Update on the Management of HER2+ Breast Cancer. Christian Jackisch, MD, PhD Sana Klinikum Offenbach Offenbach, Germany

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1 Update on the Management of HER2+ Breast Cancer Christian Jackisch, MD, PhD Sana Klinikum Offenbach Offenbach, Germany

2 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions

3 Targeting the HER2 Receptor In a period of 20 years HER2 was identified as a bad prognostic factor - Impact on DFS: early recurrences - Impact on OS: distant mets - Impact on treatment resistance: endocrine treatment and classical CMF HER2 was identified as a target for new treatment approaches - Definition of the target population: IHC and/or FISH - Definition of the treatment: humanized monoclonal antibody - Demonstration of the first clinical results: phase II-III trials - Demonstration of different modes of application (IV vs SC) Trastuzumab clearly changes the prognosis of HER2-positive MBC with a strong impact on OS in EBC & MBC

4 Approved Treatment Options in HER2 + MBC

5 Other Innovative Targeted Therapies in HER2-Positive Breast Cancer Pertuzumab* IGF-1R EGFR HER2 VEGFR Trastuzumab emtansine* FLT-3 c-kit Lapatinib* PDGFR- Tumor cell membrane PI3K PIP 2 Ras IP 3 DAG Afatinib/Neratinib Akt RAF Src Endothelial cell and pericyte membrane mtor PKC MEK MAPK Approved Under investigation Everolimus ERK *Not approved in all countries Cell differentiation Nucleus Transcription factors Angiogenesis Cell proliferation Cell survival (apoptosis inhibition) Cell adhesion/ penetration/metastasis Perez EA, et al. Cancer. 2012;118(12): Hernandez-Aya LF, et al. Oncologist. 2011;16(4):

6 Options for Dual Blockade of the HER2 Receptor Vertical dual blockade Horizontal dual blockade T Trastuzumab T P Pertuzumab Lapatinib L L Downstream signaling pathways 1 Downstream signaling pathways 2 L, lapatinib; P, pertuzumab; T, trastuzumab. 1. Konecny GE, et al. Cancer Res. 2006;66(3): ; 2. Nahta R, et al. Cancer Res. 2004;64(7):

7 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions

8 CLEOPATRA: Study Design Primary endpoint: PFS (independently assessed) Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety Women with previously untreated, HER2-positive locally recurrent/metastatic breast cancer (N = 808) Trastuzumab 6 mg/kg q3w* + Docetaxel mg/m 2 q3w + Pertuzumab (PTZ) 420 mg q3w (n = 402) Trastuzumab 6 mg/kg q3w* + Docetaxel mg/m 2 q3w + Placebo q3w (n = 406) Treatment until disease progression or unacceptable toxicity *Trastuzumab 8 mg/kg loading dose given Minimum of 6 docetaxel cycles recommended; <6 cycles permitted for unacceptable toxicity or progressive disease (PD) Pertuzumab 840 mg loading dose given Baselga J, et al. Cancer Res. 2011;71(24 Suppl): Abstract S5-5.

9 Overall Survival, % CLEOPATRA Overall Survival PTZ + TRAS + DOC 48 patients crossed over from placebo to PTZ arm after previous report of OS benefit Long-term cardiac safety profile maintained Swain SM, et al. New Engl J Med. 2015;372(8): Control, 221 events Hazard ratio, 0.68 (95% CI, ) P<.001 Months Placebo + TRAS + DOC Pertuzumab, 168 events No. at Risk Pertuzumab Control months 40.8 months HR = 0.68, P <.001

10 Other Options on the Forefront for First-Line?

11 T-DM1: Mechanism of Action 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;17(20):

12 First-Line MBC: TDM4450 Study Design HER2-positive, recurrent locally advanced breast cancer or MBC (N = 137) 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m 2 q3w (n = 70) T-DM1 3.6 mg/kg q3w IV (n = 67) PD a PD a Crossover to T-DM1 (optional) Randomized, phase II, international, open-label study b Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary endpoints: PFS by investigator assessment, and safety Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover Key secondary endpoints: OS, ORR, DOR, CBR, and QOL a Patients were treated until PD or unacceptable toxicity b This was a hypothesis-generating study; the final PFS analysis was to take place after 72 events had occurred DOR, duration of response; CBR, clinical benefit rate; QoL, quality of life Hurvitz SA, et al. J Clin Oncol. 2013;31(9):

13 Proportion Progression Free TDM4450 PFS by Investigator: Randomized Patients TRAS+ DOC (n = 70) T-DM1 (n = 67) Median PFS, months Hazard ratio % CI Log-rank P value Number of patients at risk Time, Months TRAS + DOC T-DM Hazard ratio and log-rank P value were from stratified analysis Hurvitz SA, et al. J Clin Oncol. 2013;31(9):

