NOVEDADES EN SABCS EN CANCER DE MAMA HER2+

Transcription

1 Prof. Miguel Martín Servicio de Oncología Médica Hospital General Universitario Gregorio Marañón Universidad Complutense Madrid NOVEDADES EN SABCS EN CANCER DE MAMA HER2+

2 Mukohara T. Cancer Sci 102:1, 2011

3 Impaired access of trastuzumab to HER2: Overexpression of extracellular domain-truncated HER2 (p95 HER2) Overexpression of MUC4 Mukohara T. Cancer Sci 102:1, 2011

4 Activating mutations or deletions of downstream proteins PI3K AKT Aberrating downstream signaling caused by PTEN loss Mukohara T. Cancer Sci 102:1, 2011

5 Activation of compensatory pathways Other TK receptors: IGFR1, EGFR, HER3, MET ER signaling Mucohara T. Cancer Sci 102:1, 2011

6 Cell cycle related Downregulation of p27 Cyclin E overexpression Mucohara T. Cancer Sci 102:1, 2011

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8 Pertuzumab Mechanism of action

9 There are four receptors in the HER family HER1/EGFR HER2 HER3 HER4 EGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:

10 There are four receptors in the HER family HER1/EGFR HER2 HER3 HER4 Receptors are able to homo- and heterodimerise EGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:

11 There are four receptors in the HER family HER2 HER3 Receptors are able to homo- and heterodimerise HER2 does not appear to have a direct ligand and HER3 lacks kinase activity EGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:

12 There are four receptors in the HER family HER2 HER3 Receptors are able to homo- and heterodimerise HER2 does not appear to have a direct ligand and HER3 lacks kinase activity However, HER2 and HER3 are highly complementary to each other EGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:

13 HER2:HER3 dimers initiate the strongest mitogenic signalling Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 Tzahar et al. Mol Cell Biol 1996;16: ; Citri et al. Exp Cell Res 2003;284:54 65; Huang et al. Cancer Res 2010;70:

14 HER2:HER3 dimers initiate the strongest mitogenic signalling Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER Signalling activity Tzahar et al. Mol Cell Biol 1996;16: ; Citri et al. Exp Cell Res 2003;284:54 65; Huang et al. Cancer Res 2010;70:

15 HER2 dimerises preferentially with HER3 to drive downstream signalling HER2 HER3 Baselga, Swain. Nat Rev Cancer 2009;9: ; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2: ; Graus-Porta et al. EMBO J 1997; ; Tzahar et al. Mol Cell Biol 1996;16: ; Lee-Hoeflich et al. Cancer Res 2008;68:

16 HER2 dimerises preferentially with HER3 to drive downstream signalling HER2 HER3 Ligand-activated HER2:HER3 dimer Baselga, Swain. Nat Rev Cancer 2009;9: ; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2: ; Graus-Porta et al. EMBO J 1997; ; Tzahar et al. Mol Cell Biol 1996;16: ; Lee-Hoeflich et al. Cancer Res 2008;68:

17 HER2 dimerises preferentially with HER3 to drive downstream signalling HER2 HER3 Ligand-activated HER2:HER3 dimer P P P P Phosphorylation of the HER3 intracellular domain by HER2 initiates a signalling cascade Baselga, Swain. Nat Rev Cancer 2009;9: ; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2: ; Graus-Porta et al. EMBO J 1997; ; Tzahar et al. Mol Cell Biol 1996;16: ; Lee-Hoeflich et al. Cancer Res 2008;68:

18 Please refer to disclaimer on slide 2 HER2:HER3 dimerisation initiates multiple signalling pathways, including increased tumour cell proliferation HER2 HER3 RAS RAF Sos GRb2 Shc PI3K P P P P P P P PDK1 Akt Downstream PI3K/Akt signalling is mainly mediated by HER3 after transphosphorylation by HER2 MEK mtor Cyclin 01 p27 BAD NF B GSK36 MAPK P P Apoptosis Cell cycle control Survival Angiogenesis Proliferation Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2: ; Olayioye et al. EMBO J 2000;19: ; Kim et al. J Biol Chem 1994;269: ; Soltoff et al. Mol Cell Biol 1994;14: ;

