Past, Present and Future HER2 targeted therapy in breast cancer

Transcription

1 Past, Present and Future HER2 targeted therapy in breast cancer Joseph Gligorov MD, PhD Tenon Hospital, University Cancer Institute, Paris VI, Sorbonne University Paris, France

2 Disclosures Roche GSK

3 What we will talk about?

4 The evolution of HER2+++ Breast Cancer treatments in different clinical situations Neoadjuvant Adjuvant Metastatic Past Present Future

5 METASTATIC

6 HR- HR+ 6

7 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Bad prognosis Tzb improve OS Independently of HR status Present Future

8 Do we have arguments to continue antiher2 treatments beyond trastuzumab & lapatinib in HER2 positive MBC? 2 hypothesis: No Yes: with which molecule Continue trastuzumab and change associated systemic treatment Continue lapatinib and change associated systemic treatment Continue trastuzumab and lapatinib Continue pertuzumab Continue T-DM1

9 The first demonstration that continuing HER2 inhibition after 1st line MBC trastuzumab treatment is a valid option Geyer et al. Von Minckwitz et al.

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14 CEREBEL (EGF111438): An open-label randomised Phase III study comparing the incidence of CNS metastases in patients with HER2+ metastatic breast cancer, treated with lapatinib plus capecitabine versus trastuzumab plus capecitabine Xavier Pivot 1, Bogdan Żurawski 2, Rozenn Allerton 3, Alessandra Fabi 4, Eva Ciruelos 5, Roma Parikh 6, Michelle DeSilvio 7, Sergio Santillana 7, Ramona Swaby 7 and Vladimir Semiglazov 8 EudraCT number: ClinicalTrials.gov Identifier: NCT CHU - Hôpital Jean Minjoz, Besançon, France; 2 Centrum Onkologii im. prof. L. Lukaszczyka, Bydgoszcz, Poland; 3 The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom; 4 Instituto Nazionali Tumori Regina Elena, Roma, Italy; 5 Hospital Universitario 12 de Octubre, Madrid, Spain; 6 GlaxoSmithKline, Uxbridge, United Kingdom; 7 GlaxoSmithKline, Collegeville, PA, USA; 8 Petrov Research Institute of Oncology, St. Petersburg, Russian Federation

15 Milestones Conditional approval granted for lapatinib plus capecitabine in EU: June 2008 CEREBEL was a Specific Obligation measure required by CHMP First patient randomised: April 2009 IDMC meeting for preplanned IA: June 6, 2012; Study terminated based on IDMC recommendation: June 11, 2012 Final analysis database lock: June 11, 2012; n=540 15

16 Study design Key eligibility HER2+ MBC* Prior anthracyclines or taxanes Any line therapy No CNS metastases** Evaluable systemic dx Stratification Prior trastuzumab yes vs no Prior MBC tx 0 vs >1 R A N D O M I S E D Phase III Planned N=650 Lapatinib 1250 mg/day + Capecitabine 2000 mg/m 2 /day, days 1-14 q21 days Trastuzumab 6 mg/kg q21 days + Capecitabine 2500 mg/m 2 /day, days 1-14 q21 days *FISH+/IHC 3+ **No CNS metastases at baseline confirmed by independently reviewed MRI scan Pivot et al, SABCS 2011 : 20% failure at screening with MRI 16

17 Primary endpoint: CNS endpoints (modified ITT) 17

18 Alive without progression (%) Investigator-assessed PFS (ITT population) Lap + Cap (N=271) Lap + Cap Tras + Cap Tras + Cap (N=269) Events, n (%) 160 (59) 134 (50) Median PFS, months Hazard ratio (95% CI) 1.30 ( ) Stratified log-rank p-value Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap

19 Survival (%) OS (ITT population) Lap + Cap Tras + Cap Lap + Cap (N=271) Tras + Cap (N=269) Events, n (%) 70 (26) 58 (22) Median OS, months Hazard ratio (95% CI) 1.34 ( ) Stratified log-rank p-value Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap

