Feb 20118 Jul 201115 Dec 2011OS 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%Overall survival (OS) data were immature at the time of this analysis; 200 events had been recorded at the time of database lock (25.4% in the everolimus plus exemestane arm versus 32.2% in the exemestane alone arm). Mature OS results are awaited.Abbreviations: OS, overall survival; PFS, progression free survival.1. Baselga J, et al. N Engl J Med. 2012;366(6): ; 2. Hortobagyi G, et al. SABCS 2011; abstract S3-7 (oral); 3. Piccart M, et al. J Clin Oncol. 2012;30(suppl; abstr 559)(poster).
48BOLERO-2: Most Common Adverse Events Everolimus + Exemestane (n = 482), %Placebo + Exemestane(n = 238), %All GradesGrade34Stomatitis59812< 1Rash3917Fatigue3727Diarrhea34219Appetite decreased3113Nausea29Noninfectious pneumonitisa16Hyperglycemiaa145The 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).
49Take home messageA adição de everolimo à exemestane resulta em importante redução do risco de progressão e aumento do benefício clínicoEverolimo tem efeitos colaterais como hiperglicemia, pneumonite e mucosite que demandam atenção
50Take home messageEstudo 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