ΗΕR2+ Μεηαζηαηικός καρκίνος μαζηού Παροσζίαζη και ανάλσζη περιζηαηικού

ΗΕR2+ Μεηαζηαηικός καρκίνος μαζηού Παροσζίαζη και ανάλσζη περιζηαηικού ΚΟΝΔΡΑ ΜΑΡΙΑ ΔΙΓΙΚΔΥΟΜΔΝΗ ΠΑΘΟΛΟΓΙΚΗΣ ΟΓΚΟΛΟΓΙΑΣ Β Παλεπηζηεκηαθή Παζνινγηθή Κιηληθή Ιππνθξάηεην Γεληθό Ννζνθνκείν Αζελώλ

Παροσζίαζη περιζηαηικού Γπλαίθα 56 εηώλ δηαγλώζζεθε κε πνξνγελέο δηεζεηηθό Ca καζηνύ st III ER+/ PgR-/HER2+3 (ξηδηθή ηξνπνπoηεκέλε καζηεθηνκή θαη ζύζηνηρνο ιεκθαδεληθόο θαζαξηζκόο) a. doxorubicin/cyclophosphamide x4 θαη docetaxel x4 /trastuzumab x1 έηνο b. ΑΚΘ c. ΑΙ Follow-up: 3 έηε κεηά από ηελ ζπκπιήξσζε 1 έηνπο trastuzumab,εκθαλίδνληαη ιεκθαδεληθέο κεηαζηάζεηο (ηξάρεινο θαη κεζνζσξάθην)

1. Γσναίκα με HER2+ MBC (σποηροπή μεηά από adjuvant transtuzumab) Πνηά ζεξαπεπηηθή επηινγή ζα ζπζηήλαηε; A. Trastuzumab + ΧΜΘ B. Trastuzumab + Οξκνλνζεξαπεία C. Lapatinib + capecitabine D. Μνλνζεξαπεία κε νξκνλνζεξαπεία E. Μνλνζεξαπεία κε Trastuzumab

...παροσζίαζη περιζηαηικού... Η αζζελήο ππνβάιιεηαη ζε βηνςία ηξαρειηθνύ ιεκθαδέλα θαη ε αλνζνηζηνρεκεία δείρλεη αξλεηηθνύο νξκνληθνύο ππνδνρείο (ER/PgR) θαη HER2 +3 Λακβάλεη 6 θύθινπο κε docetaxel/trastuzumab θαη επηηπγράλεη CR ελώ ζπλερίδεη ζεξαπεία ζπληήξεζεο κε trastuzumab Follow -up: 2 έηε κεηά εκθαλίδεη πλεπκνληθέο κεηαζηάζεηο Πξνζηίζεηαη vinorelbine ζην transtuzumab θαη επηηπγράλεη πάιη CR Follow-up: 9 κήλεο κήλεο κεηά εκθαλίδεη επαηηθέο κεηαζηάζεηο

2. Γσναίκα με HER2+ MBC και πρόοδο νόζοσ μεηά από Trastuzumab Πνηά ζεξαπεπηηθή επηινγή ζα ζπζηήλαηε ζε απηό ζηάδην; A. Lapatinib + capecitabine B. Lapatinib + trastuzumab C. trastuzumab + ΧΜΘ D. Σπλδπαζκέλε ΧΜΘ E. Μνλνζεξαπεία κε lapatinib

EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with T4 lesion and unlimited previous therapies* Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m 2 /day on Days 1-14 every 21 days Primary endpoint: TTP Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days Secondary endpoints: OS, PFS, ORR *No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant). Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

Cumulative Progression Free (%) Cumulative Progression Free (%) Lapatinib + Capecitabine in HER2+ MBC: TTP 100 TTP With 1 Previous Trastuzumab Regimen 100 TTP With > 1 Previous Trastuzumab Regimen 80 60 Capecitabine Lapatinib + capecitabine 80 60 Capecitabine Lapatinib + capecitabine 40 40 20 20 0 0 20 40 60 80 Wks 0 0 20 40 60 80 Wks Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2 positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc. Cameron D, et al. Oncologist. 2010;15:924-934.

Lapatinib + Capecitabine in HER2+ MBC: Efficacy Result Capecitabine (n = 201) Capecitabine + Lapatinib (n = 207 ) HR P Value Median TTP, wks [1] 18.6 31.3 0.50 <.001 OS, wks [1] 56.6 71.4 0.79.077 ORR, % [2] 13.9 23.7 --.017 Brain mets as site of first progression,* n (%) [2] n=198 in 2008 study. *Exploratory analysis. 13 (6) 4 (2) --.045 1. Cameron D, et al. Oncologist. 2010;15:924-934 2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.