20 Alive without progression (%) PFS and OS in patients with prior trastuzumab treatment (ITT) Survival (%) Investigator-assessed PFS Lap + Cap Tras + Cap OS Lap + Cap Tras + Cap Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap Lap + Cap (N=167) Tras + Cap (N=159) Events, n (%) 103 (62) 86 (54) Median PFS, months Hazard ratio (95% CI) 1.13 (0.85, 1.50) Lap + Cap (N=167) Tras + Cap (N=159) Events, n (%) 43 (26) 38 (24) Median OS, months Hazard ratio (95% CI) 1.18 (0.76, 1.83) 20

21 Alive without progression (%) PFS and OS in patients with no prior trastuzumab treatment (ITT) Survival (%) Investigator-assessed PFS Lap + Cap Tras + Cap OS Lap + Cap Tras + Cap Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap Time from randomisation (months) Subjects at risk Lap + Cap Tras + Cap NR, not reached Lap + Cap (N=104) Tras + Cap (N=110) Events, n (%) 57 (55) 48 (44) Median PFS, months Hazard ratio (95% CI) 1.70 (1.15, 2.50) Lap + Cap (N=104) Tras + Cap (N=110) Events, n (%) 27 (26) 20 (18) Median OS, months NR NR Hazard ratio (95% CI) 1.67 (0.94, 2.96) 21

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26 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Bad prognosis Tzb improve OS Independently of HR status Present Continuous HER2 inhibition Trastuzumab Lapatinib Future

27 Trastuzumab Emtansine (T-DM1): Mechanism of Action HER2 Antibody: Trastuzumab P P P Stable linker: MCC Cytotoxic: DM1 Emtansine Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

28 Trastuzumab Emtansine (T-DM1): Mechanism of Action Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of HER2 signaling Inhibition of HER2 shedding HER2 P P P Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

29 Trastuzumab Emtansine (T-DM1): Mechanism of Action Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of HER2 signaling Inhibition of HER2 shedding HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

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31 median, seven prior agents for MBC; median follow-up, 17.4 months

32 Updated Overall Survival Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib in HER2-Positive Locally Advanced or Metastatic Breast Cancer S Verma, 1 D Miles, 2 L Gianni, 3 IE Krop, 4 M Welslau, 5 J Baselga, 6 M Pegram, 7 D-Y Oh, 8 V Diéras, 9 E Guardino, 10 L Fang, 10 MW Lu, 10 S Olsen, 10 K Blackwell 11 1 Sunnybrook Odette Cancer Center, Toronto, Canada; 2 Mount Vernon Cancer Center, Northwood, UK; 3 San Raffaele Hospital, Milan, Italy; 4 Dana-Farber Cancer Institute, Boston, MA, USA; 5 Medical Office Hematology, Aschaffenburg, Germany; 6 Massachusetts General Hospital, Boston, MA, USA; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA; 8 Seoul National University College of Medicine, Seoul, Korea; 9 Institut Curie, Paris, France; 10 Genentech, Inc, South San Francisco, CA, USA; 11 Duke Cancer Institute, Durham, NC, USA 32

33 EMILIA Study Design HER2-positive LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary endpoints: PFS by independent review, OS, and safety Key secondary endpoints: PFS by investigator, ORR, DOR Statistical considerations: Hierarchical statistical analysis was performed in pre-specified sequential order: PFS by independent review OS secondary endpoints PFS analysis: 90% power to detect HR=0.75; 2-sided alpha 5% OS analyses: 80% power to detect HR=0.80; 2-sided alpha 5% 33

34 Proportion progression-free Progression-Free Survival by Independent Review Median (months) No. of events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (months) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). 34

35 Progression-Free Survival Subgroup Analyses Pre-specified Stratification Factors Baseline characteristic Total n Cap + Lap T-DM1 Median, mos Median, mos HR (95% CI) T-DM1 better Cap + Lap better All patients (0.56, 0.78) World region US Western Europe Other (0.51, 0.98) 0.56 (0.41, 0.74) 0.73 (0.56, 0.94) Number prior chemo regimens for MBC or unresectable LABC 0 1 > (0.55, 0.85) 0.63 (0.49, 0.82) Disease involvement Visceral Nonvisceral (0.45, 0.67) 0.96 (0.71, 1.30) Hazard ratio

36 Proportion surviving Overall Survival: Confirmatory Analysis % 85.2% Median (months) No. of events Cap + Lap T-DM Stratified HR=0.682 (95% CI, 0.55, 0.85); P= Efficacy stopping boundary P= or HR= % % Time (months) No. at risk: Cap + Lap T-DM Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). 36

