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Christian Jackisch Head of the Department of Gynaecology at Klinikum Offenbach Senior Lecturer at Philipps University of Marburg, Germany Chairman of the Breast Centre at Klinikum Offenbach Past deputy director of the Department of Gynaecology at the University Hospital in Marburg Long-standing member of national and international steering committees for breast and ovarian cancer trials Klinikum Offenbach Member of the German Task Force developing national guidelines for the diagnosis and treatment of breast cancer Published more than 100 papers and book chapters on obstetrics and gynaecology Philipps University of Marburg A decade of success: trastuzumab in HER2-positive metastatic breast cancer Christian Jackisch Klinikum Offenbach Germany Presentation objectives Discuss the central role of trastuzumab in the treatment of HER2-positive MBC, in the context of other available treatment options – review the evidence base to support currently available trastuzumab-based regimens Consider the potential benefits to our patients of the introduction of new trastuzumab-based regimens – evaluate the latest evidence for selected novel therapeutic approaches Introduce pertuzumab as the first in a new class of anti-HER2 therapy HER2 = human epidermal growth factor receptor 2 MBC = metastatic breast cancer HER2-positive disease HER2 expression in breast cancer HER2 amplification leads HER2 is a transmembrane protein and part to HER2 over-of the HER family of growth factor receptors expression Gene or DNA amplification and protein overexpression are indicators of HER2 status Normal HER2 overexpression HER2 leads to expression tumour proliferation Binding of trastuzumab to HER2 HER2 protein levels on the surface of HER2-positive tumour cells are several orders of magnitude greater than on adjacent normal breast epithelium1 1Lewis GD, et al. Cancer Immunol Immunother 1993;37:255–63 Role of HER2 in breast cancer 20–30% of patients with breast cancer have HER2-positive disease1,2 HER2-positive status is associated with poor prognosis, including reduced relapse-free and overall survival (OS)3,4 – suggests key role for HER2 in pathogenesis HER2 status is also an important predictor of response to chemotherapy and hormonal therapy5,6 1Owens MA, et al. Clin Breast Cancer 2004;5:63–9; 2Ross JS, et al. Mol Cell Proteomics 2004;3:379–98; 3Hynes NE, Stern DF. Biochim Biophys Acta 1994;1198:165–84 4Menard S, et al. Oncology 2001;61(Suppl. 2):67–72; 5Lohrisch C, et al. Clin Breast Cancer 2001;2:129–35; 6Piccart M, et al. Oncol 2001; 61(Suppl. 2)73–82 Trastuzumab: anti-HER2 epitope monoclonal antibody Recombinant humanised monoclonal antibody directed against the extracellular domain of HER2 Extracellular domain (632 amino acids) Ligand-binding site Plasma membrane Transmembrane domain (22 amino acids) Intracellular domain (580 amino acids) Tyrosine kinase activity Cytoplasm Trastuzumab: four mechanisms of action Activation of ADCC Prevention of p95HER2 formation Inhibition of cell proliferation Inhibition of angiogenesis ADCC = antibody-dependent cellular cytotoxicity Accurate HER2 testing is vital for appropriate patient selection Patient tumour sample FISH/CISH IHC 0 2+ 3+ FISH/CISH Trastuzumab therapy 1+ – – + Trastuzumab therapy + Trastuzumab therapy IHC = immunohistochemistry FISH = fluorescence in-situ hybridisation CISH = chromogenic in-situ hybridisation Bilous M, et al. Mod Pathol 2003;16:173–82 A decade of success: tailored treatment for HER2-positive MBC Hormonal therapy ± trastuzumab