Past, Present and Future HER2 targeted therapy in breast cancer

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

Disclosures Roche GSK

What we will talk about?

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

METASTATIC

HR- HR+ 6

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

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

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

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: 2008-000673-38 ClinicalTrials.gov Identifier: NCT00820222 1 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

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

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

Primary endpoint: CNS endpoints (modified ITT) 17

Alive without progression (%) Investigator-assessed PFS (ITT population) 100 80 60 40 Lap + Cap (N=271) Lap + Cap Tras + Cap Tras + Cap (N=269) Events, n (%) 160 (59) 134 (50) Median PFS, months 6.6 8.0 Hazard ratio (95% CI) 1.30 (1.04-1.64) Stratified log-rank p-value 0.021 20 0 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 271 147 49 20 20 7 Tras + Cap 269 154 56 26 26 15 4 7 18

Survival (%) OS (ITT population) 100 80 Lap + Cap Tras + Cap 60 40 20 0 Lap + Cap (N=271) Tras + Cap (N=269) Events, n (%) 70 (26) 58 (22) Median OS, months 22.7 27.3 Hazard ratio (95% CI) 1.34 (0.95-1.90) Stratified log-rank p-value 0.095 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 271 194 129 79 48 27 Tras + Cap 269 207 140 97 61 29 7 6 1 19

Alive without progression (%) PFS and OS in patients with prior trastuzumab treatment (ITT) Survival (%) 100 80 Investigator-assessed PFS Lap + Cap Tras + Cap 100 80 OS Lap + Cap Tras + Cap 60 40 20 60 40 20 0 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 167 96 31 12 4 2 Tras + Cap 159 89 25 12 7 2 0 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 167 127 87 53 34 17 Tras + Cap 159 126 86 57 38 17 5 5 1 Lap + Cap (N=167) Tras + Cap (N=159) Events, n (%) 103 (62) 86 (54) Median PFS, months 6.6 6.1 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 22.7 27.3 Hazard ratio (95% CI) 1.18 (0.76, 1.83) 20

Alive without progression (%) PFS and OS in patients with no prior trastuzumab treatment (ITT) Survival (%) 100 80 Investigator-assessed PFS Lap + Cap Tras + Cap 100 80 OS Lap + Cap Tras + Cap 60 40 20 60 40 20 0 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 104 51 18 8 3 2 Tras + Cap 110 65 31 14 8 5 0 0 5 10 15 20 25 30 35 40 Time from randomisation (months) Subjects at risk Lap + Cap 104 67 42 26 14 10 Tras + Cap 110 81 54 40 23 12 2 1 NR, not reached Lap + Cap (N=104) Tras + Cap (N=110) Events, n (%) 57 (55) 48 (44) Median PFS, months 6.3 10.9 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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HER2+ Breast Cancer Neoadjuvant Adjuvant Metastatic Past Bad prognosis Tzb improve OS Independently of HR status Present Continuous HER2 inhibition Trastuzumab Lapatinib Future

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.

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.

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.

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

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 www.esmo2012.org

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 www.esmo2012.org

Proportion progression-free Progression-Free Survival by Independent Review 1.0 0.8 0.6 Median (months) No. of events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (months) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR=0.66 (P<0.0001). 34 www.esmo2012.org

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 991 6.4 9.6 0.66 (0.56, 0.78) World region US Western Europe Other 270 317 404 5.7 6.4 6.9 8.5 10.9 9.6 0.70 (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 >1 609 382 6.7 5.7 10.3 8.5 0.68 (0.55, 0.85) 0.63 (0.49, 0.82) Disease involvement Visceral Nonvisceral 669 322 5.7 10.2 9.6 8.5 0.55 (0.45, 0.67) 0.96 (0.71, 1.30) Hazard ratio 0.2 0.5 1 2 5 35 www.esmo2012.org

Proportion surviving Overall Survival: Confirmatory Analysis 1.0 0.8 0.6 78.4% 85.2% Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006 Efficacy stopping boundary P=0.0037 or HR=0.727 64.7% 0.4 51.8% 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk: Cap + Lap 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). 36 www.esmo2012.org

Overall Survival Subgroup Analyses Cap + Lap T-DM1 Baseline Total Median Median HR characteristic n (mos) (mos) (95% CI) All patients 991 25.1 30.9 0.70 (0.56, 0.87) Age group <65 years 853 24.6 30.9 0.66 (0.52, 0.83) 65 74 years 113 27.1 NR 0.74 (0.37, 1.47) 75 years 25 NR 11.1 3.45 (0.94, 12.65) ER and PR status ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85) ER and PR 426 23.7 27.1 0.75 (0.54, 1.03) Line of therapy a First-line 118 27.9 NR 0.61 (0.32, 1.16) Second-line 361 NR 27.1 0.88 (0.61, 1.27) Third- and later-line 512 23.3 33.9 0.62 (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, 2012. Hazard ratio 0.2 0.5 1 2 5 37 www.esmo2012.org

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 JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 38

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

The mean duration of prior trastuzumab treatment was 87.2 weeks

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.