19 Pertuzumab is the first in a new class of targeted anticancer therapeutic agents called HER2 Dimerisation Inhibitors By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival 1 4 Pertuzumab prevents the formation of HER2:HER3 receptor pairs 1,5 HER2 HER3 Dimerisation domain 1. Agus et al. Cancer Cell 2002;2: ; 2. Baselga. Cancer Cell 2002;2:93 95; 3. Citri et al. Exp Cell Res 2003;284: Franklin et al. Cancer Cell 2004;5: ; 5. Hughes et al. Mol Cancer Ther 2009;8: Please refer to disclaimer on slide 2

20 Pertuzumab is the first in a new class of targeted anticancer therapeutic agents called HER2 Dimerisation Inhibitors By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival 1 4 Pertuzumab prevents the formation of HER2:HER3 receptor pairs 1,5 HER2 HER3 Dimerisation domain Pertuzumab 1. Agus et al. Cancer Cell 2002;2: ; 2. Baselga. Cancer Cell 2002;2:93 95; 3. Citri et al. Exp Cell Res 2003;284: Franklin et al. Cancer Cell 2004;5: ; 5. Hughes et al. Mol Cancer Ther 2009;8: Please refer to disclaimer on slide 2

21 Pertuzumab is the first in a new class of targeted anticancer therapeutic agents called HER2 Dimerisation Inhibitors By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival 1 4 Pertuzumab prevents the formation of HER2:HER3 receptor pairs 1,5 HER2 HER3 Dimerisation domain Pertuzumab 1. Agus et al. Cancer Cell 2002;2: ; 2. Baselga. Cancer Cell 2002;2:93 95; 3. Citri et al. Exp Cell Res 2003;284: Franklin et al. Cancer Cell 2004;5: ; 5. Hughes et al. Mol Cancer Ther 2009;8: Please refer to disclaimer on slide 2

22 Summary of pertuzumab combination trials in HER2-positive breast cancer EBC (Neo-adjuvant) First-line MBC Second-line MBC Third-line MBC NEOSPHERE (n=400) D+T vs D+T+P vs T+P vs D+P CLEOPATRA (n=800) D+T±P PHEREXA (n=450) Capecitabine+T±P TRYPHAENA (n=225) D+FEC+T+P vs carboplatin+d+t+p BO17929 cohorts 1+2 (n=66) P+T BO17929 cohort 3 (n=29) P mono then P+T Enrolment complete Enrolling NCI study (n=11) P+T D = docetaxel; EBC = early-stage breast cancer; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer; P = pertuzumab; T = trastuzumab Data on file. Genentech USA, Inc., CA, USA and F Hoffmann-La Roche Ltd., Basel, Switzerland

23 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Neoadjuvant Pertuzumab and Trastuzumab Concurrent or Sequential with an Anthracycline-Containing or Concurrent with an Anthracycline-Free Standard Regimen: A Randomized Phase II Study (TRYPHAENA) A Schneeweiss, 1 S Chia, 2 T Hickish, 3 V Harvey, 4 A Eniu, 5 R Hegg, 6 C Tausch, 7 J-H Seo, 8 Y-F Tsai, 9 A Ackrill, 10 G Ross, 10 J Cortés 11 1 National Center for Tumor Diseases, University Hospital, Heidelberg, Germany; 2 British Columbia Cancer Agency Vancouver Centre, University of British Columbia, Vancouver, Canada; 3 Royal Bournemouth Hospital, Bournemouth University, Bournemouth, UK; 4 Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, New Zealand; 5 Cancer Institute I Chiricuta, Cluj-Napoca, Romania; 6 Hospital Pérola Byington, São Paulo, Brazil; 7 Breast Center, Zürich, Switzerland; 8 Department of Internal Medicine, Korea University Guro Hospital, Korea; 9 Taipei-Veterans General Hospital, Taipei, Taiwan; 10 Roche Products Limited, Welwyn, United Kingdom; 11 Vall d'hebron University Hospital, Barcelona, Spain Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute.

