HER2 negativo Atualização Tratamento Sistêmico
Tratamento da Doença Metastática QT Doença Metastática   Paclitaxel vs Nab-Paclitaxel vs    Ixabepilona   Manutenção (?...
Tratamento da Doença Metastática QT Doença Metastática   Paclitaxel vs Nab-Paclitaxel vs    Ixabepilona
CALGB 40502: Bevacizumab Plus Nab- Pac, Ixabepilone, or Pac in Untreated MBC          Stratified by receipt of adjuvant ta...
Bevacizumab Plus Nab-Pac, Ixabepilone, or Paclitaxel in MBC: Interim Monitoring  First interim PFS analysis (165 events) ...
Nab-Paclitaxel vs Ixabepilone in MBC:              Survival Not Improved vs Paclitaxel                                    ...
Nab-Paclitaxel vs Ixabepilone in MBC: More Discontinuation vs Paclitaxel                        60                        ...
Nab-Paclitaxel vs Ixabepilone in MBC:              Worse Toxicities vs Paclitaxel                                         ...
Nab-Paclitaxel vs Ixabepilone vs Paclitaxel in MBC: Adverse Events Grade 3/4 Adverse Event, %            Nab-Paclitaxel   ...
Tratamento da Doença Metastática QT Doença Metastática   Paclitaxel vs Nab-Paclitaxel vs    Ixabepilona   Manutenção (?)
Phase III Study: Maintenance vs Obs in MBC with Response to First-line Pac/Gem   Stratified by visceral disease, prior adj...
Maintenance vs Observation in MBC With Response to First-line Pac/Gem: Results                            Maintenance     ...
Maint vs Obs in MBC With Response to First-line Pac/Gem: Grade ≥ 3 AEs                                       Cycles 1-6   ...
Maint vs Obs in MBC With Response to First-line Pac/Gem: Expert Perspectives  Maintenance paclitaxel/gemcitabine in respo...
Tratamento da Doença Metastática QT Doença Metastática   Paclitaxel vs Nab-Paclitaxel vs    Ixabepilona   Manutenção (?...
⌫    “Virgem” de Tratamento⌫    Tamoxifen sensível (TAM sens.)⌫    Tamoxifen resistente (TAM resist.)⌫    IA resistente (I...
Tamoxifeno (TAM)Inibidor da Aromatase (IA)Fulvestranto (Fulv)
80706050                                             45.640                 32.6 32.9         32   31.230          21.1   ...
8070                                               66.2            59.160                 55.5 56.2                       ...
12         11.1                                               9.910                                 9.4                  8...
8070                        6260                            54.35040     31.6 33.9302010        RO                   BC   ...
1210     8.38           6.86420       TAP                 TAM   FULV
⌫    “Virgem” de Tratamento⌫    Tamoxifen sensível (TAM sens.)⌫    Tamoxifen resistente (TAM resist.)⌫    IA resistente (I...
Inibidor da Aromatase (IA)Fulvestranto (Fulv)
Estudo Americano
Estudo Europeu
RR     CB    TTP*   DOCB   OS             (%)    (%)    (m)    (m)   (m)FULVESTRANT 250 mg    9.1% 39.6%     5.5    16.6  ...
RR     CB (%)   TTP              (%)             (m)FULVESTRANT   14%    41.2%    23,4ANASTROZOLE   8.8%    42%     13.1
ExemestanoExemestano + Everolimus
70605040                                32.2 31.5302010   6.7        7.4 0           RO                      BC           ...
Exemestane & Fulvestrant      3,7 months
IGF-1R, EGFR                          ER               RAS                   PI3KE   ER       AKT                         ...
Everolimus 10 mg PO daily                                                                      PFS                        ...
BOLERO2 study                 RR     CB (%)   TTP                 (%)             (m)EXEMESTANE      0,4%      -      4.1E...
HR = 0.36 (95% CI: 0.27–0.47)                     100                                                               Log ra...
40     Everolimus + Exemestane35                             33,4%     Placebo + Exemestane30                             ...
BOLERO2                    10                    AI resist.   FULV  EXEM        4                                  TAM res...
