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Focus sul carcinoma della mammella: Ruolo delle antracicline

Focus sul carcinoma della mammella: Ruolo delle antracicline. La chemioterapia della malattia metastatica: stato dell'arte. Consorzio Interuniversitario Nazionale per la Bio-Oncologia. Prof. Corrado Ficorella Medical Oncology San Salvatore Hospital University of l’Aquila.

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Focus sul carcinoma della mammella: Ruolo delle antracicline

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  1. Focus sul carcinoma della mammella: Ruolo delle antracicline La chemioterapia della malattia metastatica: stato dell'arte Consorzio Interuniversitario Nazionale per la Bio-Oncologia Prof. Corrado Ficorella Medical Oncology San Salvatore Hospital University of l’Aquila

  2. Goals of CT for advanced breast cancer • Relieve symptoms associated with advanced cancer, such as: pain, fatigue, or dispnea • Prevent symptomatic progression of tumor • Prolong survival • Enhance quality of live • Make advanced breast cancer a “chronic” condition

  3. Treatment of HER2-Negative MBC • • Use of CT over OT • • Single vs combination therapy • • What chemotherapy options exist beyond first-line • treatment ? • • Continued treatment vs palliative care

  4. Chemotherapy in Hormone-Receptor PositiveMetastatic Breast Cancer (MBC) •First-line endocrine therapygenerally used in the absence of: Rapid clinical progression HER2-positive disease (a,b) Life-threatening visceral metastasis • Predicted endocrine responsiveness Recent literature suggest HER2-targeted therapy + endocrine therapy as reasonable option (trastuzumab + anastrozole; lapatinib + letrozole) a) Kaufman B.JCO 2009 b) Johnston S. JCO 2009

  5. Sistemic treatmentof Recurrent or stage IV Disease: NCCN Guidelines

  6. Preferred CT regimens for Recurrent/MBC • Preferred single agentsOther Single Agents • • Anthracyclines • Cyclophosphamide • - Doxorubicin • Mitoxantrone • - Epirubicin • Cisplatin • - Pegylated liposomal doxo • Etoposide • • Taxanes • Vinblastine • - Paclitaxel • Fluorouracil • - Docetaxel • Ixabepilone • - Albumin-bound paclitaxel Preferred agents with Bevacizumab • • Anti-metabolites • Paclitaxel • - Capecitabine • - Gemcitabine • • Other microtubule inhibitors • - Vinorelbine • - Eribulin NCCN Guideline Version 2.2011

  7. Preferred CT regimens for Recurrent/MBC • Preferred Chemotherapy Preferred First-Line Agents for • Combinations HER2-Positive Disease • • CAF/FAC • Trastuzumab with: • • FEC - Paclitaxel ± carboplatin • • AC - Docetaxel • • EC - Vinorelbine • • AT - Capecitabine • • CMF Preferred Agents for Trastuzumab- • • Docetaxel/capecitabine Exposed HER2 Positive Disease • • Gemcitabina/paclitaxel (GT) • Lapatinib + capecitabine • • Trastuzumab + other first-line agents • • Trastuzumab + capecitabine • • Trastuzumab + lapatinib (without Cytotoxic) • NCCN Guideline Version 2.2011

  8. Single Agent vs Combination Therapy:Intergroup Phase III Trial (E1193) Doxorubicin and Paclitaxel and the Combination as Front-Line CT for MBC. • • PTS randomly assigned to: • doxorubicin (A) vs paclitaxel (T) vs combination (AT) • • Crossover permitted to the other monotherapy • • RR: 36% (A), 34% (T), 47% (AT) (A vs AT p=.007; T vs AT p= .004) • •TTF: 5.8 mo, 6.0 mo, 8.0 mo(A vs AT p= .003; T vs AT p=.009) • • OS: 18.9 mo (A), 22.2 mo (T), 22.0 mo (AT); p= not significant • • RR: pts crossing A to T 20% p= not significant • pts crossing T to A 22% • OS similar when crossover permitted • Sledge GW.JCO.2003;21:588

  9. Intergroup Phase III Trial (E1193) Doxorubicin and Paclitaxel and the Combination as Front-Line CT for MBC. Subsets Benefiting from Combination Factors Associated with Overall Survival: Multivariate Analysis Factor RR P Er neg 1.7 .0001 Visceral dominant 1.4 .004 3 or more sites 1.4 .005 1-24 mo DFI 1.3 .03 Prior systemic therapy 1.1 .03 Sledge GW.JCO.2003;21:588

  10. Single agent VS Combination Therapy • • Meta-analysis of 43 trials, ~ 10.000 women with MBC • • Combinations regimens associated with • - Modest improvement in OS (HR 0.88; P<.00001) • - Favorable time-to-progression (HR 0.78; relative RR 1.29) • - Much more toxicity • Carrik S, et al. Cochrane Database Syst Rev. 2009