37 Overall Survival Subgroup Analyses Cap + Lap T-DM1 Baseline Total Median Median HR characteristic n (mos) (mos) (95% CI) All patients (0.56, 0.87) Age group <65 years (0.52, 0.83) years NR 0.74 (0.37, 1.47) 75 years 25 NR (0.94, 12.65) ER and PR status ER+ and/or PR (0.46, 0.85) ER and PR (0.54, 1.03) Line of therapy a First-line NR 0.61 (0.32, 1.16) Second-line 361 NR (0.61, 1.27) Third- and later-line (0.46, 0.84) T-DM1 Better Cap + Lap Better a Defined as any systemic therapy including endocrine and chemotherapy NR, not reached From confirmatory OS analysis; data cut-off July 31, Hazard ratio

38 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Pertuzumab and trastuzumab have complementary mechanisms of action HER2 Pertuzumab Trastuzumab HER1/3/4 Subdomain IV Dimerization domain Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. 38

39 The mean duration of prior trastuzumab was 16.2 months ORR: 24% CB: 50%

40 The mean duration of prior trastuzumab treatment was 87.2 weeks

41 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) J Baselga, 1 S-B Kim, 2 S-A Im, 3 R Hegg, 4 Y-H Im, 5 L Roman, 6 J L Pedrini, 7 J Cortés, 8 A Knott, 9 E Clark, 9 G Ross 9 and S M Swain 10 1 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2 Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 3 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4 Hospital Pérola Byington, São Paulo, Brazil; 5 Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6 Leningrad Regional Oncology Dispensary, St Petersburg, Russian Federation; 7 CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8 Department of Oncology, Vall d Hebron University Hospital, Barcelona, Spain; 9 Roche Products Limited, Welwyn, UK; 10 Washington Cancer Institute, Washington Hospital Center, Washington D.C., USA Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

42 Study design San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 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 * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 42

43 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Prior therapy for breast cancer Prior (neo)adjuvant chemotherapy, n (%) Yes No Placebo + trastuzumab + docetaxel (n = 406) 192 (47.3) 214 (52.7) Pertuzumab + trastuzumab + docetaxel (n = 402) 184 (45.8) 218 (54.2) Components of (neo)adjuvant therapy*, n (%) Anthracycline Hormones Taxane Trastuzumab 164 (40.4) 97 (23.9) 94 (23.2) 41 (10.1) 150 (37.3) 106 (26.4) 91 (22.6) 47 (11.7) * Numbers add up to more than 100% because patients could have received more than one therapy Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 43

44 Progression-free survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently and investigator-assessed PFS Pertuzumab + T + D Placebo + T + D Pertuzumab + T + D Placebo + T + D D, docetaxel; PFS, progression-free survival; T, trastuzumab Independently assessed Investigator-assessed Independent assessment Investigator assessment HR = % CI, ; p< HR = % CI, ; p< Time (months) Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 44

45 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 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 Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 45

46 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 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 Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 46

47 Overall survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 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 Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 47

48 Cardiac tolerability San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 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 Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 48

49 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, Biomarker analyses in CLEOPATRA: A Phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC) J Baselga, 1 J Cortés, 2 S-A Im, 3 E Clark, 4 A Kiermaier, 5 G Ross, 4 and S M Swain 6 1 Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Department of Oncology, Vall d'hebron University Hospital, Barcelona, Spain; 3 Department of Internal Medicine, Seoul National University College of Medicine, Korea; 4 Roche Products Limited, Welwyn, United Kingdom; 5 F. Hoffmann-La Roche Limited, Basel, Switzerland; 6 Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute.

