Present and emerging treatment options in Her-2/neu overexpressing metastatic breast cancer

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1 Present and emerging treatment options in Her-2/neu overexpressing metastatic breast cancer Christoph C. Zielinski Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center, Medical University Vienna - General Hospital, Vienna, Austria

2 Gene expression patterns of breast carcinomas predict survival Adapted from Sorlie T et al. Proc Natl Acad S 2001;98(19):

3 Breast cancer is a heterogeneous group of diseases OS DFS Adapted from Sorlie T et al. Proc Natl Acad S 2001;98(19):

4 Incidence of metastases in dependence from the molecular subtype Cumulative incidence curves of first distant metastasis by breast cancer subtype Cumulative incidence of metastases Luminal A Luminal B Luminal HER2+ HER2+ enriched Basal Nonbasal TN p<0.001 Time since diagnosis (years) Kennecke H et al. J Clin Oncol 2010;28: Reprinted with permission (2010) American Society of Clinical Oncology. All rights reserved

5 3,726 patients Overall survival from MBC in dependence on molecular characteristics Median observation: 14.8 years Median OS from MBC: Luminal A: 2.2 years Her-2 positive: 0.7 years (remark: pre-trastuzumab) Basal: 0.5 years (p<0.001) Kennecke H et al. J Clin Oncol 2010;28:

6 The HER family of receptors Ligands Ligandbinding domain TGF-α EGF Epiregulin Betacellulin HB-EGF Amphiregulin No ligandbinding activity* Heregulin Heregulin (neuregulin-1) Epiregulin HB-EGF Neuregulins-3, -4 Tyrosine kinase domain Erb-B1 HER1 EGFR *HER2 dimerizes with other members of the HER family. Erb-B2 HER-2/neu Erb-B3 HER3 Erb-B4 HER4 Adapted from Roskoski R Jr. Biochem Biophys Res Commun 2004;319(1):1-11; Adapted from Rowinsky EK. Annu Rev Med.2004;55:

7 HER-2/neu: Molecular pathways and clinical characteristics of breast cancer HER-2 gene amplification is associated with increased tumour proliferation HER-2 amplification is associated with high-grade disease, nodal metastases, tumour size, and inversely correlated with ER status HER-2 activates ER in the presence of low estrogen ER activates intracellular signalling potentiating HER-2 activity and downregulates HER-2 expression This negative loop is neutralized by HER-2 overexpression Tumour proliferation linked to RAS/MAPK cascade Increased cell migration and lymph node involvement linked to Akt/PI3 kinase Bartlett JMS et al. J Clin Oncol 2007;25:4423

8 Her-2/neu overexpressing metastatic breast cancer: Evidence for targeted treatment Targeted monotherapy Trastuzumab Lapatinib, reversible TKI T-DM1 Targeted combinations Trastuzumab + lapatinib Trastuzumab + pertuzumab

9 Targeted therapies for HER2+ breast cancer: Trastuzumab, lapatinib, and T-DM1 Antibody: Trastuzumab HER2 Cytotoxic: DM1 P P Stable linker: MCC Emtansine P P P Trastuzumab Lapatinib P T-DM1 Nucleus Spector NL and Blackwell KL. J Clin Oncol 2009;27(31): ; Nelson MH et al. Ann Pharmacother 2006;40(2): ; Lewis Phillips GD et al. Cancer Res 2008;68(22):

10 OS in dependence from trastuzumab and Her-2/neu characteristics Dawood S et al. J Clin Oncol 2010;28(1): Reprinted with permission (2010) American Society of Clinical Oncology. All rights reserved

11 HannaH: Randomised open-label Phase III noninferiority study to compare the PK, efficacy and safety of trastuzumab SC and IV in HER2-positive EBC Herceptin SC HER2- positive EBC (N=596) R 1:1 Herceptin IV Surgery Follow-up: 24 month for EFS, OS Trastuzumab SC Fixed dose of 600 mg (5 ml over 5 minutes) Trastuzumab IV 8 mg/kg loading dose; 6 mg/kg maintenance dose Docetaxel 75 mg/m 2 FEC 500/75/500 mg/m 2 1 year (18 cycles) Herceptin Safety, tumour response pcr Safety, EFS, OS PK Primary endpoint Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed Trastuzumab C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pcr) in the breast Ismael G et al. Lancet Oncol 2012;13(9): (2012), with permission from Elsevier