  11. Single agent VS Combination Therapy • • Weakness of combination trial designs: • - Difficult to obtainhomogeneous population • - Need for dose reductions to deliver combination regimens • - Survival advantage not seen in most individual trials; • when seen, often first line setting • “There is an unresolved question regarding the benefit of combination therapy vs single agents given sequentially” • Carrik S, et al. Cochrane Database Syst Rev. 2009

  12. Duration of CT for MBC: A Systematic Review and Meta-Analysis of Randomized Clinical TrialsGennari A. JCO 2011 • 11 randomizedclinicaltrials (2.269 pts) comparingdifferent CT • durations in the first-line treatment • Longerfirst-line CT durationresulted in to: • Marginallylonger OS: HR 0.91; p=.046 • Substantiallylonger PFS: HR 0.64; p< .001

  13. Bevacizumab 13 Rossari et al. J Oncol 2012;2012:417673

  14. Bevacizumab Rossari et al. J Oncol 2012;2012:417673 14

  15. Bevacizumab Rossari et al. J Oncol 2012;2012:417673 15 15

  16. A meta-analysis of OS data from three randomized trials of Bev. and first-line CT as treatment for patients with MBC. (E2100, AVADO, RIBBON-1) Pooled Analysis Primary endpoint: PFS Secondary endpoint: OS (trials not designed to show an OS benefit) 1 yr survival rate : 76.5% (control) vs 81.6% ( BV+chemo) p=0.003 O’Shaughnessy et al. JCO vol. 28, article 15s, 2010, abstract no. 1005 16

  17. Quest for Biomarkers in HER2-Negative MBC: Results for Bevacizumab from phase III Trials E2100 study - VEGF-2578 AA genotype: superior mOS (HR 0.58; P=.023) - VEGF-1154 A allele: superior mOS (HR 0.62; P=.001) AVADO study - 7.5 mg/kg Bev • Higher plasma VEGF levels: longer PFS (HR 0.52; P=.01) • Higher plasma VEGFR2 levels: longer PFS (HR 0.46; P=.03) - 15 mg/kg Bev • Higher plasma VEGF levels: longer PFS (HR 0.49; P=.08) Schneider BP. JCO.2008 Miles DW.SABCS 2010

  18. Review of Treatments in the third-line and Beyond • …evidence-based medicine provides some support for the use of • second-line and, to a lesser degree and in selected cases, third-line CT • in MBC • Beyond third-line treatment, however, there are no data that suggest a • clear benefit for such a therapeutic approach • Cardoso F.Ann Oncol.2002 - Review • Dufresne and colleagues demonstrated that 40% of patients achieve • disease control for more than 6 months with third-linechemotherapy • Dufresne. BCRT. 2008

  19. ORR:Ind. rev. (12% vs 5%) – Invest.rev. (13% vs 7%) P=.002 - .028 PFS: Ind. rev. (3.7 vs 2.2 mo) – Invest.rev. (3.6 vs 2.2 mo) p=.14 - .002 OS: 13,12 mo vs 10,6 mo; HR 0.81, P .041) “Primary endpoint” • Synthetic analogue of halichondrin: Bloks microtubule polymerization and forms nonfunctional tubulin aggregates 19 Cortes et al. Lancet 2011; 377: 914–23

  20. EMBRACE: Pros and Cons • • Limitations: • - not a blinded study • - TPC arm cuold receive treatments they have been exposed to previously • - Supportive care option, unfair comparison • - Bias regarding choice of therapy beyond progression • • Strengths • - heavily pretreated patient population (median 4 prior regimens) • - treatment choices reflect real-world-world options • - powered to look for OS with 2-sided log-rank test

  21. nab-Paclitaxel/ABI-007: Paclitaxel bound to nanoparticles of albumin, naturally occurring vehicle for hydrophobic molecules ORR: 33% vs 19% p=.001 Nab: 260mg/mq PFS: 23 vs 17 weeks p=.006 Paclitaxel: 175 mg/mq Neutropenia G4: 9% vs 22% p<.001 (despite 49% higher paclitaxel dose) Sensory neuropathy G3: 10% vs 2% p<.001(reversible, short lived) No hypersensivity reactions Administration time 30 m (vs 3 h), no premedication 21

  22. CALGB 40502 – NCCTG N063H – CTSU 40502Open-Label Phase III Trial of First-Line Therapy for mBC:Nab-Paclitaxel 150/weekly + Beva 10mg/kg q 2 wks vsPaclitaxel 90/weekly + Beva 10 mg/kg q 2 wks • PFS • Paclitaxel (283): 10.6 mo vs Nab-Paclitaxel (271): 9.2 mo • HR 1.19; P = .12 • OS • Paclitaxel (283): 26 mo vs Nab-Paclitaxel (271): 27 mo • HR 1.02; P= .92 • Adverse Events G≥3 Nab Pac P • Hematologic 51% 21% <.0001 • Nonhematologic 60% 44% .0002 • Neuropathy 25% 16% .012 • Rugo et, al.ASCO 2012