50 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 The HER2 signalling pathway 4 HER ligands (AREG, EGF, TGFα) sher2 IGF1R EGFR HER2 HER3 HER2 PTEN mtor ER PI3K Akt ER Grb2 Sos Shc Grb2 Sos Ras Raf p27 FKHR GSK3 BAD MEK 1/2 Cyclin D1, E Cell-cycle progression Cell survival Nucleus MAPK Cell proliferation c-myc Adapted from: Gianni L, et al. SABCS 2011 (Abstract S5-1). Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 50

51 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 The HER2 signalling pathway Selection of biomarkers HER ligands (AREG, EGF, TGFα) sher2 5 IGF1R EGFR HER2 HER3 HER2 PTEN mtor ER PI3K Akt ER Grb2 Sos Shc Grb2 Sos Ras Raf p27 FKHR GSK3 BAD MEK 1/2 Cyclin D1, E Cell-cycle progression Cell survival Nucleus MAPK Cell proliferation c-myc Adapted from: Gianni L, et al. SABCS 2011 (Abstract S5-1). Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 51

52 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, Assay methods Assay method IHC (by modified H-score) qrt-pcr (by CR) Marker HER2 HER3 IGF1R PTEN pakt EGFR HER2 HER3 AREG Betacellulin Successful analyses, n FISH c-myc 591 Mutational analyses ELISA (serum analyses) PIK3CA (8 mutations, 4 hotspots) sher2 AREG EGF TGFα CR, concentration ratio Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 52

53 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, Biomarker analyses: Exploration of prognostic effects Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute.

54 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 Prognostic effects independent of treatment arm Serum markers, both arms pooled PFS Covariate effect 13 n* HR 95% CI p-value Serum AREG [pg/ml] , Serum EGF [pg/ml] , Serum TGFα [pg/ml] , Serum sher2 [ng/ml] , * Slide High biomarker levels with better prognosis Low biomarker levels with better prognosis The treatment benefit with the addition of pertuzumab was maintained in all cases HR < 1.00 in all cases (p < )* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 54

55 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 Prognostic effects independent of treatment arm HER ligands and RTKs, both arms pooled PFS Covariate effect 14 n* HR 95% CI p-value AREG mrna (qrt PCR) Betacellulin mrna (qrt PCR) EGFR mrna (qrt PCR) HER2 mrna (qrt PCR) HER2 Mem H-score HER3 mrna (qrt PCR) HER3 Mem H-score HER2/HER3 mrna (qrt PCR) IGF1R Mem H-score , , , , , , , , , * Slide High biomarker levels with better prognosis Low biomarker levels with better prognosis The treatment benefit with the addition of pertuzumab was maintained in all cases HR < 1.00 in all cases (p = < )* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 55

56 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 Prognostic effects independent of treatment arm Intracellular pathway markers, both arms pooled PFS Covariate effect 15 n* HR 95% CI p-value PIK3CA WT , PTEN Cyt H-score , PTEN Nuc H-score , pakt Cyt H-score , pakt Nuc H-score , Target:cen. ratio (c-myc) , * Slide High biomarker levels with better prognosis Low biomarker levels with better prognosis The treatment benefit with the addition of pertuzumab was maintained in all cases HR < 1.00 in all cases (p = < )* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 56

57 Independently-assessed PFS (%) San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 PIK3CA mutation associated with poorer prognosis Trastuzumab plus placebo arm Pla+T+D: WT 101 events 63 events Time (months) Number at risk Pla+T+D WT Pla+T+D Mut Pla+T+D: Mut Mut, mutated; WT, wild-type Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 57

58 Independently-assessed PFS (%) San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 PIK3CA mutation associated with poorer prognosis Both arms Number at risk Pla+T+D WT Pla+T+D Mut Ptz+T+D WT Ptz+T+D Mut Pla+T+D: WT Ptz+T+D: WT 101 events 63 events Time (months) Pla+T+D: Mut Ptz+T+D: Mut 83 events 45 events Mut, mutated; WT, wild-type Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 58

59 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 Shorter median PFS observed with mutated PIK3CA while treatment effect is maintained 18 PIK3CA status Patients, n Pla+T+D Events Median, months Patients, n Ptz+T+D Events Median, months Mut WT Overall HR (95% CI) 0.64 (0.43, 0.93) 0.67 (0.50, 0.89) 0.62 (0.51, 0.75) The prognostic impact of PIK3CA mutations cannot be attributed to a specific mutation, nor to mutation(s) in a specific exon, based on the available dataset 182 mutations detected overall (32%) Mut, mutated; WT, wild-type Exon 7: 12; exon 9: 39; exon 20: 131 Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 59

60 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Predictor of pcr OS= f(pcr) Present Future Continuous HER2 inhibition Trastuzumab Lapatinib Defining treatments resistance PI3Ki possibly the past

61 NEOADJUVANT

62 What do we learn from the neaodjuvant trials? Year RFS pcr pinv cpr cnr p= pcr pinv cpr cnr OS p= Wolmark N: JNCI Monogr, 2001

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65 pcr impact on DFS according to the subtypes Luminal A Luminal B/HER2- Luminal B/HER2+++ HER2+++ non luminal Triple negative?