EGF104900 Phase III Study: Dual HER2 Blockade in MBC Patients with HER2+ (FISH/IHC3+) MBC and progression on anthracycline, taxane, and trastuzumab Crossover allowed to lapatinib + trastuzumab if progression after at least 4 weeks on therapy Lapatinib 1500 mg/day PO (n = 148) Lapatinib 1000 mg/day PO + Trastuzumab 4 mg/kg 2 mg/kg IV weekly (n = 148) Primary endpoint: PFS Secondary endpoints: OS, ORR, clinical benefit Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks Patients with progression after 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab Steady state of single-agent lapatinib occurs at approximately 7 days Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

Lapatinib ± Trastuzumab in MBC: Efficacy Outcome Lapatinib, % (95% CI) (n = 145) Lapatinib/ Trastuzumab, % (95% CI) (n = 146) OR (95% CI) P Value ORR* 6.9 (3.4-12.3) 10.3 (5.9-16.4) 1.5 (0.6-3.9).46 Clinical benefit rate 12.4 (7.5-18.9) 24.7 (17.9-32.5) 2.2 (1.2-4.5).01 *Confirmed CR + PR. Confirmed CR + PR + stable disease 6 mos. Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

Lapatinib ± Trastuzumab in MBC: PFS Outcome Lapatinib (n = 145) Lapatinib/ Trastuzumab (n = 146) HR (95% CI) 6-mos PFS, % 13 28 0.73 (0.57-0.93) P Value.008 Progressed or died, n 128 127 -- -- Median PFS, wks 8.1 12.0 -- -- Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

Alive without Progression (Cumulative %) EGF104900: OS With Lapatinib ± Trastuzumab in MBC (ITT Population) 100 OS Outcome L (n = 145) L + T (n = 146) 80 80% Died, n (%) 113 (78) 105 (72) Median, mos 9.5 14 60 70% 56% HR (95% CI) 0.74 (0.57-0.97) Log-rank P value.026 6 Month OS 40 41% 20 L L + T 12 Month OS 0 0 5 10 15 20 25 30 35 Patients at Risk, n Mos From Randomization L 148 121 88 64 43 25 1 L + T 148 102 65 47 28 13 Blackwell KL, et al. SABCS 2009. Abstract 61.

Lapatinib ± Trastuzumab in Heavily Pretreated MBC: Selected Adverse Events Adverse Event (All Grades), % Lapatinib + Trastuzumab (n = 149) Lapatinib (n = 146) P Value Nausea 28 28 NS Fatigue 21 19 NS Diarrhea* 60 48.03 Rash 22 29 NS *7% grade 3/4 events on each treatment arm. Cardiac Events Total no. patients with events Symptomatic Lapatinib + Trastuzumab (n = 149) 8 3 Lapatinib (n = 146) Therapy related 8 3 Deaths 1 0 Defined by 20% LVEF drop relative to baseline and below institution s lower limits of normal. 2 patients had > 1 occurrence. Cause of death: pulmonary thromboembolism. Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130. 3 2

Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial Patients with progressive MBC or LABC, HER2 overexpression, previous trastuzumab within 6 wks, and LVEF 50 (N = 156*) Primary endpoint: TTP Trastuzumab 6 mg/kg every 3 wks + Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Secondary endpoints: OS, ORR, safety *Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

Probability of PFS Probability of OS BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC 1.0 PFS 1.0 OS 0.8 0.6 X XH Censored Log-rank P =.0338 0.8 0.6 X XH Censored Log-rank P =.2570 0.4 0.4 0.2 0.2 0 0 10 20 30 40 Mos Pts at Risk, n Pts at Risk, n X 74 40 15 8 5 3 2 1 1 X 74 66 50 33 XH 77 55 29 12 4 3 1 1 1 XH 77 68 59 47 Reprinted with permission. 2008 American Society of Clinical Oncology. All rights reserved. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009. 0 0 10 20 30 40 Mos 21 27 10 15 3 6 3 1 2 1

Trastuzumab Beyond Progression in HER2+ MBC: Effect of Previous Treatment Previous treatments (N = 156) First-line taxane + trastuzumab (n = 111) Trastuzumab alone or with other first-line chemotherapy (n = 42) Taxane + trastuzumab as adjuvant therapy (n = 3) Outcome Capecitabine Capecitabine + Trastuzumab HR P Value Median TTP, mos 5.6 8.2 0.69.034 Median OS, mos 20.4 25.5 0.76.26 ORR, % 27.0 48.1 --.012 CBR,* % 54.1 75.3 --.0068 *CBR: CR + PR + SD > 24 wks. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