ER-positive; low risk HER2-positive MBC ER-negative ER-positive; high risk ER-negative ER-positive; high risk No prior taxanes Prior taxanes Trastuzumab + taxanes Trastuzumab + other CT Trastuzumab monotherapy ER = oestrogen receptor; CT = chemotherapy Data from monotherapy trials show that trastuzumab is active in HER2-positive MBC 114 first-line patients randomised to trastuzumab at standard or high dose (8mg/kg followed by 4mg/kg weekly) Patients RR (%) (95% CI) All 26 (18–34) IHC3-positive 35 (24–44) IHC2-positive 0 (0–15) FISH-positive 34 (26–56) Clinical benefit rate (CR + PR + SD >6m) = 48%; IHC2-positive RR=0 RR = response rate CI = confidence interval; CR = complete response; PR = partial response SD = stable disease; Vogel CL, et al. J Clin Oncol 2002;20:719–26 Trastuzumab plus taxanes Trastuzumab plus taxanes: well-established survival benefit of first-line therapy H0648g (HER2 IHC3-positive) Outcome T+P (n=68) P (n=77) ORR (%) 49.0 TTP (months) OS (months) M77001 (HER2 FISH-/IHC3-positive) p value T+D (n=92) D (n=94) p value 17.0 Not reported 61.0 34.0 0.0002 7.1 3.0 <0.05 11.7 6.1 0.0001 25.0 18.0 Not reported 31.2 22.7* 0.0325 *53 patients (57%) crossed over to receive trastuzumab after discontinuation of docetaxel; OS in this group was 30.3 months, vs 16.6 months in patients who did not cross over T = trastuzumab; P = paclitaxel D = docetaxel; ORR = overall response rate; TTP = time to progression Baselga J. Oncology 2001;61(Suppl. 2):14–21 Herceptin® EU Summary of product characteristics Marty M, et al. J Clin Oncol 2005;23:4265–74 Smith IE. Anticancer Drugs 2001;12(Suppl. 4):S3–10 Trastuzumab plus docetaxel: long-term survival 50 Trastuzumab + docetaxel Docetaxel Patients (n) 40 79% of the patients in the docetaxelalone arm who survived ≥3 years had crossed over to receive trastuzumab 30 20 10 0 >3 >4 Long-term survival (years) >4.5 Marty M, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S102 (Abstract 2067) Estimated probability Evidence suggests trastuzumab should be used upfront 1.0 Trastuzumab + docetaxel (n=92) Docetaxel alone/cross over (n=53) 0.8 Docetaxel alone (n=41) 0.6 0.4 0.2 16.6 0 0 5 10 15 30.3 20 25 30 Months 31.2 35 40 45 50 Marty M, et al. J Clin Oncol 2005;23:4265–74 Trastuzumab plus taxanes Dramatic improvements in survival demonstrated with trastuzumab in the first-line setting – similar magnitudes of improvement have been reported only rarely (in any therapeutic area) – trastuzumab is the only HER2-targeted therapy shown to improve survival in MBC patients with HER2-positive tumours – benefits of trastuzumab were apparent regardless of age, ER/PR status, or tumour burden – cross-over patients in M77001 did benefit from later trastuzumab, but survival times were shorter than with first-line use Evidence indicates trastuzumab should be initiated as soon as possible PR = progesterone receptor Case study Locally-advanced breast cancer (LABC) and MBC: what are your options? 13.10.00 Invasive ductal breast cancer confirmed by high speed biopsy HER2-neu overexpression (IHC3-positive), ER-positive, PR-negative LABC and MBC: what are your options? 