12 Herceptin SC vial vs. SID Comparative pharmacokinetics of trastuzumab subcutaneous formulation administered using a proprietary single-use injection device, or manually using a syringe Bioequivalence for the co-primary PK endpoints, AUC 0 21 days and C max, between Herceptin SC administered using the SID and handheld manual syringe was demonstrated Overall secondary PK parameters were also comparable between the two methods of administration SID: no failures, consistently high performance; tolerability did not differ from administration from the hand-held syringe Herceptin SID may have even greater potential to improve patient convenience Wynne C et al. ESMO 2012;abstr 2219

13 HannaH sub-analysis Pathological complete response to trastuzumab subcutaneous fixed-dose formulation in the HannaH study Subgroup analysis of patient demographics and tumour characteristics and influence of body weight (BW) and serum trough (C trough ) concentration of trastuzumab: Numerically higher pcr rate point estimate in Herceptin SC vs. IV in the majority of subgroups The 600 mg fixed dose of Herceptin SC is efficacious irrespective of body weight Additional analyses and MLR showed neither body weight nor serum C trough of Herceptin affected efficacy in either treatment arm Melichar B et al. ESMO 2012 Poster discussion;abstr 2546(254PD)

14 Trastuzumab: Escape-mechanisms High EGFR expression (Smith et al. 1993) Overexpression of insulin-like growth factor receptor I (IGF-RI) with amplification of the PI-3K pathway (Nahta et al. 2005) Somatic mutations of the HER2 gene (Shigematsu et al. 2006) Siena S et al. J Natl Cancer Inst 2009;101(19): By permission of Oxford University Press

15 New treatment options 2013 Her-2/neu directed therapies Pertuzumab T-DM1

16 Hallmarks of the human epidermal growth factor receptor 2 (HER2) -HER3 activation and signaling pathway Makhija S et al. J Clin Oncol 2010;28(7): Reprinted with permission (2010) American Society of Clinical Oncology. All rights reserved

17 Pertuzumab and trastuzumab bind to different regions on HER2: Synergistic activity Badache A and Hynes NE. Cancer Cell 2004;5: (2004), with permission from Elsevier

18 CLEOPATRA Trial A phase III study of docetaxel plus trastuzumab +/- pertuzumab in Her-2/neu overexpressing metastatic breast cancer Progression-free survival (%) Independently assessed progression-free survival Pertuzumab (median, 18.5 mo) Control (median, 12.4 mo) Hazard ratio, 0.62 (95% CI, ) p< Months No. at risk Pertuzumab Control Redrawn from Baselga J et al. N Engl J Med 2011;366:

19 CLEOPATRA Trial: Progression-free survival in prespecified subgroups Subgroup No.of pts Hazard ratio (95% CI) All pts ( ) Previous neoadjuvant or adjuvant chemotherapy No ( ) Yes ( ) Geographic region Europe ( ) North America ( ) South America ( ) Asia ( ) Age group <65 yr ( ) 65 yr ( ) <75 yr ( ) 75 yr ( ) Race or ethnic group White ( ) Black ( ) Asian ( ) Other ( ) Disease type Visceral disease ( ) Nonvisceral disease ( ) Hormone-receptor status ER-positive, PgR-positive, or both ( ) ER-negative and PgR-negative ( ) ER and PgR status unknown 12 - HER2 status IHC ( ) FISH-positive ( ) Pertuzumab better Redrawn from Baselga J et al. N Engl J Med 2011;366: Placebo better

20 CLEOPATRA Trial A phase III study of docetaxel plus trastuzumab +/- pertuzumab in Her-2/neu overexpressing metastatic breast cancer Overall survival 100 Overall survival (%) Hazard ratio, 0.64 (95% CI, ) p= Pertuzumab, 69 events Control, 96 events Months No. at risk Pertuzumab Control Redrawn from Baselga J et al. N Engl J Med 2011;366:

21 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;17:6437

22 Schematic of trastuzumab-dm1 (T-DM1) including the [N-maleimidomethyl]cyclohexane-1- carboxylate (MCC) linker Krop IE et al. J Clin Oncol 2010;28(16): Reprinted with permission (2010) American Society of Clinical Oncology. All rights reserved

23 T-DM1: Analysis of efficacy according to line of treatment 1. Pretreated Her-2/neu overexpressing MBC: EMILIA Trial phase III trial (T-DM1 vs. lapatinib/capecitabine) 2. First-line treatment for Her-2/neu- positive MBC: Randomized phase II trial (T-DM1 vs. trastuzumab + docetaxel)

24 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Adapted from Blackwell K et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1