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
22   atualização tratamento sistêmico
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22 atualização tratamento sistêmico

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  • CALGB, Cancer and Leukemia Group B; HR, hazard ratio; MBC, metastatic breast cancer; Nab-Pac, nab-paclitaxel; ODAC, Oncology Drugs Advisory Committee; Pac, paclitaxel; SD, stable disease.For more information on this study, go to: http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/CRA1002.aspx
  • MBC, metastatic breast cancer; Nab-Pac, nab-paclitaxel; PFS, progression-free survival.For more information on this study, go to: http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/CRA1002.aspx
  • CI, confidence interval; HR, hazard ratio; MBC, metastatic breast cancer; nab, nab-paclitaxel; OS, overall survival; pac, paclitaxel; PFS, progression-free survival.For more information on this study, go to: http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/CRA1002.aspx
  • MBC, metastatic breast cancer.
  • AE, adverse event; MBC, metastatic breast cancer.For more information on this study, go to: http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/CRA1002.aspx
  • MBC, metastatic breast cancer. For more information on this study, go to: http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202012/Tracks/Breast%20Cancer/Capsules/CRA1002.aspx
  • CR, complete response; DOR, duration of response; HR, hormone receptor; MBC, metastatic breast cancer; OS overall survival; Pac/Gem, paclitaxel and gemcitabine; PR, partial response; QOL, quality of life; q3w, every 3 weeks; SD, stable disease.
  • AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Maint, maintenance; MBC, metastatic breast cancer; Obs, observation.
  • CI, confidence interval; HR, hazard ratio; Maint, maintenance; MBC, metastatic breast cancer; Obs, observation; Pac/Gem, paclitaxel, gemcitabine; PFS, progression-free survival; QoL, quality of life.
  • 22 atualização tratamento sistêmico

    1. 1. HER2 negativo Atualização Tratamento Sistêmico
    2. 2. Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona  Manutenção (?) Hormonioterapia  Faslodex na primeira linha  Everolimus  Duplo bloqueio hormonal (?)
    3. 3. Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
    4. 4. CALGB 40502: Bevacizumab Plus Nab- Pac, Ixabepilone, or Pac in Untreated MBC Stratified by receipt of adjuvant taxanes Disease progression† and HR status Paclitaxel 90 mg/m2/wk + Bevacizumab* 10 mg/kg q2w (n = 283) Treatment-naive patients Nab-paclitaxel 150 mg/m2/wk + with locally recurrent or Bevacizumab* 10 mg/kg q2w metastatic breast cancer (n = 271) (N = 799) Ixabepilone 16 mg/m2/wk + Bevacizumab* 10 mg/kg q2w (n = 245) Note: All chemotherapy given for 3 wks on, 1 wk off. *Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab. †Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone.Rugo HS, et al. ASCO 2012. Abstract CRA1002.
    5. 5. Bevacizumab Plus Nab-Pac, Ixabepilone, or Paclitaxel in MBC: Interim Monitoring  First interim PFS analysis (165 events) – Ixabepilone vs paclitaxel crossed superiority futility boundary – Accrual to ixabepilone arm closed July 2011  Second interim PFS analysis (236 events) – Nab-paclitaxel vs paclitaxel crossed superiority futility boundary – Study closed November 2011Rugo HS, et al. ASCO 2012. Abstract CRA1002.