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

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

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 100 90 80 70 60 50 40 30 20 10 0 Pertuzumab + T + D Placebo + T + D Pertuzumab + T + D Placebo + T + D 0 5 10 15 20 25 30 35 40 D, docetaxel; PFS, progression-free survival; T, trastuzumab Independently assessed Investigator-assessed Independent assessment Investigator assessment HR = 0.62 95% CI, 0.51 0.75; p<0.0001 HR = 0.65 95% CI, 0.54 0.78; p<0.0001 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

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 808 0.63 0.52 0.76 432 0.63 0.49 0.82 376 0.61 0.46 0.81 306 0.72 0.53 0.97 135 0.51 0.31 0.84 114 0.46 0.27 0.78 253 0.68 0.48 0.95 681 0.65 0.53 0.80 127 0.52 0.31 0.86 789 0.64 0.53 0.78 19 0.55 0.12 2.54 480 0.62 0.49 0.80 30 0.64 0.23 1.79 261 0.68 0.49 0.95 37 0.39 0.13 1.18 Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive 630 0.55 0.45 0.68 178 0.96 0.61 1.52 388 0.72 0.55 0.95 408 0.55 0.42 0.72 12 721 0.60 0.49 0.74 767 0.64 0.53 0.78 0 0.2 0.4 0.6 1 2 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

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 10.4 16.9 12.6 21.6 Hazard ratio (CI) 0.62 (0.35 1.07) 0.60 (0.43 0.83) 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

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 100 90 80 70 60 50 HR = 0.64* 95% CI 0.47 0.88 p = 0.0053* 40 30 20 10 Ptz + T + D: 69 events Pla + T + D: 96 events 0 0 5 10 15 20 25 30 35 40 45 n at risk Time (months) Pertuzumab + T + D 402 387 367 251 161 87 31 4 0 0 Placebo + T + D 406 383 347 228 143 67 24 2 0 0 * The interim OS analysis did not cross the pre-specified O Brien-Fleming stopping boundary (HR 0.603; p 0.0012) 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

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

San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 1 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.

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

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

San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 6 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 806 497 486 497 465 720 748 740 673 583 684 723 714 727 721 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

San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 12 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.

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] 714 1.13 0.93, 1.38 0.2229 Serum EGF [pg/ml] 727 0.96 0.79, 1.17 0.6965 Serum TGFα [pg/ml] 721 1.15 0.94, 1.40 0.1660 Serum sher2 [ng/ml] 729 1.23 1.01, 1.49 0.0433 * Slide 9 0.2 0.4 0.6 1 2 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 < 0.0001)* 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 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 673 0.94 0.77, 1.16 0.5783 583 1.08 0.86, 1.35 0.5055 720 1.09 0.89, 1.34 0.3845 748 0.77 0.63, 0.93 0.0080 806 0.83 0.69, 1.00 0.0502 740 0.81 0.66, 0.98 0.0348 497 0.86 0.67, 1.09 0.2042 740 0.85 0.70, 1.04 0.1142 486 1.18 0.93, 1.51 0.1721 * Slide 10 0.2 0.4 0.6 1 2 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 = 0.0004 < 0.0001)* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 55

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 557 0.63 0.49, 0.80 0.0001 PTEN Cyt H-score 497 1.17 0.92, 1.48 0.2091 PTEN Nuc H-score 497 1.12 0.88, 1.42 0.3622 pakt Cyt H-score 465 1.09 0.85, 1.41 0.4854 pakt Nuc H-score 465 0.80 0.62, 1.02 0.0741 Target:cen. ratio (c-myc) 591 1.07 0.84, 1.36 0.5762 * Slide 11 0.2 0.4 0.6 1 2 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 = 0.0003 < 0.0001)* Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 56