13.10.00 Paclitaxel weekly: 80mg/m² q7d x 8 + trastuzumab: 4/2mg/kg q7d x 8 14.12.00 q7d = every 7 days LABC and MBC: what are your options? Still alive and doing fine 100.000 10.000 1000 Radiation Bone scan CA 125 Trastuzumab Paclitaxel TCT ACT CA 15-3 CEA 100 10 Trastuzumab q3w Tamoxifen Bisphosphonate (p.o.) 0 2002 2003 Year 3 2004 2005 2006 Year 5 Year 4 Year 6 Year 2 Year 1 q3w = every 3 weeks; p.o. = by mouth; CEA = carcinoembryonic antigen; CA = cancer antigen; TCT = computed tomography of the thorax; ACT = computed tomography of the abdomen Are other trastuzumab-based treatment options needed for HER2-positive MBC? Unmet clinical need, i.e. – patient has received prior taxanes – patient is not responding to taxanes Other trastuzumab-based options include – non-taxane chemotherapy – triplet combinations – endocrine therapy Potential for new treatment options based on trastuzumab 1. Trastuzumab plus non-taxane combinations Trastuzumab plus vinorelbine: phase II trials 100 First-line1–4 First-/second-line5,6 Second-line7–9 ORR (%) 80 60 40 20 0 30 25 25 30 25 25 25 25 35 Weekly vinorelbine schedule (mg/m2) 1Jahanzeb M, et al. Oncologist 2002;7:410–17; 2Burstein HJ, et al. J Clin Oncol 2003;21:2889–95 3Bernado G, et al. J Clin Oncol 2004;22(Suppl. 23):59s (Abstract 731) 4Chan A, et al. Br J Cancer 2006;95:788–93; 5Bayo J, et al. J Clin Oncol 2004;22(Suppl. 23):67s (Abstract 763) 6Glogowska I, et al. J Clin Oncol 2004;22(Suppl. 23):235s (Abstract 3165) 7De Wit M, et al. J Clin Oncol 2004;22(Suppl. 23):84s (Abstract 831) 8Burstein HJ, et al. J Clin Oncol 2001;19:2722–30; 9Papaldo P, et al. Ann Oncol 2006;17:630–6 Trastuzumab plus gemcitabine in MBC Phase II study O’Shaughnessy et al. Christodoulou et al. Patients (n) 64 28 Gemcitabine regimen 1,200mg/m2 days 1, 8 q3w 1,000mg/m2 days 1, 8, 15 q4w Anthracycline-/taxanepretreated (%) 95 100 ORR (%) 38 36 CR (%) 0 4 PR (%) 38 32 Median TTP (months) 5.8 7.8 Median OS (months) 14.7 18.7 q4w = every 4 weeks O’Shaughnessy JA, et al. Clin Breast Cancer 2004;5:142–7 Christodoulou C, et al. Proc Am Soc Clin Oncol 2003;22:42 (Abstract 166) Trastuzumab plus anthracycline: clinical trials in MBC n ORR (%) CHF (%) EC (60/600mg/m2) EC (90/600mg/m2) 26 25 62 64 0 8 Liposomal doxarubicin (50mg/m2 q3w) P (80mg/m2 qw) 24 91 0 Theodoulou et al. 2002 Liposomal doxarubicin (60mg/m2 q3w) 37 58 3 Author Untch et al. 2004 Baselga et al. 2004 EC = epirubicin/ cyclophosphamide CHF = congestive heart failure Regimen (+ trastuzumab) Untch M, et al. Eur J Cancer 2004;40:988–97 Baselga J, et al. Eur J Cancer 2004;2:132 (Abstract 262) Theodoulou M, et al. Proc Am Soc Clin Oncol 2002;21:55a (Abstract 216) Trastuzumab plus non-taxane combinations Promising phase II data for trastuzumab plus vinorelbine in HER2-positive MBC; high activity, favourable safety and tolerability – RR 6080% in first line; activity comparable to weekly taxane – active and well tolerated when used beyond disease progression Trastuzumab plus gemcitabine has shown activity in several phase II trials High RR shown with trastuzumab plus anthracycline Further clinical trials will better define the role for non-taxane combinations Potential for new treatment options based on trastuzumab 2. Trastuzumab-based triplet regimens Trastuzumab-based triplet regimens Combining more than two agents has the potential to further improve ORR and increase survival Several trastuzumab combinations of interest – – – – trastuzumab/docetaxel/capecitabine (CHAT study) trastuzumab/paclitaxel/carboplatin trastuzumab/docetaxel/epirubicin trastuzumab/paclitaxel/gemcitabine Phase II study of trastuzumab plus docetaxel ± capecitabine in first-line MBC (CHAT) HER2-positive LABC and MBC patients (n=225*) Trastuzumab 8mg/kg loading dose, then 6mg/kg + docetaxel 100mg/m2, q3w (n=110) Trastuzumab 8mg/kg loading dose, then 6mg/kg + docetaxel 75mg/m2, q3w + capecitabine 950mg/m2 b.i.d., days 1–14 (n=112) *Three patients did not receive treatment b.i.d. = twice daily Death or disease progression Wardley A, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S101 (Abstract 2063) CHAT: TTP significantly increased with the triplet than the doublet Estimated probability 1.0 Events HR 95% CI p value 70 82 0.704 0.51–0.971 0.029 TDC TD 0.8 0.6 0.4 0.2 13.6 0 0 5 10 18.6 15 20 25 30 35 40 45 50 Months HR = hazard ratio C = capecitabine Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309) CHAT: longer median PFS with the triplet than the doublet Estimated probability 1.0 Events HR 95% CI p value 75 85 0.725 0.529–0.99 0.0402 TDC TD 0.8 0.6 0.4 0.2 12.8 0 0 5 10 17.9 15 20 25 30 35 40 45 50 Months PFS = progression-free survival Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309) Manageable safety profile Adverse event (AE) Alopecia Diarrhoea Nausea Hand-foot syndrome Vomiting Asthenia Fatigue Mucosal inflammation Peripheral oedema Myalgia Patients with grade 3/4 treatment-related AEs (%) TDC TD (n=112) (n=110) 6 8 11 4 1 0 17 1 4 0 4 3 1 2 1 2 1 4 0 1 Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309) CHAT: summary Effective first-line strategy for HER2-positive MBC TDC significantly prolonged both TTP (0.029) and PFS (0.0402) by approximately 5 months compared with TD High tumour RRs and good tolerability The potential of these agents as sequential therapy was not addressed in this trial Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309) Paclitaxel plus trastuzumab plus carboplatin (%) Paclitaxel Paclitaxel + Weekly paclitaxel Paclitaxel + trastuzumab + trastuzumab trastuzumab + carboplatin + carboplatin RR1 65 RR2 RR3 36* 57* 41 17 1Perez *HER2 IHC3+ 71 E, et al. Breast Cancer Res Treat 2003;82(Suppl. 1) (Abstract 216) 2Robert N, et al. J Clin Oncol 2006;24:2786–92 3Slamon DJ, et al. N Engl J Med 2001;344:783–92 Potential for new treatment options based on trastuzumab 3. Trastuzumab plus endocrine therapy Trastuzumab plus hormonal therapy: rationale Up to 50% of HER2-positive breast cancers are also ER-positive Evidence of crosstalk between HER2 and ER signalling pathways Simultaneous targeting of both pathways may improve outcomes over monotherapy Not all patients require chemotherapy (i.e. ER-positive patients at low risk) Ellis M. Oncologist 2004;9(Suppl. 3):20–26 Piccart-Gebhart MJ, et al. N Engl J Med 2005;353:1659–72 Crosstalk between signal transduction and endocrine pathways Growth factor Oestrogen Trastuzumab IGFR EGFR/HER2 Plasma membrane P P P P P Anastrozole PI3-K Cell survival Akt P SOS RAS RAF P MEK P ER p90RSK P MAPK Cell growth Cytoplasm P Nucleus EGFR = epidermal growth factor receptor ERE = oestrogen response element IGFR = insulin-like growth factor receptor P P P P Basal transcription machinery ER p160 ER CBP ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res 2005;11:889s–99s Phase III study of first-line trastuzumab plus anastrozole in MBC (TAnDEM) Postmenopausal women with HER2positive (IHC3positive and/or FISHpositive) and ERand/or PR-positive MBC (n=207) Anastrozole 1mg/day p.o.* (n=104) Anastrozole 1mg/day p.o. + trastuzumab 4mg/kg i.v. loading dose then 2mg/kg weekly (n=103) *Trastuzumab offered to patients who progressed on anastrozole alone Disease progression Mackey JR, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S5–6 (Abstract 3) Doubled PFS in HER2-positive MBC: TAnDEM trial 1.0 Events Probability 0.8 An + T An only Median PFS (months) 95% CI 4.8 2.4 87 99 3.7–7.0 2.0–4.6 p value HR 0.0016 0.63 0.6 0.4 0.2 0 No. at risk An + T An only An = anastrozole 0 5 10 15 20 25 103 104 48 36 31 22 17 9 14 5 13 4 30 35 Months 11 2 9 1 40 45 50 55 60 4 0 1 0 1 0 0 0 0 0 Mackey