14 Progression-Free Survival, Proportion TDM4450 Duration of Response (DOR): Randomized Patients Median DOR n Months 95% CI HT to 10.6 T-DM1 43 NR Duration of Objective Response, Months No. at Risk HT T-DM Hurvitz SA, et al. J Clin Oncol. 2013;31(9):

15 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity

16 EMILIA Trial HER2-positive (central) LABC or MBC (N = 991) n = 495 T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic therapy or within 6 months of adjuvant therapy 1:1 n = 496 Lapatinib 1250 mg/day orally qd Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w PD Primary endpoint: independently assessed PFS, OS, safety Key secondary endpoints: investigator-assessed PFS, ORR LABC, locally advanced breast cancer; MBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; IV, intravenous; PD, progressive disease; qd, once daily; bid, twice daily; PFS, progression-free survival; OS, overall survival; ORR, objective response rate. Verma S, et al. N Engl J Med. 2012;367(19):

17 Overall Survival, % 1.0 EMILIA: OS 85.2% (95% CI, ) Median, Months No. Events CAP + L T-DM % (95% CI, ) % (95% CI, ) % (95% CI, ) No. at risk: CAP + L Time, Months 496 Stratified HR: 0.68; (95% CI, ); P<.001 Efficacy stopping boundary, P =.0037 HR: T-DM Verma S, et al. N Engl J Med. 2012;367(19):

18 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions

19 TH3RESA Study Schema HER2-positive (central) advanced BC a (N = 600) 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 2 1 T-DM1 3.6 mg/kg q3w IV (n = 400) Treatment of physician s choice (TPC) b (n = 200) PD PD T-DM1 c (optional crossover) Stratification factors: World region, number of prior regimens for advanced BC, d presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety a Advanced BC includes MBC and unresectable locally advanced/recurrent BC b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy c First patient in: Sep Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD d Excluding single-agent hormonal therapy BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks Krop IE, et al. Lancet Oncol. 2014;15(7):

20 Overall Survival, % TH3RESA Overall Survival 100 Physician s choice Trastuzumab emtansine Physician s choice (n = 198) Trastuzumab emtansine (n = 404) 40 Median OS (95% CI), months 14.9 (11.27-NE) NE 20 0 Number at risk Physician s choice Trastuzumab emtansine Events Stratified HR (95% CI ); P<.0034 Efficacy stopping boundary; HR 0.370; P< Unstratified HR* (95% CI ); P< Months since randomization Krop IE, et al. Lancet Oncol. 2014;15(7):

21 EGF trial HER2-positive MBC (central) (N = 296) Prior taxane, anthracyclines and trastuzumab Progression on trastuzumab within most recent regimen for MBC Patients were stratified by hormone receptor and visceral disease status 1:1 n = 148 n = 148 Lapatinib 1000 mg qd Trastuzumab 4 mg/kg load, then 2 mg/kg weekly Lapatinib * 1500 mg qd *Lapatinib is not approved for use as a single agent. Primary endpoint: PFS Key secondary endpoints: OS, ORR, CBR, safety MBC, metastatic breast cancer; qd, once daily; PFS, progression-free survival; OS, overall survival; ORR, overall response rate; CBR, clinical benefit rate. Blackwell KL, et al. J Clin Oncol. 2010;28(7):

22 Overall Survival, % Overall Survival in ITT % 80% 6-month OS 56% L n = 145 L + TRAS n = 146 Died, n (%) 113 (78) 105 (72) Median, months HR (95% CI) 0.74 (0.57 to 0.97) Log-rank P L + T L 41% 12-month OS Time Since Random Assignment, months 35 Blackwell KL, et al. J Clin Oncol. 2012;30(21):

23 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions

24 Probability of Progression, % Survival Probability, % Taking Care of CNS Metastases Postponing WBRT Time to Progression by CNS Response Survival (Dashed lines Are 95% CI) Patients who did not respond to treatment Patients who responded to treatment Number at risk Time, Months 0 No response Time, Months Response No. at risk Bachelot T, et al. Lancet Oncol. 2013;14:64-71.

25 Taking Care of CNS Metastases CEREBEL: Optimizing Systemic Therapy 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 Z 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 X, et al. J Clin Oncol Jan 20 [Epub ahead of print].