  23. Nab-Paclitaxel vs Docetaxel: First-line Phase II Randomized Study PFS: (Nab 150/W)13 mo vs 7.5 mo (Docetaxel/100 q3w) (p=.0065) ORR: 45% (100/w), 49%(150/w) vs 35%(docetaxel/100 q3w) not significant No difference in PFS e OS: Nab 300 q3w vs docetaxel (100 q3w) G3/4 fatigue, neutropenia, febrile neutropenia less frequent in all nab-paclitaxel arms. 23

  24. Malattia HER2-positiva Ian Krop, SABCS 2011

  25. Pivotal Combination Trial of First-Line Chemotherapy ± Trastuzumab in MBC: Efficacy/Toxicity CT CT + T p value ORR 32% 50% <.0001 TTP 4.6 mo 7.4 mo <.0001 Median OS 20.3 mo 25.1 mo .046 1 year OS 68% 79% .008 CardiacDysfunction AC: 8% AC-T: 27% P: 1% P-T: 13% Slamon et al. NEJM 2001 Mar 15;344(11):783-92

  26. Trastuzumab: PFS Slamon et al. NEJM 2001 Mar 15;344(11):783-92 26

  27. Trastuzumab: OS Slamon et al. NEJM 2001 Mar 15;344(11):783-92

  28. CardiacDisfunction (CD) in the TrastuzumabClinicalTrialsExperienceRetrospectivereviewfromsevenphase II/III trastuzumabclinicaltrialsbyIndependentCardiacReview and EvaluationCommittee (CREC)Seidman A,et al. JCO 2002

  29. Cardiac Disfunction (CD) in the Trastuzumab Clinical Trials ExperienceSeidman A,et al. JCO 2002 • Retrospective review from seven phase II/III trastuzumab clinical trials by Independent Cardiac Review and Evaluation Committee (CREC) • Study Treatment Prior Antrac. CD% NYHA Class III/IV % • H0551g Trastuzumab ? 7 4 • H0552 Trast + CDDP ? 3 3 • H0648g Trast + AC 1% 27 16 • AC 1% 8 4 • Trast + Paclitaxel 91% 13 2 • Paclitaxel 97% 1 1 • H0649g Trastuzumab ? 5 4 • H0650g Trastuzumab ? 3 2 • H0659g Trast ± other CT ? 6 3 • H0693g Trast ± other CT ? 4 3 • Most Trastuzumab treated pts developing CD were symptomatic (75%) and most improved • with standard treatment for CHF (79%)

  30. Trastuzumab Trastuzumab hadimostrato una significativa attività in combinazione conmolti agenti chemioterapici

  31. In patients with MBC, loss of response to HER2-targeted therapy is the norm: Mechanism of resistance • • Barriers to antibody binding • Increased expression of p-95-HER2, Epitope masking • • Upregulation of downstream signaling • PTEN loss, PI3K muts, Increased Akt kinase activity • • Crosstalk • Increased IGF-IR signaling, Continued signaling from HER2/HER3 • heterodimers, HER3 or EGFR upregulation, Increased c-Met • expression, Upregulation of ER signaling, Increased AXL signaling • • Failure of ADCC • Fc receptor polymorphisms

  32. HER2 Therapy: Horizons and Advances Optimizing the use of currently available agents, novel agents (Pertuzumab), trastuzumab emtansine conjugate, novel TKI (Afatinib, Neratinib) Tsang et al. Br J Cancer 2012 Jan 3;106(1):6-13

  33. Trastuzumab Beyond Progression Primary end-point TTP Secondary endpoints ORR, OS Duration of response Safety Von Minckwitz et al. JCO 2009 Apr 20;27(12):1999-2006

  34. Trastuzumab Beyond Progression TTP 8,2 mo vs 5,6 mo (p 0.0338) OS 25,5 mo vs 20,4 mo (p 0,257) ORR 48,1% vs 27% (p 0,0115) ESMO Guidelines: evidence suggests continuing anti-HER2 therapy for as long as possible (Ann Oncol 2012) Von Minckwitz et al. JCO 2009 Apr 20;27(12):1999-2006

  35. mBC: Lapatinib ± Trastuzumab (CT-free regimen) Blackwell et al. 2010 Mar 1;28(7):1124-30