66 Overall population HER2 neg population HER2 pos w/o Tzb HER2 pos with Tzb 66

67 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Predictor of pcr OS & RFS= f(pcr) Essentially in HER2+++, HR- population Present Future

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70 pcr of primary tumour: intent-to-treat population Patients, % % p=0.002 p= % p=0.003 p= % 17% 20% 16% 0 With H Without H HER2 negative HER2 positive pcr With H Without H HER2 negative HER2 positive tpcr tpcr: total pathologic complete response in breast and nodes Gianni et al. 2008; Eiermann et al 2008; Semiglazov et al 2008.

71 Mean trastuzumab concentration Subcut vs IV mg/kg IV 8 mg/kg SC Exposure to trastuzumab comparable for 8 mg/kg subcutaneous vs 6 mg/kg intravenous in patients with HER2-positive EBC 50 C trough * Nominal time (h) *C trough of 20 µg/ml depicts PK target established from preclinical xenograft models Wynne C et al., Clin. Pharmacol Feb 22 [Epub ahead of print]

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74 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Predictor of pcr OS & RFS= f(pcr) Essentially in HER2+++, RH- population Present Trastuzumab IV & subcut FuturE

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79 The futur of drugs approval in HER2 positive breast cancers?

80 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Predictor of pcr OS & RFS= f(pcr) Essentially in HER2+++, RH- population Present Trastuzumab IV & subcut Future Trastuzumab based Double HER2 inhibition

81 ADJUVANT

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83 Joensuu H. et al. Clin. Cancer Res. 2003;9:

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86 HER2+ Breast Cancer Neoadjuvant Adjuvant Past Bad prognosis HER2+++ assoc with Tam resistance Present Future

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88 DFS ITT DFS CA OS ITT OS CA 88

89 DFS (landmark analysis): selective crossover and no crossover Patients alive and disease free (%) Selective crossover No crossover Months from randomisation No. at risk Gianni et al St Gallen 2011

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96 HERA TRIAL DESIGN Accrual (n=5102) Women with locally determined HER2- positive invasive early breast cancer Surgery + (neo)adjuvant CT RT Centrally confirmed IHC 3+ or FISH+ and LVEF 55% Randomization OBSERVATION n=1698 After ASCO 2005, option of switch to Trastuzumab 1 year Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n= years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701 CT, chemotherapy; RT, radiotherapy

97 Disease-free survival (%) HERA trial: DFS FOR 2 YEARS VS. 1 YEAR OF TRASTUZUMAB AT 8 YRS MFU % 86.7% 81.6% 81.0% 75.8% 76.0% 60 Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year Goldhirsch et al. ESMO 2012

98 Protocol of Herceptin Adjuvant with Reduced Exposure PHARE* Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin, Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar. *lighthouse in French

99 Study design trastuzumab up to 12 months Clinical exam LVEF trastuzumab 6 months R Stratification 1. ER pos / neg 2. Chemo: conco/ seq stop trastuzumab mos Mammography Up to 60 mos R: Randomization after informed consent

100 Probability Disease Free Survival Events HR 95%CI p-value H 12m 176 H 6m ( ) Months At risk H-12m H 6m H-12m H-6m * Cox model stratified by ER status and concomitant chemotherapy Pivot et al. ESMO 2012

101 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Bad prognosis Tam resistance Present Trastuzumab IV 1 year Futur

102 ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/ Herceptin HER2-positive early breast cancer (n=8000) Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy No taxane Concurrent taxanes e for 12 weeks H a q3w for 52 weeks L b qd for 52 weeks H c qw for 12 weeks L d qd + H c q3w for 52 weeks H a q3w for 52 weeks L b qd for 52 weeks H c qw for 12 weeks L d qd + H c q3w for 52 weeks 6-week washout 6-week washout L b qd for 34 weeks L b qd for 34 weeks a Herceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; b Lapatinib 1500 mg; c Herceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; d Lapatinib 1000 mg; e Paclitaxel 80 mg/m 2 qw or docetaxel q3w