2. Γσναίκα με HER2+ MBC και πρόοδο νόζοσ μεηά από Σrastuzumab Πνηά ζεξαπεπηηθή επηινγή ζα ζπζηήλαηε ζε απηό ζηάδην; A. Lapatinib + capecitabine (πξνηηκόκελε) B. Lapatinib + trastuzumab (ινγηθή) C. Σπλδπαζκέλε ΧΜΘ D. Μνλνζεξαπεία κε lapatinib E. trastuzumab + ΧΜΘ

...παροσζίαζη περιζηαηικού... Η αζζελήο έιαβε lapatinib/capecitabine κε απνηέιεζκα ηε ζηαζεξνπνίεζε ηεο λόζνπ Follow-up: 6 κήλεο κεηά εκθαλίδεη PD ζηηο επαηηθέοθαη πλεπκνληθέο εληνπίζεηο

3. Γσναίκα με HER2+ MBC και σποηροπή μεηά από Transtuzumab και Lapatinib Πνηά ζεξαπεπηηθή επηινγή ζα ζπζηήλαηε ζε απηό ζηάδην; A. Lapatinib/trastuzumab B. Έληαμε ζε θιηληθή κειέηε κε λέν αληη-her2+ παξάγνληα γηα ηνλ θαξθίλν ηνπ καζηνύ C. Trastuzumab + bevacizumab D. Lapatinib/trastuzumab + ΧΜΘ E. Trastuzumab +ΧΜΘ

Trastuzumab-DM1: Novel Antibody-Drug Conjugate Target expression: HER2 Monoclonal antibody: Trastuzumab Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent DM1 MCC Linker: SMCC Systemically stable T-DM1 Average drug:antibody ratio 3.5:1

Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC PD Trastuzumab + Taxane (n = 364) Patients with HER2+, previously untreated MBC (N = 1092) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) Primary endpoints: PFS as assessed by IRF, AEs Superiority design with a noninferiority analyses Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR ClinicalTrials.gov. NCT01120184.

EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC PD or unacceptable toxicity Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane and trastuzumab (N = 980) T-DM1 q3w (n = 490) Lapatinib + Capecitabine q3w (n = 490) Primary endpoint: PFS by IRF, OS, safety Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment ClinicalTrials.gov. NCT00829166.

Proportion Progression Free T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS 1.0 0.8 0.6 Capecitabine/lapatinib T-DM1 Median, Mos 6.4 9.6 Stratified HR: 0.650 (95% CI: 0.55-0.77; P <.0001) Events, n 304 265 0.4 T-DM1 0.2 Capecitabine/ lapatinib 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Blackwell KL, et al. ASCO 2012. Abstract LBA1. Used with permission.

Proportion Surviving T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): OS (Interim Analysis) 1.0 0.8 0.6 77.0% Median, Mos Events, n Capecitabine/lapatinib 23.3 129 T-DM1 NR 94 Stratified HR: 0.621 (95% CI: 0.48-0.81; 84.7% P =.0005) Efficacy stopping boundary P =.0003 or HR: 0.617 65.4% T-DM1 0.4 0.2 47.5% Capecitabine/lapatinib 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Blackwell KL, et al. ASCO 2012. Abstract LBA1. Used with permission.

Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex I Pertuzumab I Dimerization domain II II III III Trastuzumab IV IV Inhibits HER2 dimerization with other HER family receptors (particularly HER3) Activates ADCC Inhibits multiple HER-mediated signaling pathways Hubbard SR. Cancer Cell. 2005;7:287-288. Activates ADCC Inhibits HER-mediated signaling pathways Prevents HER2 domain cleavage

CLEOPATRA Phase III Trial: Trastuzumab + Docetaxel ± Pertuzumab in HER2+ MBC Patients with HER2+ MBC and no previous treatment for metastatic disease (N = 808) Docetaxel 75 mg/m 2 + Trastuzumab 8 mg/kg 6 mg/kg + Placebo q3w Docetaxel 75 mg/m 2 + Trastuzumab 8 mg/kg 6 mg/kg + Pertuzumab 840 mg 420 mg q3w Primary endpoint: PFS (IRF evaluation) Secondary endpoints: OS, incidence of CHF and LVEF events, safety ClinicalTrials.gov. NCT00567190.