JR, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S5–6 (Abstract 3) TAnDEM: summary Addition of trastuzumab to anastrozole significantly extended PFS in women with HER2-positive, hormone receptor-positive MBC >15% of patients receiving anastrozole plus trastuzumab experienced 2 years PFS – could allow delay in use of chemotherapy Addition of trastuzumab improved median OS – although increase was non-significant (p=0.325) AEs were as expected and manageable Mackey JR, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S5–6 (Abstract 3) Trastuzumab therapy in multiple lines No resistance to trastuzumab Issue of anti-HER2 therapy resistance remains unproven – is this true resistance? Various options can be considered – continue with trastuzumab, but change chemotherapy i.e. TBP – use of other HER2 agent, i.e. lapatinib plus capecitabine after progression on trastuzumab therapy for MBC (EGF100151 study) – retreatment with trastuzumab after second-/ third-line therapy TBP = treatment beyond progression Geyer CE, et al. J Clin Oncol 2007;25(Suppl. 18):40s (Abstract 1035) Patients still benefit from trastuzumab after progression in the metastatic setting Treatment in multiple lines Fountzilas et al. 2003 Gelmon et al. 2004 Tripathy et al. 2004 Garcìa-Sáenz et al. 2005 Stemmler et al. 2005 Bartsch et al. 2006 Montemurro et al. 2006 Morabito et al. 2006 Orlando et al. 2006 Tokajuk et al. 2006 Bachelot et al. 2007 Baselga et al. 2007 Metro et al. 2007 Antoine et al. 2007 Von Minckwitz et al. 2007 NR = not reported No. of patients ORR for second trastuzumab-based regimen (%) 80 65 93 31 23 54 40 7 11 27 17 33 37 107 78 24 32 11 26 39 26 18 29 18 50 29 18 29 NR 49 GBG-26: trastuzumab beyond progression study Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w Randomisation n=78 each arm Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w + trastuzumab continuation 6mg/kg q3w Capecitabine Capecitabine + trastuzumab 24.6 48.9 Median PFS (months) 5.6 53 events 8.5 48 events 0.71 Median OS (months) 19.9 31 events 20.3 26 events 0.79 ORR (%) HR Von Minckwitz G, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S185 (Abstract 4056) Hermine cohort study Patients with HER2-positive MBC (n=623) Trastuzumab as first-line therapy (n=221) Trastuzumab as second-line therapy (n=138) Patients who progressed or died during 2-year follow-up (n=185*) Patients who progressed or died during 2-year follow-up (n=121†) Trastuzumab continued after disease progression (n=107) Trastuzumab stopped at disease progression (n=70) *Data unavailable for eight patients †Data unavailable for four patients Trastuzumab continued after disease progression (n=87) Trastuzumab stopped at disease progression (n=30) Antoine EC, et al. Eur J Cancer 2007;5 (Suppl. 4):213 (Abstract 2099) HERMINE study: longer OS for patients receiving trastuzumab as first-line therapy T continued after disease progression T stopped at disease progression Median OS (months) 95% CI p value NR 16.8 30.4–NR 12.5–19.4 <0.0001 1.0 Median follow-up: 24.1 months Probability 0.8 0.6 0.4 0.2 16.8 0 0 5 10 15 20 25 30 35 Months Median OS from date of progression: 4.6 vs 21.3 months 40 Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099) HERMINE study: cardiac safety in patients receiving trastuzumab as first-line therapy Patients, n (%) Trastuzumab stopped at PD (n=70) Trastuzumab continued after PD (n=107) LVEF assessed during study 57 (81) 97 (91) LVEF worst value Absolute decrease 15% Value of <40% Value of <50% 5 (21.7) 3 (7.3) 10 (24.4) 9 (20.5) 2 (2.6) 10 (12.7) 1 (1.4) 1 (0.9) Congestive