  36. mBC: Lapatinib ± Trastuzumab TTP 12 weeks vs 8,1 weeks (p 0.008) OS 51,6 weeks vs 39 weeks (p 0.106) ORR 10,3% vs 6,9% (p 0,46) CBR 24,7% vs 12,4% (p 0.01) Median no. Prior CT regimens: 4 (L) , 5 (L+T); Prior trastuzumab regimens: 3 (L), 3 (L+T) Dual Inhibition of HER2 is both safe and effective Blackwell et al. 2010 Mar 1;28(7):1124-30

  37. Overall Survival Benefit With Lapatinib + Trastuzumab for Patients with HEGFR2-Positive MBC: Final Results From The EGF104900 Study Kimberly L, et al. JCO 2012;30:2585-92 • PFS 11.1 weeks vs 8,1 weeks (HR, 0.74; p= .011) • OS 14 mo vs 9.5 mo (HR, 0.74; p= .026) * • (*despite the fact that > 50% of pts crossed to combination therapy) • Median no. Prior CT regimens: 4 (L), 5 (L+T) • Median Prior trastuzumab regimens: 3 (L), 3 (L+T) • Continuing Trastuzumab Beyond Progression either + Ct or with • lapatinib/trastuzumab combination is both safe and effective

  38. Progressive HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab (trastuzumab for metastatic disease) No prior capecitabine Primary end-point TTPSecondary endpoints ORR, OSSafety Lapatinib 1250 mg/die continuously + Capecitabine 2000 mg/mq gg1-14 q21 Capecitabine 2000 mg/mq gg1-14 q21 Geyer et al. NEJM 2006 Dec 28;355(26):2733-43

  39. TTP 8,4 mo vs 4,4 mo (p <0.001) OS 36 events vs 35 events (p 0,72) ORR 22% vs 14% (p 0,09) Geyer et al. NEJM 2006 Dec 28;355(26):2733-43

  40. Paclitaxel + Lapatinib vs Paclitaxel alone for first-line treatment of mBC

  41. MA.31: Taxane based CT with Lapatinib or Trastuzumab as First-Line Treatment for HER2+ mBC • HER2 mBCpatients • Trastuzumab + Taxane x 24 weeks➜ Trastuzumabuntil PD (TTAX/T) • VS • Lapatinib + Taxane x 24 weeks ➜ Lapatinibuntil PD (LTAX/L) • PFS (centrallyConfirmed HER2+ Analysis) • Median PFS TTAX/T = 13.7 mo • Median PFS LTAX/L = 9.0 mo • HR = 1.48; P = .003 • Gelmon K. ASCO 2012

  42. Pertuzumab: “HER Dimerization Inhibitor” FDA-approved + trastuzumab and CT for treatment-naive, HER2-positive, MBC World JCO 2011 February 10; 2(2): 125-134

  43. Pertuzumab ± Trastuzumab in MBC progressing during prior trastuzumab therapy (Phase II Study) * Ptsprogressing while takingpertuzumab Adverse events mild to moderate Baselga J,et al.JCO 2010;28:1138-1144 Cortés J, et al.JCO 2012;30:1594-1600

  44. Phase III trial CLEOPATRA Baselga J, et al. New Engl J Med2012;366:109-19

  45. CLEOPATRA: Docetaxel + Trastuzumab ± Pertuzumab (First-line treatment for MBC) Docetaxel (75mg) + Trastuzumab + placebo First-line HER2-positive MBCI Docetaxel (75mg) + Trastuzumab + Pertuzumab N = 808 Baselga J, et al. New Engl J Med2012;366:109-19

  46. Pertuzumab:phase III studies (CLEOPATRA) Baselga J, et al. NEJM2012;366:109-19

  47. Pertuzumab: phase III study (CLEOPATRA) PFS 18,5 mo vs 12,4 mo (HR, 0.62; p <0.001) OS interim analysis: 96 events vs 69 (HR,0.64; P=.0053) ORR 80,2% vs 69,3% (p 0,001) safety slight increase in Diarrhea, G≥3: 7.9% vs 5% and Febrile neutropenia, G≥3: 13.8% vs 7.6%) Left ventr. syst. dysf. G≥3 : 1.2% (PTD) vs 2.8% (TD)

  48. Trastuzumab Emtansine (T-DM1) Nel T-DM1 il Trastuzumab è legato ad un potente agente citotossico (emtansine) Il DM1 è un inibitore dei microtubuli da 20 a 100 volte più potente della vincristina A ciascun anticorpo si legano una media di 3,5 molecole di DM1 T-DM1 si lega a HER2 con un’affinità simile a quella del Trastuzumab

  49. T-DM1: the antibody delivers a cytotoxic agent right to the cancer cell

  50. Trastuzumab-DM1:single-arm Phase II TrialsBurris HA. JCO 2011Krop IE. JCO 2012

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