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Carlos L. Arteaga, M.D. Departments of Medicine and Cancer Biology Breast Cancer Research Program

Are We About To Cure HER2- Positive Breast Cancer?. Carlos L. Arteaga, M.D. Departments of Medicine and Cancer Biology Breast Cancer Research Program Vanderbilt Ingram Comprehensive Cancer Center Vanderbilt University School of Medicine.

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Carlos L. Arteaga, M.D. Departments of Medicine and Cancer Biology Breast Cancer Research Program

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  1. Are We About To Cure HER2- Positive Breast Cancer? Carlos L. Arteaga, M.D. Departments of Medicine and Cancer Biology Breast Cancer Research Program Vanderbilt Ingram Comprehensive Cancer Center Vanderbilt University School of Medicine

  2. HER2/Neu (ErbB2) oncogene is associatedwith poor prognosis in breast cancer HER2 geneamplification (Southern) Median Survival HER2 overexpression 3 yrsHER2 normal 6-7 yrs HER2 protein overexpression (IHC) Slamon et al. Science 237:177,1987

  3. HER2 Control HER2 Soft Agar HER2 (ErbB2) is Oncogenic

  4. Ligands and Receptors of the HER (ErbB) family ErbB4 HER4 ErbB3 HER3 ErbB2 HER2 EGFR/ErbB1 HER1 Heregulin HB-EGF Betacellulin Epiregulin Heregulin (Neuregulin) EGF TGFa Amphiregulin HB-EGF Betacellulin Epiregulin ? Ligands Ligand binding 44 100 36 48 EC IC Tyr-Kinase 82 100 59 79 100 33 24 28 C-terminus

  5. Some facts about the HER2 receptor network and HER2+ breast cancer HER2 is the most potent kinase and HER2-HER3 the most potent signaling dimer of this receptor network The main survival program activated by the HER (ErbB) network is the PI-3 kinase/Akt pathway The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are approved by the FDA for the treatment of HER2+ breast cancer

  6. EGF30001: Phase III trial of paclitaxel ± lapatinib in first line or metastatic breast cancer

  7. No benefit from lapatinib when analyzing the whole cohort

  8. Benefit from the addition of lapatinib to paclitaxel was significant in patients with HER2+ cancers

  9. Adjuvant trastuzumab prolongs survival ofpatients with HER2+ breast cancer 100 Trastuzumab(133 events) 87.1% 90 85.3% 80 Control(261 events) % Surviving disease-free 75.4% 70 67.1% 60 p<0.0001HR=0.48 50 0 0 1 2 3 4 5 Years after randomization No. at risk 3351 2379 1455 801 133 0 Control 1679 1162 689 374 59 0 Trastuzumab 1672 1217 766 427 74 0 Romond, Perez, Bryant, et al. NEJM 2005

  10. Lapatinib prolongs progression-free survivalafter trastuzumab (Geyer et al. NEJM 2006) Lapatinib + Capecitabine Capecitabine No. of pts 160 161 Progressed or died* 45 (28%) 69 (43%) 90 Median TTP, wks 19.7 36.9 80 Hazard ratio (95% CI) 0.51 (0.35, 0.74) 70 P-value (log-rank, 1-sided) 0.00016 60 50 40 30 20 10 0 % patients free from progression* 100 10 20 50 0 30 60 40 70 Time (weeks) * Censors 4 patients who died due to causes other than breast cancer

  11. Linker: MCC Derivative of Maytansine Trastuzumab HER2 • Normal-tissue target expression • Fc-mediated uptake • Non-specific uptake Target-dependent cytotoxic activity Processing of trastuzumab-DM1 conjugate

  12. Trastuzumab-DM1 but not trastuzumab induces apoptosis and cell lysis and works in trastuzumab-resistant tumors Lewis Phillips et al. Cancer Res. 68:9280, 2008

  13. Krop et al. SABCS 2009 (late breaking abstract 710)

  14. Key eligibility criteria • HER2+ disease by FISH or 3+ IHC by local lab • Measurable disease by CT scan as per RECIST • Prior anthracycline, trastuzumab, taxane, capecitabine and lapatinib therapy in any setting • Prior treatment with two HER2-directed regimens in the metastatic setting • Documented progression on their most recent treatment regimen • No history of significant cardiac disease; left ventricular ejection fraction (LVEF) ≥50% • No history of Grade ≥3 hypersensitivity to trastuzumab or toxicity requiring discontinuation • No Grade ≥3 peripheral neuropathy • No untreated or symptomatic brain metastases, or any treatment for brain metastases within 3 months of first dose

