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 22 atualização tratamento sistêmico Presentation Transcript

  • HER2 negativo Atualização Tratamento Sistêmico
  • Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona  Manutenção (?) Hormonioterapia  Faslodex na primeira linha  Everolimus  Duplo bloqueio hormonal (?)
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • Tratamento da Doença Metastática QT Doença Metastática  Paclitaxel vs Nab-Paclitaxel vs Ixabepilona  Manutenção (?) Hormonioterapia  Faslodex na primeira linha  Everolimus  Duplo bloqueio hormonal (?)
  • ⌫ “Virgem” de Tratamento⌫ Tamoxifen sensível (TAM sens.)⌫ Tamoxifen resistente (TAM resist.)⌫ IA resistente (IA resist.)
  • Tamoxifeno (TAM)Inibidor da Aromatase (IA)Fulvestranto (Fulv)
  • 80706050 45.640 32.6 32.9 32 31.230 21.1 2120 1710 ANAST ANAST LETRO EXEMEST TAM IA
  • 8070 66.2 59.160 55.5 56.2 5050 45.6 41.740 38302010 ANAST ANAST LETRO EXEMEST TAM IA
  • 12 11.1 9.910 9.4 8.2 8.28 5.6 6 5.86420 ANAST ANAST LETRO EXEMEST TAM IA
  • 8070 6260 54.35040 31.6 33.9302010 RO BC TAM FULV
  • 1210 8.38 6.86420 TAP TAM FULV
  • ⌫ “Virgem” de Tratamento⌫ Tamoxifen sensível (TAM sens.)⌫ Tamoxifen resistente (TAM resist.)⌫ IA resistente (IA resist.)
  • 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 22.8 500 mg 10.2% 45.6% 6.5 13.9 22,8*HR=0.80; p=0.006
  • 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 EXEMEST FULV
  • Exemestane & Fulvestrant 3,7 months
  • IGF-1R, EGFR ER RAS PI3KE ER AKT RAF TSC2 TSC1 MEK mTOR ERK E ER Cell Proliferation
  • 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
  • BOLERO2 study RR CB (%) TTP (%) (m)EXEMESTANE 0,4% - 4.1EXE + Everolimus 9.0% - 10,6
  • 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)
  • 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
  • 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