25 EMILIA: Patient disposition Cap + Lap T-DM1 Randomized, n Treated, n On treatment at data cutoff date Median follow-up, mos (range) 12.4 (0 35) 12.9 (0 34) First patient in: February 23, 2009 Last patient in: October 13, 2011 Clinical data cutoff: January 14, 2012 Blackwell K et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1

26 EMILIA: Prior systemic treatment Prior treatment type, n (%) Taxanes Anthracyclines Endocrine agents Prior therapy for MBC, n (%) Yes No Prior trastuzumab treatment, n (%) EBC only Duration of trastuzumab treatment, n (%) <1 yr 1 yr Cap + Lap (n=496) 494 (100) 302 (61) 204 (41) 438 (88) 58 (12) 495 (100) 77 (16) 212 (43) 284 (57) T-DM1 (n=495) 493 (100) 303 (61) 205 (41) 435 (88) 60 (12) 495 (100) 78 (16) 210 (42) 285 (58) Median time since last trastuzumab, mos (range) 1.5 (0 98) 1.5 (0 63) Blackwell K et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1

27 Percent ORR Difference: 12.7% (95% CI, 6.0, 19.4) P= % 120/389 Cap + Lap EMILIA: Objective response rate (ORR) and duration of response (DOR) in patients with measurable disease 43.6% 173/397 T-DM1 Proportion progression-free No. at risk Cap + Lap T-DM1 DOR Median, mos (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) Blackwell K et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1

28 Trastuzumab emtansine for HER2-positive MBC: Progression-free survival (EMILIA Trial) Progression-free survival (%) Median no. of months Stratified hazard ratio, 0.65 (95% CI, ) p<0.001 T-DM1 Lapatinib-capecitabine Months No. at risk Lapatinib capecitabine T-DM No. of events Lapatinib-capecitabine T-DM Redrawn from Verma S et al. N Engl J Med 2012;367(19):

29 Trastuzumab emtansine for HER2-positive MBC: 2nd interim analysis of OS (EMILIA Trial) 100 Median no. of months No. of events Lapatinib-capecitabine T-DM % (95% CI, ) Overall survival (%) % (95% CI, ) Stratified hazard ratio, 0.68 (95% CI, ) p<0.001 Efficacy stopping boundary, p= or hazard ratio, % (95% CI, ) 51.8% (95% CI, ) T-DM1 Lapatinib-capecitabine Months No. at risk Lapatinib capecitabine T-DM Redrawn from Verma S et al. N Engl J Med 2012;367(19):

30 First-line treatment for Her-2/neu-positive MBC: A randomized phase II trial (T-DM1 vs. trastuzumab + docetaxel) PFS (primary endpoint): T-DM1 (n=67): 14.2 months TD (n=70): 9.2 months ORR: T-DM1: 64.2% ( %) TD: 58% ( %) Hurvitz SA et al. J Clin Oncol 2013;31(9):

31 HER2 somatic mutations in breast cancer 2013 by American Association for Cancer Research Weigelt B and Reis-Filho JS. Cancer Discovery 2013;3(2): (2013) Reprinted with permission from AACR

32 Trastuzumab resistance: Redundancy of signal transduction Preclinical models suggest increased EGFR-expression, increased EGFR-phosphorylation and increased heregulinexpression 1 Upregulation of Her2/EGFR-heterodimers 1 Increased Her2/Her3 signalling 2,3 Increased activity of the IGF-1 pathway 4,5 Neoadjuvant trial: IGF-1 receptor-expression correlates inversely with trastuzumab response 6 1 Ritter CA et al. Clin Cancer Res 2007;13: ; 2 Sergina NV et al. Nature 2007;445: ; 3 Chen FL et al. Clin Cancer Res 2008;14: ; 4 Nahta R et al. Cancer Res 2005;65: ; 5 Lu Y et al. J Natl Cancer Inst 2001;93: ; 6 Harris LN et al. Cancer Res 2007;13:

33 Different molecular mechanisms determine response and resistance to trastuzumab and lapatinib PI3K / AKT activation as resistance mechanism in Her-2/neu overexpressing breast cancer resulted in clinical trials of PI3K inhibitors in trastuzumabresistance 2010 by American Association for Cancer Research O'Brien NA et al. Mol Cancer Ther 2010;9: Reprinted by permission from the American Association for Cancer Research

34 Lapatinib: Mechanisms of action Lapatinib inhibits Akt and ERK1/2, resulting in upregulation of pro-apoptotic genes 1-3 Increased rate of apoptosis is associated with clinical response (n=33 biopsy samples) 4 Day 0 Day 21 1 Rusnak DW et al. Mol Cancer Ther 2001;1:85-94; 2 Hegde PS et al. Mol Cancer Ther 2007;6: ; 3 Xia W et al. Oncogene 2002;21: ; 4 Spector NL et al. J Clin Oncol 2005;23: Reprinted with permission (2011) American Society of Clinical Oncology. All rights reserved