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 16 100 90 80 70 60 50 40 30 20 10 0 8.6 13.8 Pla+T+D: WT 101 events 63 events 0 3.3 6.6 10.9 13.2 16.4 19.7 23.0 26.3 29.6 32.9 Time (months) Number at risk Pla+T+D WT 191 164 136 114 66 46 23 17 9 3 1 Pla+T+D Mut 90 76 56 37 21 17 8 4 3 2 1 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

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 17 100 90 80 70 60 50 40 30 20 10 0 8.6 12.5 13.8 Number at risk Pla+T+D WT 191 164 136 114 66 46 23 17 9 3 1 Pla+T+D Mut 90 76 56 37 21 17 8 4 3 2 1 Ptz+T+D WT 190 179 159 137 90 71 46 26 16 5 3 Ptz+T+D Mut 86 71 61 44 29 25 12 6 2 1 1 21.8 Pla+T+D: WT Ptz+T+D: WT 101 events 63 events 0 3.3 6.6 10.9 13.2 16.4 19.7 23.0 26.3 29.6 32.9 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

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 90 63 8.6 86 45 12.5 WT 191 101 13.8 190 83 21.8 Overall 406 242 12.4 402 191 18.5 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

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

NEOADJUVANT

What do we learn from the neaodjuvant trials? 100 80 60 40 20 0 Year RFS pcr pinv cpr cnr p=0.00005 0 2 4 6 8 pcr pinv cpr cnr OS p=0.0008 2 4 6 8 Wolmark N: JNCI Monogr, 2001

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

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

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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pcr of primary tumour: intent-to-treat population Patients, % 50 40 30 43% p=0.002 p=0.29 38% p=0.003 p=0.43 20 10 23% 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.

Mean trastuzumab concentration Subcut vs IV 250 200 6 mg/kg IV 8 mg/kg SC 150 100 Exposure to trastuzumab comparable for 8 mg/kg subcutaneous vs 6 mg/kg intravenous in patients with HER2-positive EBC 50 C trough * 0 0 500 1000 1500 2000 2500 Nominal time (h) *C trough of 20 µg/ml depicts PK target established from preclinical xenograft models Wynne C et al., Clin. Pharmacol. 2012 Feb 22 [Epub ahead of print]

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

The futur of drugs approval in HER2 positive breast cancers?

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

ADJUVANT

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

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DFS ITT DFS CA OS ITT OS CA 88

DFS (landmark analysis): selective crossover and no crossover Patients alive and disease free (%) 100 80 60 40 20 0 0 Selective crossover No crossover 6 12 18 24 30 36 42 48 Months from randomisation No. at risk 885 885 884 878 870 851 822 690 480 469 468 455 438 408 388 358 302 232 Gianni et al St Gallen 2011

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HERA TRIAL DESIGN Accrual 2001 2005 (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=1703 2 years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701 CT, chemotherapy; RT, radiotherapy

Disease-free survival (%) HERA trial: DFS FOR 2 YEARS VS. 1 YEAR OF TRASTUZUMAB AT 8 YRS MFU 100 80 89.1% 86.7% 81.6% 81.0% 75.8% 76.0% 60 Trastuzumab 2 years 40 20 Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years 1553 367 0.99 (0.85-1.14) 0.86 1 year 1552 367 0 0 1 2 3 4 5 6 7 8 9 Years from randomization No. at risk Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194 Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205 Goldhirsch et al. ESMO 2012

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

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 0 3 6 9 12 15 18 21 24 30 mos Mammography Up to 60 mos R: Randomization after informed consent

Probability Disease Free Survival 1.00 97.0 93.8 90.7 87.8 0.75 95.5 91.2 87.8 84.9 0.50 0.25 0.00 Events HR 95%CI p-value H 12m 176 H 6m 219 1.28 (1.05 1.56) 0.29 0 12 24 36 Months 48 60 At risk H-12m 1690 1613 1390 980 544 18 H 6m 1690 1586 1353 939 526 23 H-12m H-6m * Cox model stratified by ER status and concomitant chemotherapy Pivot et al. ESMO 2012

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

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

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

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

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 2008 33 countries Placebo po qd x 1 yr Diagnosis 4 yr

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 (0.69-1.03) 0.81 (0.52-1.26) 0.70 (0.50-0.99) 0.98 (0.77-1.25) 0.68 (0.52-0.89) 0.86 (0.69-1.07) 0.78 (0.57-1.07) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 Hazard Ratio (Lapatinib / Placebo) L= lapatinib; P=placebo Favors Lapatinib Favors Placebo

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: NCT01358877 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

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 = 3806 1750 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

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

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

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