PFS (%) CLEOPATRA: Independently Assessed PFS 100 80 Ptz + T + D: median 18.5 mos Pbo + T + D: median 12.4 mos 60 40 20 (HR: 0.62; 95% CI: 0.51-0.75; P <.001) Pts at Risk, n Ptz + T+ D Pbo + T + D 0 0 5 10 15 20 25 30 35 40 Mos 402 406 345 311 267 209 139 93 Stratified by previous treatment status and region Baselga J, et al. N Engl J Med. 2012;366:109-119. 83 42 32 17 10 7 0 0 0 0

mtor Inhibition May Overcome Trastuzumab Resistance IGF-1R EGFR/HER2 Nutrients Increased signaling through IGF-1R LKB1 AMPK PI3K PTEN AKT TSC1 TSC2 RHEB Truncated HER2 Constitutive PI3K/AKT activation Absent or low PTEN Elevated AKT or pakt Growth & proliferation Angiogenesis mtor Cell metabolism mtor inhibitor Downstream inhibition with mtor inhibitor counters these resistance mechanisms Synergy of mtor inhibition and trastuzumab in vitro and in vivo Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496. Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.

BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab Everolimus in HER2+ MBC Stratification by previous adjuvant or neoadjuvant trastuzumab and presence of visceral metastases 28-day cycle Patients with HER2- overexpressing, unresectable locally advanced or metastatic breast cancer, no previous trastuzumab or chemotherapy within 12 mos for advanced disease (N = 717) 2:1 Everolimus 10 mg/day PO + Paclitaxel 80 mg/m 2 on Days 1, 8, 15 + Trastuzumab 4 mg 2 mg/kg on Days 1, 8, 15, 22 Paclitaxel 80 mg/m 2 on Days 1, 8, 15 + Trastuzumab 4 mg 2 mg/kg on Days 1, 8, 15, 22 + Placebo PO daily Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, PK, biomarkers ClinicalTrials.gov. NCT00876395.

AVEREL Phase III Study: Trastuzumab ± Bevacizumab in 1st-line HER2+ MBC Locally recurrent or MBC, HER2+ No previous chemotherapy for MBC RT for metastatic bone pain relief only (N = 407) Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w + Docetaxel 100 mg/m 2 IV q3w Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w + Bevacizumab 15 mg/kg IV q3w + Docetaxel 100 mg/m 2 IV q3w Primary endpoint: PFS Secondary outcomes: OS, OR, DR, TTF, QoL, safety/tolerability ClinicalTrials.gov. NCT00391092.

AVEREL: PFS, Interim OS Analysis, and Response Outcome, Mos Median PFS (Investigator assessment) Median PFS (IRC assessment) T + Doc + Bev (n = 216) T + Doc (n = 208) 16.5 13.7 16.8 13.9 Median OS 38.5 38.3 ORR similar between T + Doc + Bev and T + Doc in investigator assessment (74.3% vs 69.9, respectively; P =.3492) ORR significantly higher with addition of Bev in IRC assessment (76.5% vs 65.9, respectively; P =.0265) HR (95% CI) 0.82 (0.65-1.02) 0.72 (0.54-0.94) 1.01 (0.74-1.38) (unstratified) 0.94 (0.68-1.30) (stratified) P Value.0775.0162.9543.7078 Gianni L, et al. SABCS 2011. Abstract S4-8.

Targeted Agents for HER2+ Breast Cancer Bevacizumab phase III VEGF Trastuzumab T-DM1 phase III Sunitinib phase II VEGFR EGFR HER2 Pertuzumab phase III Akt/PKB P P P P PI3-K P P P P Everolimus phase III mtor 4E-BP1 PTEN Lapatinib phase III Neratinib phase III S6K1 elf-4e Gefitinib phase II Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis

3. Woman With HER2+ MBC, Relapse Following Transtuzumab and Lapatinib Πνηά ζεξαπεπηηθή επηινγή ζα ζπζηήλαηε ζε απηό ζηάδην; A. Lapatinib/trastuzumab (ινγηθή) B. Έληαμε ζε θιηληθή κειέηε κε λέν αληη-her2+ παξάγνληα γηα ηνλ θαξθίλν ηνπ καζηνύ (πξνηηκόκελε) C. Trastuzumab + bevacizumab D. Lapatinib/trastuzumab + ΧΜΘ E. Trastuzumab +ΧΜΘ (ινγηθή)