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

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

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

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  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. Índice Estudo MA.31 (Taxano + LapatinibevsTaxano + Trastuzumab) Estudo CLEOPATRA (Pertuzumab + Trastuzumab + Docetaxel vsTrastuzumab + Docetaxel) Estudo HannaH (Trastuzumab SC vs EV) Estudo EMILIA (Capecitabina + Lapatinibvs TDM-1) BOLERO-2 (ExemestanevsExemestane + Everolimo após IA na primeira linha)

  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. 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 ClinOncol 30, 2012 (suppl; LBA671)

  5. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31Selected Patient Characteristics J ClinOncol 30, 2012 (suppl; LBA671)

  6. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 J ClinOncol 30, 2012 (suppl; LBA671)

  7. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 J ClinOncol 30, 2012 (suppl; LBA671)

  8. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31Overall Survival J ClinOncol 30, 2012 (suppl; LBA671)

  9. Taxane-based chemotherapy with lapatinib or trastuzumab as first-line for HER2+ ABC: MA.31 *Central confirmation of HER2 Toxicity: More grade 3-4 diarrhea and rash was observed with Lapatinib (p<0.001). J ClinOncol 30, 2012 (suppl; LBA671)

  10. Take home message • Taxano + Trastuzumabaumenta TLP quandocomparado com Taxano + Lapatinib • Nãoháaumentoda SG

  11. 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,6J 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 • Baselgaet al. N Engl J Med 366:109, 2012

  12. Study design Placebo + trastuzumab + docetaxel(n = 406) Patients withHER2-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 • Baselgaet al. N Engl J Med 366:109, 2012

  13. IRF-assessed progression-free survival 1.0 Pertuzumab + T + D: median 18.5 months ∆ = 6.1 months Placebo + T + D: median 12.4 months 0.9 0.8 0.7 0.6 0.5 0.4 HR = 0.6295% CI 0.51‒0.75p<0.0001 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 Time (months) n at risk 406 311 209 93 42 17 7 0 0 Pertuzumab + T + D 402 345 267 139 83 32 10 0 0 Placebo + T + D D, docetaxel; IRF, independent review facility; T, trastuzumab • Baselgaet al. N Engl J Med 366:109, 2012

  14. All 808 0.63 0.52‒0.76 De novo(Neo)adjuvant 432 0.63 0.49‒0.82376 0.61 0.46‒0.81 Prior treatment EuropeNorth AmericaSouth AmericaAsia 306 0.72 0.53‒0.97135 0.51 0.31‒0.84114 0.46 0.27‒0.78253 0.68 0.48‒0.95 Region 681 0.65 0.53‒0.80127 0.52 0.31‒0.86 <65 years≥65 years Age group WhiteBlackAsianOther 480 0.62 0.49‒0.8030 0.64 0.23‒1.79261 0.68 0.49‒0.9537 0.39 0.13‒1.18 Race Visceral diseaseNon-visceral disease Disease type PositiveNegative 388 0.72 0.55‒0.95408 0.55 0.42‒0.72 ER/PgR status IHC 3+FISH-positive HER2 status 721 0.60 0.49‒0.74 767 0.64 0.53‒0.78 IRF-assessed PFS in predefined subgroups Favors pertuzumab Favors placebo n HR 95% CI 630 0.55 0.45‒0.68178 0.96 0.61‒1.52 0 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 • Baselgaet al. N Engl J Med 366:109, 2012

  15. Overall survival: predefined interim analysis 1.0 0.9 0.8 0.7 HR = 0.64*95% CI 0.47‒0.88p = 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 0 5 10 15 20 25 30 35 40 45 Time (months) n at risk Pertuzumab + T + D 406 383 347 228 143 67 24 2 0 0 402 387 367 251 161 87 31 4 0 0 *The interim overall survival analysis did not cross the O’Brien-Fleming stopping boundary threshold. Placebo + T + D D, docetaxel; NS, not significant; T, trastuzumab • Baselgaet al. N Engl J Med 366:109, 2012

  16. IRF-assessed objective responsein patients with measurable disease at baseline IRF, independent review facility • Baselgaet al. N Engl J Med 366:109, 2012

  17. Adverse events grades ≥3 (≥5% incidence) • Baselgaet al. N Engl J Med 366:109, 2012

  18. Cardiac tolerability CRC, cardiac review committee; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction • Baselgaet al. N Engl J Med 366:109, 2012

  19. Take home message • A adição de Pertuzumab à Docetaxel + Trastuzumabaumenta a RG, TLP e resultaem forte tendenciaparaaumentoda SG. • Há um aumentodaincidencia de diarreia e neutropeniafebril com bloqueioduplo

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

  21. 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. 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

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

  24. HannaH Phase III Study SC trastuzumab HER2-positive EBC (N=596)* R 1:1 Surgery 18 cycles/ 1 year Follow-up: 24 mo IV trastuzumab Clinical stage Ic to IIIc including IBC pCR Neoadjuvant Adjuvant FEC500/75/500 Trastuzumab IV6 mg/kg q3w (8 mg/kg loading dose) Docetaxel75 mg/m2 Trastuzumab SC 600 mg/5 mL q3w (fixed dose) Objective: Show non-inferiority of SC vs. IV based on co-primary endpoints • PK: observed trastuzumabCtrough 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