35 Lapatinib: Alternative mechanisms of action 1 Receptor dimerization results in receptor internalization and degradation in lysosomes Lapatinib blocks ubiquitination and inhibits degradation by receptor stabilization within the membrane Potentially improves activity of anti-her2-mabs 1 Scaltriti M et al. Oncogene 2009;28:

36 MA.31 (NCT )1: First direct comparison of trastuzumab vs. lapatinib in MBC Prospective randomized phase III study 636 patients, Her2-positive MBC (525 centrally confirmed), first-line treatment Trastuzumab plus taxane versus lapatinib plus taxane First direct comparison of trastuzumab vs. lapatinib in MBC Taxanes: Paclitaxel weekly or docetaxel every three weeks Combination therapy for 24 weeks followed by anti-her2 maintenance 1 Gelmon KA et al. J Clin Oncol 2012;30(18_suppl):abstr LBA671

37 MA.31 (NCT ): PFS 1 1 Gelmon KA et al. J Clin Oncol 2012;30(18_suppl):abstr LBA671. Reprinted with permission (2012) American Society of Clinical Oncology. All rights reserved

38 Lapatinib: Indications In particular clinical situations? Depending upon tumour biology:...upon trastuzumab resistance? in CNS metastases...in endocrine (in)dependence? 1 Bartsch R et al. BMC Cancer 2009;9:367; 2 Gianni L et al. Cancer Res 71(3_suppl):abst S5-S1; 3 Xu B et al. Cancer Res 71(3_suppl):abst S3-S3; 4 Loibl S et al. J Clin Oncol 2011;29(suppl):abstr 530

39 Lapatinib in brain metastases Prospective phase II patients, Her2-positive MBC, BM Progression upon whole brain radiotherapy RR lapatinib 6%; minor response 21% RR lapatinib + capecitabine 20%; minor response 40% PFS lapatinib: 2.4 months ( ) PFS lapatinib + capecitabine: 3.65 months (95% CI ) OS lapatinib: 6.37 months ( ) OS lapatinib + capecitabine: Not reported 1 Lin NU et al. Clin Cancer Res 2009;15:

40 CEREBEL-Study 1 Prevention of brain metastases with early use of lapatinib? Validation study Prospective randomized phase III study No significant reduction of incidence of brain metaseses with early switch to lapatinib as compared to trastuzumab beyond progression MRI screening for brain metastases required - thus, patients with asymptomatic CNS disease excluded. Activity of lapatinib plus capecitabine notably in patients with limited CNS disease 1 Pivot X et al. ESMO 2012;abstr LBA11

41 Impact of anti-her2 after diagnosis of brain mets 1 Survival depends upon ongoing systemic therapy: No further treatment: 3 months (95% CI ) Chemotherapy only: 9 months (95% CI ) + Trastuzumab: 13 months (95% CI ) + Lapatinib: Median OS not reached at 24 months median time of observation Survival functions Cumulative survival TOO 1 Adapted from Bartsch R et al. Br J Cancer 2012;106(1):25-31

42 Primary systemic therapy of brain metastases? Rationale: Delay of whole brain radiotherapy (late toxicity!) 1 LANDSCAPE: Lapatinib plus capecitabine in Her2-positive patients with brain metastases 2 Single-arm phase II study Primary endpoint RR (CNS): 66% Secondary endpont time to radiotherapy: 8.3 months Caveat: 40% asymptomatic, 95% ECOG <2, no data concerning QoL 1 Chang EL et al. Lancet Oncol 2009;10: ; 2 Bachelot T et al. Lancet Oncol 2013;14(1):64-71

43 T plus L: Dual Her2 inhibition in MBC: PFS and OS benefit 1 PFS OS 1 Blackwell KL et al. J Clin Oncol 2010;28(7): Reprinted with permission (2012) American Society of Clinical Oncology. All rights reserved

44 1 Adapted frpm Baselga J et al. Lancet 2012;379: NeoAltto 1 : Benefit for combination

45 Conclusions: Evidence for ameliorated efficacy of Her-2/neu targeting MBC Targeted monotherapy Trastuzumab Lapatinib, reversible TKI T-DM1 Targeted combinations Trastuzumab + lapatinib Trastuzumab + pertuzumab

46 Thank you!