  15. Clinical activity of trastuzumab-DM1 (n=110) IRF, independent review facilityObjective response – CR or PR determined by two consecutive tumour assessments at least 28 days apart Clinical benefit – objective response or SD maintained for at least 6 months Krop I et al. SABCS 2009 (late breaking abstract 710)

  16. Implications Even in advanced stages, HER2+ tumors remain HER2-dependent Single agent anti-HER2 therapies do not inhibit the HER2 network completely Combinations of HER2-targeted drugs early in the treatment of HER2+ breast cancers is the rational way to go The optimal combination(s) of anti-HER2 agents up front may abrogate acquired resistance, shorten the duration of therapy, and dispense the need of chemotherapy

  17. Akt BT474 HR5  + lapatinib  +  + lapatinib P-HER3 250 160 P-Tyr 105 75 HER3 HER3 P-Akt p85 Akt p85 i.p. In order to induce an antitumor effect, anti-HER2 therapies should inhibit the PI3K/Akt pathway

  18. Trastuzumab disrupts ligand-independent HER2/HER3/PI3K complexes Yakes et al. Cancer Res. 62:4132, 2002; Junttila et al. Cancer Cell 15:429, 2009

  19. Contributed by Jenny Chang (Baylor), SABCS 2008

  20. Pre-therapy Post-therapy (2 wks) Inhibition of the HER2 with lapatinib is followed by upregulation of HER3 in primary HER2+ tumors p=0.01 P-HER3 was also upregulated upon tx No change in S473 P-Akt Inhibition of P-HER2 was incomplete Under review In collaboration with Jenny Chang (Baylor)

  21. BT474 SKBR3 lapatinib: 0 1 4 13 24 48 0 1 4 13 24 48 h P-EGFR (Y1068) EGFR P-HER2 (Y1248) lapatinib 0 1 4 13 24 48 0 1 4 13 24 48 0 1 4 13 24 48 h HER2 HER3 P-HER3 (Y1197) β-actin P-HER3 (Y1222) BT474 SKBR3 SUM225 P-HER3 (Y1289) short P-HER3 (Y1289) long HER3 P-Akt (S473) P-Akt (T308) Akt P-Erk Erk P-S6 S6 β-actin Upon inhibition of the HER2 kinase, HER2+ cells upregulate total and activated HER3 Garrett J, Arteaga CL. Unpublished

  22. HER2 ErbB3 p85 EGFR PI3K p110 Akt P P P P P IRS-1 p85 P P P PI3K p110 Akt Is compensatory upregulation of HER3 a possible mechanism of drug resistance? Activation of Compensatory Pathways IGF-IR Met lapatinib Tyrosine kinases that can activate HER3: MET, EGFR, FGFR2, Src, IGF-IR (?), BRK (?) Implication: Upregulation of HER3 provides a mechanism for maintenance of PI3K and escape from drug action

  23. BT474 SKBR3 BEZ235 0 1 4 13 24 48 0 1 4 13 24 48 h P-HER3 (Y1289) HER3 β-actin Inhibition of either HER2 or PI3K/Akt results in upregulation of HER3 RNA and protein and P-HER3

  24. Active Akt mutant limits lapatinib-induced upregulation of HER3 mRNA and protein

  25. TO-PRO-3 Merge FOXO3a 2° Ab alone DMSO 1 h lap 4 h lap DMSO 13 h lap 24 h lap C N C N C N FOXO3a Upregulation of HER3 upon inhibition of HER2 blockade is dependent on PI3 kinase and FoxO3a

  26. BT474 SKBR3 ctrl HER3 ctrl HER3 siRNA HER3 β-actin DMSO 0.33 µM lap 1.0 µM lap siCTRL siHER3 RNAi of HER3 enhances lapatinib action against HER2+ br ca cells * p<0.05 * * *

  27. Neutralizing HER3 monoclonal antibody sensitizes BT-474 xenografts to lapatinib * * * # ## ## # ** * ** ** ** Tx days • * p<0.05, ** p<0.01 versus control • # p<0.05, ## p<0.01 versus lapatinib

  28. p=.00005 Pre-tx 2 weeks p=.034 p=.006 control lapatinib p=.029 p=.000007 lap + AMG-888 Combination of lapatinib and AMG-888 inhibits FDG-PET