24 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Study design Cycles A FEC Docetaxel HER2-positive EBC centrally confirmed (n = 225) B C Pertuzumab + trastuzumab FEC Docetaxel Docetaxel Pertuzumab + trastuzumab Pertuzumab + trastuzumab S u r g e r y Trastuzumab to complete 1 year Carboplatin All 3 arms were experimental Study dosing q3w: FEC: 500 mg/m 2, 100 mg/m 2, 600 mg/m 2 Carboplatin: AUC 6 Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Pertuzumab: 840 mg loading dose, 420 mg maintenance Docetaxel: 75 mg/m 2 (escalating to 100 mg/m 2 if tolerated, in Arms A and B only) AUC, area under the plasma concentration-time curve; EBC, early breast cancer; FEC, 5-fluorouracil, epirubicin, cyclophosphamide Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 24

25 Study endpoints San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Primary endpoint: Cardiac safety Symptomatic LVSD (grade 3) LVEF declines ( 10 percentage points and below 50%) Secondary endpoints: Toxicity pcr (defined as the absence of invasive tumor residues in the breast at surgery; remaining in situ lesions allowed; ypt0/is) Study was not powered for formal comparison between arms Clinical response rate Rate of breast-conserving surgery Disease-free survival and overall survival Biomarker evaluation LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; pcr, pathologic complete response Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 25

26 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Cardiac events during neoadjuvant treatment FEC+H+P x3 T+H+P x3 n = 72 FEC x3 T+H+P x3 n = 75 TCH+P x6 n = 76 Symptomatic LVSD (grade 3), n (%) 0 (0.0) 2 (2.7) 0 (0.0) LVSD (all grades), n (%) 4 (5.6) 3 (4.0) 2 (2.6) LVEF decline 10% points and below 50%, n (%) 3 (4.2) 4 (5.3) 3 (3.9) FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 26

27 Pathologic complete response (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Pathologic complete response ypt0/is ypt0 ypn FEC+H+P x3 T+H+P x3 (n = 73) FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 27

28 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Summary and conclusions Results from TRYPHAENA indicate a low incidence of symptomatic and asymptomatic LVSD across all arms Concurrent administration of pertuzumab plus trastuzumab with epirubicin resulted in similar cardiac tolerability compared with sequential administration or the anthracyclinefree regimen Regardless of chemotherapy chosen, the combination of pertuzumab with trastuzumab in the neoadjuvant setting resulted in high pcr rates (57 66%) TRYPHAENA supports the ongoing APHINITY study, a Phase III trial to evaluate pertuzumab and trastuzumab plus standard chemotherapy in the adjuvant setting (poster: OT ) (NCT ) Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 28

29 Original Article Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer José Baselga, M.D., Ph.D., Javier Cortés, M.D., Sung-Bae Kim, M.D., Seock-Ah Im, M.D., Roberto Hegg, M.D., Young-Hyuck Im, M.D., Laslo Roman, M.D., José Luiz Pedrini, M.D., Tadeusz Pienkowski, M.D., Adam Knott, Ph.D., Emma Clark, M.Sc., Mark C. Benyunes, M.D., Graham Ross, F.F.P.M., Sandra M. Swain, M.D., for the CLEOPATRA Study Group N Engl J Med Volume 366(2): January 12, 2012

30 CLEOPATRA: Study design n=406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n=402 Docetaxel* 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated MBC, metastatic breast cancer; PD, progressive disease * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion

31 Primary endpoint Study endpoints Independently assessed progression-free survival (PFS) Secondary endpoints PFS by investigator assessment Objective response rate Overall survival Safety Duration of response Evaluation of biomarkers and correlation with clinical outcomes Time to symptom progression