    6. 6. Nab-Paclitaxel vs Ixabepilone in MBC: Survival Not Improved vs Paclitaxel PFS OS Comparison HR P Value 95% CI Comparison HR P Value 95% CI Nab vs Pac 1.19 .12 0.96-1.49 Nab vs Pac 1.02 .92 0.75-1.38 Ixa vs Pac 1.53 < .0001 1.24-1.90 Ixa vs Pac 1.28 .10 0.95-1.72 1 1Proportion Progression Free 0.8 0.8 Proportion Alive Paclitaxel Nab-paclitaxel 0.6 0.6 Ixabepilone 0.4 0.4 Paclitaxel Nab-paclitaxel 0.2 0.2 Ixabepilone 0 0 0 10 20 30 0 10 20 30 Mos MosRugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
    7. 7. Nab-Paclitaxel vs Ixabepilone in MBC: More Discontinuation vs Paclitaxel 60 50 Paclitaxel Discontinued (%) Nab-paclitaxel 40 Ixabepilone 30 20 10 0 1 2 3 4 5 Cycle number  45% dose reductions with nab-paclitaxel by cycle 3 compared with 15% for both ixabepilone and paclitaxelRugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
    8. 8. Nab-Paclitaxel vs Ixabepilone in MBC: Worse Toxicities vs Paclitaxel P = .004 P = .005 90 P < .0001 P = .0002 Nab-paclitaxel (n = 258) 79Grade ≥ 3 Adverse Event (%) 80 Paclitaxel (n = 262) 70 Ixabepilone (n 237) 59 60 60 55 56 51 50 44 40 30 21 20 12 10 0 Any Hematologic Nonhematologic Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
    9. 9. Nab-Paclitaxel vs Ixabepilone vs Paclitaxel in MBC: Adverse Events Grade 3/4 Adverse Event, % Nab-Paclitaxel Paclitaxel Ixabepilone (n = 258) (n = 262) (n = 237) Leukopenia 17 (P = .0004) 7 3 (P = .042) Neutropenia 47 (P = .0001) 18 7 (P = .0002) Hypertension 7 8 11 Fatigue 16 (P = .010) 9 15 (P = .036) Pain 10 (P = .010) 4 4 Neuropathy  Motor 10 (P = .0003) 2 6 (P = .021)  Sensory 25 (P = .012) 16 25 (P = .022) • Grade 3 24 16 22 • Grade 4 1 <1 3Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
    10. 10. Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona  Manutenção (?)
    11. 11. Phase III Study: Maintenance vs Obs in MBC with Response to First-line Pac/Gem Stratified by visceral disease, prior adjuvant taxane, response (CR/PR vs SD), HR status Maintenance Paclitaxel and Gemcitabine* until progression Patients with (n = 116) MBC and CR, PR, or SD to 6 cycles first-line paclitaxel/gemcitabine* (N = 231) Observation until progression (n = 115) *Paclitaxel 175 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days, 1, 8 q3w  Primary endpoint: PFS from randomization  Secondary endpoints: OS, toxicity, QOL, DORIm Y-H, et al. ASCO 2012. Abstract 1003.
    12. 12. Maintenance vs Observation in MBC With Response to First-line Pac/Gem: Results Maintenance Observation HR (95% CI) P Value (n = 116) (n = 115) Median PFS, mos 7.5 3.8 0.73 (0.55-0.96) .026 Median OS, mos 36.8 28.0 0.65 (0.42-0.99) .048 Dose delivery, %  Paclitaxel 94.7 95.9  Gemcitabine 86.6 91.7Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.
    13. 13. Maint vs Obs in MBC With Response to First-line Pac/Gem: Grade ≥ 3 AEs Cycles 1-6 Cycle 7 and Beyond Grade 3/4 AE, n (%) Maint Obs Maint Obs P Value P Value (n = 116) (n = 115) (n = 116) (n = 115) Neutropenia 80 (69.0) 78 (67.8) .57 71 (61.2) 1 (0.9) < .0001 Thrombocytopenia 0 1 (0.9) .50 1 (0.9) 0 .50 Anemia 3 (2.6) 6 (5.2) .33 1 (0.9) 0 .50 Azotemia 0 0 NS 5 (4.3) 0 .06 AST ↑ 0 0 NS 1 (0.9) 1 (0.9) .10 ALT ↑ 4 (3.4) 2 (1.7) .68 0 0 NS Febrile neutropenia 0 3 (2.6) .12 0 0 NS Diarrhea 0 2 (1.7) .25 1 (0.9) 1 (0.9) .10 Grade 3 neuropathy 4 (3.4) 1 (1.7) .68 4 (3.4) 2 (1.7) .68 Grade 2/3 neuropathy 32 (27.6) 39 (33.9) .30 49 (42.2) 18 (15.7) < .0001Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.