  29. Biomarkers of combined HER2 and HER3 inhibition ctrl lap lap+AMG-888 HER3 * P-Akt * * FoxO3a

  30. Trastuzumab inhibits recovery of P-HER3 after lapatinib lapatinib lap + trast 0 1 4 13 24 48 1 4 13 24 48 h P-HER3 BT474 β-actin 0 1 4 13 24 48 1 4 13 24 48 h P-HER3 SKBR3 β-actin Src, MET, FGFR2, IGF-IR, EGFR inhibitors and pertuzumab Did not block recovery of P-HER3 Garret J, …….., Arteaga CL, Unpublished

  31. Phase III study to test if total HER2 blockade improves clinical outcome RANDOMIZATION • Key Inclusion • HER2+(FISH+/ IHC3+) MBC • Progression on • Anthracycline • Taxane • Trastuzumab • Progression on most recent trastuzumab regimen Lapatinib 1500 mg/day PO N=148 Crossover if PD after 4wk therapy (N=73) • Stratification Factors • Visceral Disease • Hormone Receptor Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV qw N=148 31 Study conducted and funded by GlaxoSmithKline

  32. Lapatinib + trastuzumab improves OS compared to lapatinib in patients progressing on or after trastuzumab Blackwell KL, et al. J Clin Oncol 2010; 28;1124–1130

  33. Neoadjuvant lapatinib randomized Phase III trial neo-ALTTO (adjuvant lapatinib ± trastuzumab treatment optimization) trial (n=450)

  34. Summary Current therapeutic inhibitors of HER2 do not inhibit output to HER3 and PI3K/Akt completely Compensatory upregulation of HER3 function occurs by transcriptional and post-translational mechanisms To completely inhibit the HER2 network (and the PI3K pathway), compensatory upregulation of HER3 should be eliminated The best therapeutic strategy to eliminate HER3 function remains to be determined

  35. Anti-HER3 (ErbB3) strategies in clinical development Human antibody (IgG1) AMG-888 (AMGEN-U3) Human antibody (IgG2) MM-121 (Merrimack-Sanofi) HER3 antisense EZN-3920 (Enzon Pharmaceuticals)

  36. PI3K/AKT pathway inhibitors in clinical development

  37. Ansamycins bind the ADP/ATP switch site in Hsp90 Hsp70 Hip, etc Protein Protein Protein Protein Protein I I I P P P p p p 2 2 2 3 3 3 17-AAG 17AAG ATP ATP Hsp90 Ubiquination/ degradation Proteins degraded: EGFR/HER2 MET Raf kinase Steroid Receptors Akt CDK4 Hif1a Hsp90 Hsp90 Release of the mature/refolded protein

  38. Tumour regressions only seen in heavily pretreated HER2+ patients

  39. Best response and target lesion change (n=25)* * One additional patient had complete regression of a single target lesion but overall response of progressive disease based on non-target lesions. One patient withdrawn for clinical progression without radiological assessment

  40. Response rates for novel HER2-targeting agents after progression on trastuzumab P<0.0001 90 80 70 60 50 Response rates (%) 40 N=45 N=31 N=112 N=66 30 20 10 0 17-AAG Pertuzumab Neratinib T-DM1 Modi S et al, ASCO 2008; Gelmon KA et al, ASCO 2008; Swaby R et al, ASCO 2009; Burris HA et al, ESMO 2009

  41. We have a good problem (many drugs) in HER2+ breast cancer – we are just learning how to combine them now Pertuzumab (anti-HER2 antibody) Irreversible HER2 kinase inhibitors (neratinib) HER3 antibodies (AMG-888, MM-121) PI3K inhibitors (GDC-0941, XL-147, BKM120) Akt inhibitors (MK-2206) IGF-IR inhibitors (R1507, MK-0646, OSI-906) HSP90 inhibitors Trastuzumab-DM1 (fusion toxin) Bevacizumab and other angiogenesis inhibitors MET, Src, and TGFb inhibitors

  42. Implications There are several 2-drug combinations that can aim at completely inhibiting the HER2 network and its output to PI3K Lapatinib + trastuzumab Trastuzumab + AMG-888 Trastuzumab + pertuzumab Trastuzumab (or lapatinib) + a PI3K or a AKT inhibitor Trastuzumb-DM1 + a PI3K or a AKT inhibitor Neoadjuvant therapy provides a space where these can be compared (using path CR as an endpoint) Some molecular phenotypes may be more sensitive to some specific combinations (i.e., tumors with PI3K pathway mutations) Although efficacy may be equivalent, toxicity and cost will be major differentiating factors

  43. Vanderbilt Charles ManningWilliam Pao Baylor (Houston) Jenny Chang Bhuvanesh Dave Novartis Carlos Garcia-Echeverria Stanford Anne Brunet AMGEN-U3 Dan Freeman Robert Radinsky Thore Hetmann Acknowledgements

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