heart failure LVEF = left ventricular ejection fraction Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099) HERMINE study: longer OS for patients receiving trastuzumab as second-line therapy T continued after disease progression T stopped at disease progression Median OS (months) 95% CI p value 27.1 15.6 22.7–32.9 6.0–NR 0.08 1.0 Median follow-up: 23.1 months Probability 0.8 0.6 0.4 0.2 15.6 0 0 5 10 15 27.1 20 25 30 35 Months Median OS from date of progression: 11.0 vs 15.3 months 40 Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099) Importance of side effects in the treatment of breast cancer Patients with breast cancer can expect to receive multiple lines of therapy during the course of their disease First diagnosis Surgery Neoadjuvant Adjuvant MBC First line Second line Safety is important for all women with breast cancer, but for women receiving multiple lines of treatment, safety is of particular importance Trastuzumab: safety and tolerability Trastuzumab is generally well tolerated and not associated with the typical side effects of chemotherapy The most relevant AEs associated with trastuzumab are – serious infusion-related reactions (0.3%) – congestive heart failure (2% in MBC trials)1 Patients at risk can be identified prior to therapy and the majority of events are manageable Cardiac safety and clinical symptoms should be continuously monitored (i.e. every 3 months) during trastuzumab therapy 1Ewer MS, O’Shaughnessy JA. Clin Breast Cancer 2007;7:600–7 Pertuzumab: a new class of anti-HER2 therapy Pertuzumab Monoclonal antibody against HER2 Binds different HER2 epitope to trastuzumab1 – prevents receptor dimerisation1 – inhibits HER2-mediated signalling1 First in a new class of HER2-targeted therapies Complementary mechanism of action to trastuzumab suggested by preclinical evidence2,3 1Agus DB, et al. J Clin Oncol 2005;23:2534–43 T, et al. Ann Oncol 2006;17(Suppl. 9):ix58 3Arpino G, et al. J Natl Cancer Inst 2007;99:694–705 2Friess Phase II trial: pertuzumab plus trastuzumab in MBC progressing during treatment with trastuzumab Stage I (n=24) Trastuzumab + pertuzumab* 2 PR or 1 PR + 12 SD or 13 SD Safety evaluation for IDSMB YES Stage II (n=66) NO Stop trial n=58 fully evaluable patients ORR = 18.2% Clinical benefit rate = 39.4% Updated efficacy data will be reported in 2008 The study is being monitored by an IDSMB No safety objections raised, study continuing to stage II – only two patients had a falling LVEF (≤50% and ≥10%) *Trastuzumab: 4mg/kg loading dose 2mg/kg qw or 8mg/kg loading dose 6mg/kg q3w; Pertuzumab: 840mg loading dose 420mg q3w IDSMB = International Data Safety Monitoring Board Baselga J, et al. J Clin Oncol 2007;25(Suppl. 18S):33s (Abstract 1004) Phase III trastuzumab plus pertuzumab trial in first-line MBC A 400 patients Placebo + trastuzumab + docetaxel Tumour assessments R B 400 patients Endpoints PFS OS Quality of life Pertuzumab + trastuzumab + docetaxel Survival follow-up A decade of success: the first agent to improve survival in HER2-positive MBC Introduction of first-line trastuzumab has shown OS can be significantly improved in HER2-positive MBC Trastuzumab is effective and well tolerated – adding little to the toxicity of systemic chemotherapy regimens and without impacting quality of life – limited long-lasting/acute side effects Trastuzumab should be used as soon as HER2-positive status is identified for best results Several trastuzumab-based regimens are now available, providing clinicians with treatment options in different lines of therapy and for a broad range of patients