26 Progression-Free Survival, % Overall Survival, % Taking Care of CNS Metastases CEREBEL: Optimizing Systemic Therapy Progression-Free Survival Lap + Cap n = 271 Tras + Cap n = 269 Events, n 160 (59%) 134 (50%) PFS, months (95% CI) First quartile 3.9 (2.8 to 5.4) 5.5 (4.8 to 5.6) Median 6.6 (5.7 to 8.1) 8.1 (6.1 to 8.9) Third quartile 12.2 (9.0 to 13.8) 18.2 (12.0 to 25.1) Hazard ratio (95% CI) 1.30 (1.04 to 1.64) Stratified log-rank P Survival Lap + Cap Tras + Cap Lap + Cap n = 271 Tras + Cap n = 269 Events, n 70 (26%) 58 (22%) OS, mos (95% CI) 1 st quartile 14.5 (12.8 to 15.4) 16.2 (14.3 to 19.7) Median 22.7 (19.5 to NR) 27.3 (23.7 to NR) 3 rd quartile NR 33.6 (33.6 to NR) HR (95% CI) (1.04 to 1.64) Stratified log-rank P Lap + Cap Tras + Cap Time Since Random Assignment, Months Number at risk Lap + Cap Tras + Cap Time Since Random Assignment, Months Number at risk Lap + Cap Tras + Cap Trial was terminated early (n = 540/650) Incidence of CNS-mets as first site of relapse was 3% (Tras + Cap) vs 5% (Lap + Cap) PFS & OS & SAE were in favor of Tras + Cap over Lap + Cap Different result according to pretreatment with trastuzumab Pivot X, et al. J Clin Oncol Jan 20 [Epub ahead of print].

27 Proportion Surviving Taking Care of CNS Metastases EMILIA: Retrospective Analysis of CNS-Mets Survival Time, Months No. at Risk XL T-DM In the EMILIA trial, 95/991 patients had CNS mets at baseline CNS progression: No CNS baseline (2% T-DM1; 0.7% XL) CNS baseline (22.2% T-DM1; 16.0% XL) Patients with baseline had significantly improved survival (26.8 mos vs 12.9 mos) Krop IE, et al. Ann Oncol. 2015;26(1): Median, months XL n = 50 T-DM1 n = Stratified HR =.382 (95% CI ) P =.0081

28 Taking Care of CNS Metastases EMILIA: Retrospective Analysis Progression-Free Survival Survival Krop IE, et al. Ann Oncol. 2015;26(1):

29 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions

30 Cardiac Dysfunction Secondary to HER2 Treatment Strategies in the Metastatic Setting Study, n Median Age, Years Previous Treatment LVEF Drop <50% and >10 20 Points Chronic Heart Failure Trastuzumab+ docetaxel 1 (First line) CLEOPATRA (406) 54 40% Anthracyclines 23% Taxanes 10% Trastuzumab 6.6% 0% Lapatinib + capecitabine 2 (Mainly second and third line) EMILIA (496) 53 61% Anthracyclines 100% Taxanes 100% Trastuzumab 1.6% NR T-DM1 2 (Mainly second and third line) EMILIA (495) 53 61% Anthracyclines 100% Taxanes 100% Trastuzumab 1.7% NR Trastuzumab+ pertuzumab+ docetaxel 1 (First line) CLEOPATRA (402) 54 37% Anthracyclines 23% Taxanes 12% Trastuzmab 3.8% <1% Lapatinib+ trastuzumab 3 (Second line onwards) EGF (148) % Anthracyclines 100% Taxanes 100% Trastuzumab 2.5% <1% LVEF, left ventricular ejection fraction; NR, not reported; T-DM1, trastuzumab emtansine 1. Baselga J, et al. N Engl J Med. 2012;366(2): ; 2. Verma S, et al. N Engl J Med. 2012;367(19): ; 3. Tyverb Assessment Report. Available at _Variation/human/000795/WC pdf. Accessed 10 March 2015.

31 Outline Treatment strategies for HER2-positive metastatic breast cancer since First line Second line Third line and beyond Managing special situations Brain metastasis Cardiac morbidity Future directions OF/LPD/0005/14. Date of preparation: March 2014.

32 MARIANNE trial Challenging first-line treatment (recruitment complete) HER2-positive locally recurrent or advanced breast cancer (N=1095) Blinded T-DM1 (3.6 mg/kg IV q3w) Pertuzumab (840 mg LD, 420 mg IV q3w) PD Stratified by: World region Neo/adjuvant therapy (Y/N) Trastuzumab- and/or lapatinib-based therapy (Y/N) Visceral disease (Y/N) 1:1:1 Blinded Open label T-DM1 (3.6 mg/kg IV q3w) Placebo Trastuzumab Taxane (docetaxel or paclitaxel) PD PD Primary endpoints: Key secondary endpoints: OS PFS, AEs T-DM1, trastuzumab emtansine; IV, intravenous; PD, progressive disease; LD, loading dose; PFS, progression-free survival; OS, overall survival. MARIANNE trial. Available at (accessed March 2014). OF/LPD/0005/14. Date of preparation: March 2014.

33 Future Directions in HER2+ MBC for Biosimilars First line: Pertuzumab-Trastuzumab-Taxane Future: T-DM1+pertuzumab? Second line: T-DM1 Third line: Many options optimal timing unknown Lapatinib-trastuzumab Lapatinib-capecitabine Trastuzumab-other chemo