32 Baseline characteristics (I) Median age, years (range) Region, n (%) Asia Europe North America South America ECOG PS, n (%) Placebo + trastuzumab + docetaxel (n = 406) 54.0 (27 89) 128 (31.5) 152 (37.4) 68 (16.7) 58 (14.3) 248 (61.1) 157 (38.7) 1 (0.2) Pertuzumab + trastuzumab + docetaxel (n = 402) 54.0 (22 82) 125 (31.1) 154 (38.3) 67 (16.7) 56 (13.9) 274 (68.2) 125 (31.1) 3 (0.7) ECOG PS, Eastern Cooperative Oncology Group performance status

33 Progression-free survival (%) Primary endpoint: Independently assessed PFS n = 433 PFS events n at risk Ptz + T + D Pla + T + D Time (months) D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months = 6.1 months HR = % CI p< Stratified by prior treatment status and region

34 Independently assessed PFS in predefined subgroups Favors pertuzumab Favors placebo n HR 95% CI Prior (neo)adjuvant chemotherapy Region Age group Race All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive Unstratified analyses ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PgR, progesterone receptor; PFS, progression-free survival

35 Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy Prior (neo)adjuvant trastuzumab treatment (n = 88) No prior (neo)adjuvant trastuzumab treatment (n = 288) Placebo + trastuzumab + docetaxel Median PFS, months Pertuzumab + trastuzumab + docetaxel Median PFS, months Hazard ratio (CI) 0.62 ( ) 0.60 ( ) PFS, progression-free survival

36 Independently reviewed objective response In patients with measurable disease at baseline Objective response rate, n (%) Complete response rate, n (%) Partial response rate, n (%) Placebo + trastuzumab + docetaxel (n = 336) 233 (69.3) 14 (4.2) 219 (65.2) Pertuzumab + trastuzumab + docetaxel (n = 343) 275 (80.2) 19 (5.5) 256 (74.6) p = * Stable disease, n (%) 70 (20.8) 50 (14.6) Progressive disease, n (%) 28 (8.3) 13 (3.8) Unable to assess or no assessment, n (%) * The statistical test result is deemed exploratory 5 (1.5) 5 (1.5)

37 Overall survival (%) Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events HR = 0.64* 95% CI p = * Ptz + T + D: 69 events Pla + T + D: 96 events n at risk Time (months) Pertuzumab + T + D Placebo + T + D * The interim OS analysis did not cross the pre-specified O Brien-Fleming stopping boundary (HR 0.603; p ) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

38 Safety results

39 Cardiac tolerability Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Investigator-assessed symptomatic LVSD* Independently adjudicated symptomatic LVSD* Fall in LVEF to <50% and by 10 percentage points from baseline 1.8% 1.0% 1.0% 1.0% 6.6% 3.8% * LVSD was defined as NYHA class III/IV LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

40 Adverse events (all grades) 25% incidence or 5% difference between arms Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea 184 (46.3) 272 (66.8) Alopecia 240 (60.5) 248 (60.9) Neutropenia 197 (49.6) 215 (52.8) Nausea 165 (41.6) 172 (42.3) Fatigue 146 (36.8) 153 (37.6) Rash 96 (24.2) 137 (33.7) Decreased appetite 105 (26.4) 119 (29.2) Mucosal inflammation 79 (19.9) 113 (27.8) Asthenia 120 (30.2) 106 (26.0) Peripheral edema 119 (30.0) 94 (23.1) Constipation 99 (24.9) 61 (15.0) Febrile neutropenia 30 (7.6) 56 (13.8) Dry skin 17 (4.3) 43 (10.6)

41 Summary and conclusions CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC Median PFS increased by 6.1 months from 12.4 to 18.5 months The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature) The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin These adverse events were primarily grades 1 2, manageable, and occurred during docetaxel therapy There was no increase in cardiac adverse events or LVSD This new regimen may be practice-changing in HER2-positive first-line MBC