    14. 14. Maint vs Obs in MBC With Response to First-line Pac/Gem: Expert Perspectives  Maintenance paclitaxel/gemcitabine in responding patients with MBC substantially prolonged PFS vs observation – 3.8 vs 7.5 mos (HR: 0.73; 95% CI: 0.55-0.96; P = .026)  OS significantly prolonged in maintenance arm  Maintenance therapy was tolerable and feasible  No negative effect on QoL with maintenance  Maintenance paclitaxel/gemcitabine after 6 cycles should be considered for selected patients – Hormone receptor negative – 50 yrs of age or younger – Visceral disease – Premenopausal – High tumor burdenIm Y-H, et al. ASCO 2012. Abstract 1003.
    15. 15. Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona  Manutenção (?) Hormonioterapia  Faslodex na primeira linha  Everolimus  Duplo bloqueio hormonal (?)
    16. 16. ⌫ “Virgem” de Tratamento⌫ Tamoxifen sensível (TAM sens.)⌫ Tamoxifen resistente (TAM resist.)⌫ IA resistente (IA resist.)
    17. 17. Tamoxifeno (TAM)Inibidor da Aromatase (IA)Fulvestranto (Fulv)
    18. 18. 80706050 45.640 32.6 32.9 32 31.230 21.1 2120 1710 ANAST ANAST LETRO EXEMEST TAM IA
    19. 19. 8070 66.2 59.160 55.5 56.2 5050 45.6 41.740 38302010 ANAST ANAST LETRO EXEMEST TAM IA
    20. 20. 12 11.1 9.910 9.4 8.2 8.28 5.6 6 5.86420 ANAST ANAST LETRO EXEMEST TAM IA
    21. 21. 8070 6260 54.35040 31.6 33.9302010 RO BC TAM FULV
    22. 22. 1210 8.38 6.86420 TAP TAM FULV
    23. 23. ⌫ “Virgem” de Tratamento⌫ Tamoxifen sensível (TAM sens.)⌫ Tamoxifen resistente (TAM resist.)⌫ IA resistente (IA resist.)
    24. 24. Inibidor da Aromatase (IA)Fulvestranto (Fulv)
    25. 25. Estudo Americano
    26. 26. Estudo Europeu
    27. 27. RR CB TTP* DOCB OS (%) (%) (m) (m) (m)FULVESTRANT 250 mg 9.1% 39.6% 5.5 16.6 22.8 500 mg 10.2% 45.6% 6.5 13.9 22,8*HR=0.80; p=0.006
    28. 28. RR CB (%) TTP (%) (m)FULVESTRANT 14% 41.2% 23,4ANASTROZOLE 8.8% 42% 13.1
    29. 29. ExemestanoExemestano + Everolimus
    30. 30. 70605040 32.2 31.5302010 6.7 7.4 0 RO BC EXEMEST FULV
    31. 31. Exemestane & Fulvestrant 3,7 months
    32. 32. IGF-1R, EGFR ER RAS PI3KE ER AKT RAF TSC2 TSC1 MEK mTOR ERK E ER Cell Proliferation
    33. 33. Everolimus 10 mg PO daily PFS Exemestane 25 mg PO dailyPostmenopausal (N=485)ER+, Her2- OS, unresectable locally ORRadvanced or metastatic R Bone Markersbreast cancer refractory Placebo PO daily Safetyto letrozole or Exemestane 25 mg PO daily PKanastrozole N = 724 (N=239) 2:1 (everolimus:placebo)  Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease  No cross-over
    34. 34. BOLERO2 study RR CB (%) TTP (%) (m)EXEMESTANE 0,4% - 4.1EXE + Everolimus 9.0% - 10,6
    35. 35. HR = 0.36 (95% CI: 0.27–0.47) 100 Log rank P value = 3.3 x 10 -15Probability of Event (%) 80 EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 60 40 20 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (weeks)
    36. 36. 40 Everolimus + Exemestane35 33,4% Placebo + Exemestane30 P < 0.00012520 18,0% P < 0.000115 9,5%10 5 0,4% 0 Response Clinical Benefit
    37. 37. BOLERO2 10 AI resist. FULV EXEM 4 TAM resist. FULV 5 5 IA 5 500 mg FULV 23,4 Naive/ IA TAM sens. 10 TAM 6 0 5 10 15 20 25

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