103 ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/ Herceptin HER2-positive early breast cancer (n=8000) Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy No taxane Concurrent taxanes e for 12 weeks H a q3w for 52 weeks L b qd for 52 weeks Risk of inferiority H c qw for 12 weeks 6-week washout L d qd + H c q3w for 52 weeks H a q3w for 52 weeks L b qd for 52 weeks Risk of inferiority H c qw for 12 weeks 6-week washout L d qd + H c q3w for 52 weeks L b qd for 34 weeks L b qd for 34 weeks a Herceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; b Lapatinib 1500 mg; c Herceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; d Lapatinib 1000 mg; e Paclitaxel 80 mg/m 2 qw or docetaxel q3w

104 TEACH TYKERB Evaluation After Chemotherapy (TEACH) Trial 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, Ian Smith, Joyce O Shaughnessy, Bent Ejlertsen, Manfred Kaufmann, Francis Boyle, Aman Buzdar, Pierre Fumoleau, William Gradishar, Miguel Martin, Beverly Moy, Martine-Piccart-Gebhart, Kathleen I. Pritchard, Deborah Linquist, Gursel Aktan, Erica Rappold, Lisa Williams, Diane Finkelstein

105 TEACH Trial Study Design 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 Stratification Time from initial diagnosis ( 4 vs > 4 yr) Lymph nodes (+ vs -) ER + and/or PgR+ vs ER-/PgR - R A N D O M I Z A T I O N N 3,000 Lapatinib 1500 mg po qd x 1 yr N = 3147 August 2006 May countries Placebo po qd x 1 yr Diagnosis 4 yr

106 TEACH: Forest Plot of DFS for Subgroups in ITT Population Time since initial diagnosis 4 years (n=2248; L=175, P=219) > 4 years (n=899; L =35, P=45) < 1 year (n=647; L =55, P=79) Hormone receptor status ER and/or PgR + (n=1859; L =125, P=136) ER and PgR - (n=1288; L =85, P=128) Lymph node involvement Positive (n=1753; L=146, P=174) Negative (n=1394; L=64, P=90) Hazard Ratio (95% CI) 0.84 ( ) 0.81 ( ) 0.70 ( ) 0.98 ( ) 0.68 ( ) 0.86 ( ) 0.78 ( ) Hazard Ratio (Lapatinib / Placebo) L= lapatinib; P=placebo Favors Lapatinib Favors Placebo

107 HER2-Positive Breast Cancer: Applying the Latest Developments to Clinical Practice clinicaloptions.com/oncology APHINITY: Study Schema S U R G E R Y N = 3806 Central confirmation of HER2 status R A N D O M I Z A T I O N Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline based chemotherapy allowed Chemotherapy + trastuzumab and placebo Anthracycline or non-anthracycline based chemotherapy allowed F O L L O W U P 10 Y R S Randomization within 7 wks of surgery Start treatment within 1 wk ClinicalTrials.gov Identifier: NCT Anti-HER2 therapy for a total of 1 yr (52 wks) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

108 HER2-Positive Breast Cancer: Applying the Latest Developments to Clinical Practice clinicaloptions.com/oncology KAITLIN: Study Schema S U R G E R Y N = Central confirmation of HER2 status R A N D O M I Z A T I O N Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline based chemotherapy allowed Chemotherapy + TDM1 and pertuzumab Anthracycline or non-anthracycline based chemotherapy allowed F O L L O W U P 10 Y R S Randomization within 7 wks of surgery Start treatment within 1 wk Anti-HER2 therapy for a total of 1 yr (52 wks) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

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110 HER2+ Breast Cancer Neoadjuvant Adjuvant Past Bad prognosis Tam resistance Present Trastuzumab IV 1 year Future Trastuzumab subcut Double inhibition

111 HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Predictor of pcr OS= f(pcr) Bad prognosis Tam resistance Predictor of pcr OS= f(pcr) Present Trastuzumab IV & subcut Trastuzumab IV 1 year Continuous HER2 inhibition Trastuzumab Lapatinib Futur Trastuzumab based Double HER2 inhibition Trastuzumab subcut Double inhibition Defining treatments resistance PI3Ki possibly the past

112 THANKS 112