  25. PK Results Pharmacokinetic per protocol population 20 µg/mL is the therapeutic target threshold Lancet Oncol 13:869, 2012

  26. Efficacy Results Lancet Oncol 13:869, 2012 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

  27. Take home message • Trastuzumabadministradopor via SC tem eficácia e toxicidadesemelhante à administradapor via EV • Grande conveniênciapara a adjuvância

  28. Trastuzumabemtansine for HER2-positive advanced breast cancer (EMILIA) Vermaet al. N Engl J Med 367:1783, 2012

  29. TargetedTherapies for HER2+ BreastCancer: 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 P Trastuzumab Lapatinib T-DM1 Nucleus SpectorNL, Blackwell KL. J ClinOncol 2009; Nelson MH, et al. Ann Pharmacother 2006; Lewis Philips GD, et al. Cancer Res 2008.

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

  31. 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-positivetumor cell

  32. EMILIAStudy Design EMILIA Study Design HER2+ (central) LABCorMBC (N=980) T-DM1 3.6 mg/kg q3wIV PD PD 1:1 • Prior taxaneandtrastuzumab • Progressiononmetastatictxorwithin6 mosofadjuvanttx Capecitabine 1000 mg/m2 orally, days 1-14, q3w + Lapatinib 1250 mg/day orally qd • 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 Vermaet al. N Engl J Med 367:1783, 2012

  33. PatientDisposition Patient Disposition Except for OS, allanalysisweredonewith a medianfuofapproximately 1 year Vermaet al. N Engl J Med 367:1783, 2012

  34. Progression-FreeSurvivalbyIndependentReview 1.0 0.8 StratifiedHR = 0.650 (95% CI, 0.55, 0.77) P < 0.0001 0.6 Proportionprogression-free 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) No. atriskbyindependentreview: 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 UnstratifiedHR=0.66 (P=0.0001).

  35. Overall Survival: Confirmatory Analysis 1.0 85.2% 0.8 78.4% 64.7% 0.6 Proportion surviving 51.8% 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk: Cap + Lap 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

  36. Objective Response Rate (ORR) ad Durationof Response (DOR) in PatientswithMeasuraleDiasease 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 43.6% 1.0 0.8 0.6 0.4 0.2 0.0 50 40 30 20 10 0 30.8% proportionprogression-free Percent 120/389 173/397 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Cap + Lap T-DM1 No. atrisk 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 0 2 0 0 0 0 0 0 0 0 0 0 0 0

  37. Non-Hematologogic Adverse Events Grade ≥ 3 AEswithIncidence≥ 2% Non-Hematologic Adverse EventsGrade ≥3 AEs With Incidence ≥2% ALT, alnineaminotransferase; AST, aspartateaminotransferase

  38. Hematologogic Adverse Events Hematologic Adverse Events

  39. Take home message • Quandocomparado com Capecitabina + Lapatinibenasegundalinha, TDM-1 demonstraaumendoda RG, TLP e SG e com menortoxicidade

  40. 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) • 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.

  41. 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/mTORblockade2 • 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 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. YamnikRL, 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.

  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.

  43. BOLERO-2: Primary Endpoint, PFS(Local Assessment) HR = 0.45(95% CI = 0.38, 0.54) 100 Log-rank P value: < .0001 Everolimus + Exemestane: 7.8mo(E/N = 310/485) 80 Placebo + Exemestane: 3.2mo(E/N = 200/239) 60 Probability (%) of Event 40 20 0 0 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 485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0 Everolimus + Exemestane Placebo + Exemestane 239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0 Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival. Piccart M, et al. J ClinOncol. 2012;30(suppl; abstr 559)(poster).

  44. 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: 4.1mo(E/N = 132/239) 60 Probability (%) of Event 40 20 0 0 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 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 5 0 0 0 Everolimus + Exemestane 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 ClinOncol. 2012;30(suppl; abstr 559)(poster).

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

  46. BOLERO-2: PFS in Prespecified Subgroups Favors Everolimus + Exemestane Favors Placebo + Exemestane Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSAI, nonsteroidal aromatase inhibitor; PgR, progesterone receptor. Piccart M, et al. J ClinOncol. 2012;30(suppl; abstr 559)(poster).

  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 ClinOncol. 2012;30(suppl; abstr 559)(poster).

  48. BOLERO-2: Most Common Adverse Events a Adverse events of special interest. Piccart M, et al. J ClinOncol. 2012;30(suppl; abstr 559)(poster).

  49. Take home message • A adição de everolimo à exemestaneresultaemimportanteredução do risco de progressão e aumento do benefícioclínico • Everolimo tem efeitoscolateraiscomohiperglicemia, pneumonite e mucositequedemandamatenção

  50. Take home message Estudo MA.31 (Taxano + LapatinibevsTaxano + Trastuzumab) Trastuzumab + Taxano é superior a Lapatinibe + Taxano Estudo CLEOPATRA (Pertuzumab + Trastuzumab + Docetaxel vsTrastuzumab + 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 + Lapatinibvs TDM-1) TDM-1 tem eficácia maior e é menos tóxico que capecitabina + lapatinib BOLERO-2 (ExemestanevsExemestane + Everolimo após IA na primeira linha) Adição de Everolimo aumenta eficácia do Exemestano

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