42 An Update on Metastatic Breast Cancer clinicaloptions.com/oncology AVEREL: Study Design Primary endpoint: PFS (investigator assessed) Secondary endpoints: OS, ORR, duration of response, TTF, safety Stratified by previous (neo)adjuvant taxane, adjuvant trastuzumab, hormone receptor status, measurable disease Treatment until disease progression or unacceptable toxicity* Women with previously untreated HER2-positive locally recurrent/metastatic breast cancer (N = 424) Trastuzumab 6 mg/kg + Docetaxel 100 mg/m 2 + Bevacizumab 15 mg/kg, all given q3w (n = 216) Trastuzumab 6 mg/kg + Docetaxel 100 mg/m 2, both given q3w (n = 208) *Planned minimum of 6 docetaxel cycles administered. Trastuzumab 8 mg/kg loading dose given. Gianni L, et al. SABCS Abstract S4-8.

43 An Update on Metastatic Breast Cancer clinicaloptions.com/oncology 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) Median OS 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 ( ) 0.72 ( ) 1.01 ( ) (unstratified) 0.94 ( ) (stratified) P Value Gianni L, et al. SABCS Abstract S4-8.

44 An Update on Metastatic Breast Cancer clinicaloptions.com/oncology AVEREL: Conclusions Addition of bevacizumab to first-line treatment with trastuzumab and docetaxel in patients with HER2-positive advanced breast cancer may prolong PFS Findings not significant according to investigator-assessed PFS (primary endpoint; P =.0775) Findings significant according to independent review of PFS (exploratory endpoint; P =.0162) Bevacizumab-associated AEs led to higher incidence of discontinuation of any study drug Gianni L, et al. SABCS Abstract S4-8.

45 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 A Phase 2, Randomized, Open-label Study of Neratinib (HKI-272) Versus Lapatinib Plus Capecitabine for 2nd/3rd-line Treatment of HER2+ Locally Advanced or Metastatic Breast Cancer Miguel Martin, 1 Jacques Bonneterre, 2 Charles E. Geyer Jr, 3 Yoshinori Ito, 4 Jungsil Ro, 5 Istvan Lang, 6 Sung-Bae Kim, 7 Caroline Germa, 8,* Jennifer Vermette, 9 Marie-Louise Vo Van, 8 Kenneth Wang, 9,* Kongming Wang, 9 Ahmad Awada 10 1 Hospital Universitario Gregorio Marañón, Madrid, Spain; 2 Centre Oscar Lambret, Lille, France; 3 University of Texas Southwestern Medical Center, Dallas, TX, USA; 4 The Cancer Institute Hospital of JFCR, Tokyo, Japan; 5 National Cancer Center, Goyang, Korea; 6 National Institute of Oncology, Budapest, Hungary; 7 Asan Medical Center, Seoul, Korea; 8 Pfizer Global Research and Development, Paris, France; 9 Pfizer Inc, Cambridge, MA, USA; 10 Jules Bordet Institute, Brussels, Belgium. 45 *This author was employed at Pfizer during the conduct of this study, but has since become employed at another company. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

46 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Study Design (cont) Phase 2, open-label trial in HER2+ locally advanced or metastatic BC patients R A N D O M I Z E Neratinib 240 mg/day n = 117 L + C L 1,250 mg/day + C 2,000 mg/m 2 per day n = 116 Randomization is stratified based on geographical regions. 46 Patients were randomized 1:1 to neratinib or L + C Neratinib was administered orally at 240 mg/day continuously L 1,250 mg/day was administered orally continuously; C 2,000 mg/m 2 was administered orally on Days 1 to 14 of each 21-day cycle This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

47 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Phase 2 Sample Size Determination Non-inferiority design intended to show that neratinib monotherapy was not inferior to L + C Assumption was for non-inferiority in terms of PFS, defined as a non-inferiority margin of 15% equivalent to retaining 50% of the benefit demonstrated for L + C over capecitabine monotherapy 1 A total of 163 PFS events were needed for analysis, given the following assumptions for sample size calculations Median PFS of 27.5 weeks for the L + C arm and 33.9 weeks for the neratinib arm (25% improvement in median PFS; true hazard ratio = 0.80) Enrollment rate of approximately 3 patients per week Design based on a 1-sided log-rank test Alpha = 0.1; power = 85%; 1-year dropout rate = 20% Calculated from data published in Cameron D, et al. Breast Cancer Res Treat. 2008;112(3): This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

48 48 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Baseline Characteristics: ITT Population Characteristic Neratinib (n = 117) L + C (n = 116) Median age (range), y 52 (28 79) 56 (30 79) Ethnicity, % White Asian Other 7 5 ECOG Performance Status, % a Estrogen receptor positive, % b Progesterone receptor positive, % c No. of prior anti-cancer regimens, % Prior trastuzumab therapy, % Adjuvant/neoadjuvant settings Metastatic setting L, lapatinib; C, capecitabine; ECOG, Eastern Cooperative Oncology Group. a ECOG information was missing for 1 patient (1%) in the neratinib arm and 3 (3%) patients in the L + C arm. b Estrogen receptor status was unknown for 1 (1%) patient in the neratinib arm and 2 (2%) patients in the L + C arm. c Progesterone receptor status was unknown for 31 (26%) patients in the neratinib arm and 32 (28%) patients in the L + C arm. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

49 Patients with diarrhea (%) Patients with PPE (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Incidences of Diarrhea and PPE: Safety Population P = Neratinib L + C Grade 1/2 Grade 1/2 Grade 3/4 Grade 3/ % all grades 28% grade 3/4 68% all grades 10% grade 3/ P < % all grades 14% grade 3/ % all grades 0% grade 3/4 0 Neratinib L + C n = 116 n = Neratinib L + C n = 116 n = PPE, palmar-plantar erythrodysesthesia syndrome; L, lapatinib; C, capecitabine. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

50 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Treatment Modifications, Discontinuations, and Deaths Due to Adverse Events Modification, % Neratinib (n = 116) L + C (n = 115) Dose reduction Dose delay Treatment discontinuations a 6 17 Diarrhea 2 4 Nausea 0 2 Stomatitis 0 2 PPE 0 4 Dizziness 0 2 Deaths 0 0 L, lapatinib; C, capecitabine; PPE, palmar-plantar erythrodysesthesia syndrome. a Adverse events leading to 2 discontinuations are listed in the table. 50 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

51 Probability of PFS (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 PFS: ITT Population Time since randomization (mo) Neratinib L + C n Median PFS 95% CI P value Neratinib mo mo L + C mo mo L, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval. 51 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

52 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Analysis of Non-inferiority Non-inferiority of treatment with neratinib versus L + C could not be demonstrated ITT population PP population a Non-inferiority margin HR (Ner/L + C) Non-inferiority margin HR (Ner/L + C) Neratinib better L + C better Neratinib better L + C better ITT, intent-to-treat; PP, per protocol; HR, hazard ratio; L, lapatinib; C, capecitabine. a PP protocol population included patients who were randomized and received at least 1 week of study treatment, incurred no major protocol violations, and had tumor assessments at screening and at least 1 valid post-baseline tumor assessment. 52 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

53 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Best Overall Response: ITT Population Modification, % Neratinib (n = 117) L + C (n = 116) Complete response 2 4 Partial response Stable disease 24 weeks Stable disease <24 weeks Progressive disease 17 7 Unknown/missing 9 5 L, lapatinib; C, capecitabine. The ORR was 29% in the neratinib arm compared with 40% in the L + C arm 53 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

54 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Conclusions Neratinib did not demonstrate non-inferiority versus L + C in terms of PFS In addition, the antitumor activity of neratinib monotherapy in heavily pretreated patients with advanced or metastatic HER2+ BC was robust (ORR of 29%) Diarrhea was the most frequently reported adverse event, but was typically transient and manageable These findings support the continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC Burstein HJ, et al. J Clin Oncol. 2010;28(8): This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

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58 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Results of the TEACH Trial Lapatinib in Women With Early-Stage HER2-Overexpressing Breast Cancer A Double-blind, Placebo-controlled, Phase III Trial Paul Goss 1, Ian Smith 2, Joyce O Shaughnessy 3, Bent Ejlertsen 4, Manfred Kaufmann 5, Frances Boyle 6, Aman Buzdar 7, Pierre Fumoleau 8, William Gradishar 9, Miguel Martin 10, Beverly Moy 1, Martine Piccart-Gebhart 11, Kathleen I. Pritchard 12, Deborah Lindquist 13, Gursel Aktan 14, Erica Rappold 14, Lisa Williams 14, Dianne Finkelstein 1 1 Massachusetts Gen Hosp, Boston MA; 2 Royal Marsden Hosp, London, UK; 3 Baylor Sammons Cancer Ctr and US Oncology, Dallas TX; 4 Rigshospitalet, Copenhagen, Denmark; 5 JW Goethe-Universität, Frankfurt, Germany; 6 Mater Hosp, Sydney, Australia; 7 UT MD Anderson Cancer Ctr, Houston TX; 8 Centre GF Leclerc, Dijon, France; 9 Northwestern Univ, Chicago IL; 10 Hospital Universitario Gregorio Maranon, Madrid, Spain; 11 Jules Bordet Inst, Brussels, Belgium; 12 Sunnybrook Odette Cancer Ctr, Toronto, Ontario; 13 Arizona Oncology and US Oncology, Sedona, AZ; 14 GlaxoSmithKline, Collegeville PA and Uxbridge, UK. This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

59 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH Trial Eligibility HER2+ Local IHC3+ or FISH +ve Resected Stage I-IIIc primary BRCA No prior trastuzumab Neo-/adjuvant chemotherapy (CMF, anthracycline, or taxane) Appropriate endocrine therapy <1 yr only if unable or did not receive trastuzumab R A N D O M I Z E Stratification Time from diagnosis 4 vs >4 yrs Lymph node +ve vs -ve ER+ and/or PgR+ vs ER /PgR Lapatinib 1500 mg qd 1 yr N=3147 Aug 2006-May countries Placebo qd 1 yr Diagnosis 1 yr 4 yr 59 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

60 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH Trial Objectives Primary Disease-free survival (DFS): Secondary local, regional, distant recurrence, contralateral BRCA other 2 nd primary cancers death from any cause Recurrence-free survival Distant recurrence-free survival Overall survival (OS) Rate of CNS recurrences and recurrence-free survival DFS in key-defined subgroups, including all strata Health-related quality of life Compliance and treatment exposure Safety, including cardiac and liver abnormalities 60 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

61 Centrally Confirmed FISH Patient Population by Region (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH: ITT and Confirmed FISH+ Patient Population Central FISH+ 79% Confirmed N. America/ Canada (n=473) Latin America (n=344) Europe (n=1235) Asia Pacific (n=863) Confirmed FISH+ 61 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

62 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH Primary Endpoint: K-M Plot of DFS in ITT Population Time From Randomization HR 0.83 ( ); p=0.053 a Lapatinib Placebo Median Follow up: 4 years 0.0 Number of patients at risk Lapatinib 1500 mg Placebo a p value based on 2-sided stratified log-rank test 62 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

63 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH: K-M Plot of DFS in Confirmed FISH+ Population Time From Randomization Lapatinib Placebo HR 0.82 ( ); p=0.04 a 0.0 Number of patients at risk Lapatinib 1500 mg Placebo a p value based on 2-sided stratified log-rank test. 63 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

64 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH Common AEs: Maximum NCI CTC Toxicity Grades NCI=National Cancer Institute; CTC=Common Toxicity Criteria. 64 This presentation is the intellectual property of the authors/presenter. Contact them at for permission to reprint and/or distribute.

65 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 TEACH Conclusions Although DFS did not reach statistical significance in the overall patient population enrolled over a broad time frame, in centrally confirmed FISH+ tumors, DFS improvement reached statistical significance In the overall patient population, DFS improvement was significant in key prespecified subgroups ER/PgR-ve patients Patients 1 year from diagnosis Predominantly low grade diarrhea and skin rash affect compliance, but no new or unexpected serious safety concerns were found 65 This presentation is the intellectual property of the authors/presenter. Contact them at pgoss@partners.org for permission to reprint and/or distribute.

66 T-DM1: A novel antibody drug conjugate Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic drug: DM1 Highly potent chemotherapy (DM1, a tubulin destabiliser) Linker Systemically stable T-DM1

67 1:1 TDM4450g Phase II Study: T-DM1 vs Trastuzumab + Docetaxel in HER2-Positive MBC HER2-positive, recurrent, LABC or MBC (N=137) No prior therapy for advanced breast cancer or MBC T-DM1 3.6 mg/kg q3w until PD/unnacceptable toxicity or study termination Trastuzumab (8-mg/kg loading dose, then 6 mg/kg) + docetaxel (75 or 100 mg/m 2 ) q3w PD Crossover to T-DM1 Multicenter, randomized study Primary end points PFS by INV Safety Secondary end points Overall survival (OS), ORR, CBR, duration of response, duration of survival, pharmacokinetics, time-to-treatment failure (TTF) PD, progressive disease. Perez et al. UPDATE FROM ESMO Abstract/oral presentation LBA3. Please refer to disclaimer on slide 2

68 Selected Patient Demographic and Baseline Characteristics Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Median age, y (range) 52.0 (33 75) 55.0 (27 82) World region, % US Non-US ECOG PS 0, % ECOG PS 1, % a 36.2 a HER2-positive status by central lab, % b ER+ and/or PR+, % ER and PR, % ER and PR unknown, % Lung or liver involvement, % Yes No Unknown Disease-free interval, % <24 months >24 months a ECOG PS data were available for 69 patients in the trastuzumab + docetaxel arm. b Central testing for HER2 status was performed for 61 patients in the trastuzumab + docetaxel arm and 61 patients in the T-DM1 arm. 68

69 Proportion progression-free Progression-Free Survival by Investigator Randomized Patients Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Median PFS, mos Hazard ratio % CI Log-rank P value Time (months) Number of patients at risk T+D T-DM Hazard ratio and log-rank P value were from stratified analysis. 69

70 Cardiac Safety Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively Asymptomatic LV dysfunction Local assessment LVEF assessment Trastuzumab + docetaxel T-DM1 Patients assessed Patients with post-baseline LVEF 40% 2 a 0 Central assessment Patients assessed Patients with post-baseline LVEF 40% 1 b 0 There were no clinically significant cardiac events reported a Both patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting. b This patient did not receive prior treatment with an anthracycline. 70

71 Summary and Conclusions This is the first randomized study to evaluate an antibody-drug conjugate for HER2-positive MBC First-line treatment of HER2-positive MBC with T-DM1, compared with trastuzumab + docetaxel was associated with: A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P value=0.0353) A lower rate of grade 3 AEs (46.4% vs 89.4%) T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC 71

72 CONCLUSIONES -Pertuzumab en asociación con trastuzumab incrementa significativamente la actividad de éste sin apenas añadir toxicidad -TDM-1 posee una gran actividad antitumoral en tumores HER2+ -El papel del lapatinib como adyuvancia tardía está pendiente de definir -El neratinib parece poseer una interesante actividad en cáncer de mama HER2+ -El bloqueo dual del receptor de HER2 se traduce de nuevo en un beneficio clínico