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19th Annual NOCR Meeting Session I: Breast Cancer HER-2+ Disease

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1 19th Annual NOCR Meeting Session I: Breast Cancer HER-2+ Disease
Christy A Russell, MD Keck School of Medicine University of Southern California

2 HER-2+ Breast Cancer Adjuvant and Neoadjuvant Therapy
Combining Trastuzumab with other HER2-directed agents Second generation choices Novel agents and conjugates

3 Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab
Hudis C. N Engl J Med. 2007;357:39-51. 3

4 Metastatic Breast Cancer Front-line Options

5 Trastuzumab Combinations as First-line Therapy for MBC: Pivotal Phase III Trial
Paclitaxel (n = 96) Previous adjuvant AC Patients with HER2+ (IHC 2+/3+) MBC, no previous chemotherapy, measurable disease, KPS ≥ 60% (N = 469) Trastuzumab + Paclitaxel (n = 92) AC (n = 138) No previous adjuvant AC Trastuzumab + AC (n = 143) Slamon DJ, et al. N Engl J Med. 2001;344: Slamon et al. N Engl J Med. 2001;344:783. Herceptin® (trastuzumab) PI. November 2006.

6 Trastuzumab in MBC: The Pivotal Trial
Treatment Objective Response Rate, % Median TTP, Mos Median OS, Mos Chemo 32 4.6 20.3 Chemo + Trastuzumab 50 7.4 25.1 P < .001 for all comparisons. Slamon DJ, et al. N Engl J Med. 2001;344:

7 Trastuzumab in Recommended First-line Combinations for HER2+ MBC
HER2+ disease without previous trastuzumab: trastuzumab plus Paclitaxel ± carboplatin Docetaxel Vinorelbine Capecitabine NCCN. Clinical practice guidelines in oncology: breast cancer. v

8 Trastuzumab in Triple-Combination Regimens: Response Rates
Yardley et al, 2004 (N = 24) H + V + T Untch et al, 2004 (N = 25) H + E90 + C Untch et al, 2004 (N = 26) H + E60 + C Dirix et al, 2006 (N = 34) H + Carbo + T Chan et al, 2007 (N = 34) H + V + X Fountzilas et al, 2004 (N = 40) H + G + P Yardley et al, 2006 (N = 41) H + G + Carbo Miller et al, 2002 (N = 45) H + G + P Venturini et al, 2006 (N = 45) H + E + T Perez et al, 2005 (N = 43) H + Carbo + P every 3 wks Perez et al, 2005 (N = 48) H + Carbo + P every wk Cortes et al, 2004 (N = 54) H + TLC D-99 + P Yardley et al, 2002 (N = 61) H + Carbo + T Pegram et al, 2004 (N = 59) H + Carbo + T Pegram et al, 2004 (N = 62) H + Cisplatin + T Robert et al, 2006 (N = 92) H + Carbo + P Wardley et al, 2006 (N = 111) H + X + T Forbes et al, 2006 (N = 130) H + Carbo + T 10 20 30 40 50 60 70 80 90 100 ORR (%)

9 Hormonal Therapy in HER2+ MBC
Regimen ORR, % PFS, Mos Trastuzumab (N = 79)[1] 26 Anastrozole + trastuzumab (N = 103)[2] 20 4.8 Anastrozole (N = 104)[2] 7 2.4 Lapatinib + letrozole (N = 642)[3] 28 8.2 Letrozole (N = 644)[3] 15 3.0 Lapatinib (N = 138)[4] 24 NA 1. Vogel C, et al. J Clin Oncol. 2002;20: 2. Mackey JR, et al. SABCS Abstract 3. 3. Johnston S, et al. J Clin Oncol. 2009;27: 4. Gomez HL, et al. J Clin Oncol. 2008;26:

10 Mechanism of Action of Lapatinib Compared to Trastuzumab
1 1 2 2 1 2 Erb receptors Lapatinib L Downstream signaling pathways Cell proliferation Cell survival

11 Lapatinib as First-line Treatment for HER2-Amplified LABC or MBC
Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients) Endpoint Lapatinib 1500 mg/day (n = 69) 500 mg BID All Patients (N = 138) Response rate, n (%) 15 (22) 18 (26) 33 (24) Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31) 6-mo PFS, % 41 45 43 Gomez HL, et al. J Clin Oncol. 2008;26: 11

12 Trastuzumab vs Lapatinib First-Line Therapy for MBC

13 Sample size: ~ 600 (536 patients centrally confirmed with HER2+)
MA.31/EGF108919: Design Randomize Experimental Arm 24 Wks: Lapatinib + taxane Until PD: Lapatinib Standard Arm 24 Wks: Trastuzumab + taxane Until PD: Trastuzumab Primary Outcome: PFS Sample size: ~ 600 (536 patients centrally confirmed with HER2+) ClinicalTrials.gov. NCT Gelmon, ASCO 2012

14 [TITLE]

15 Continued HER2 blockade
NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure Continued HER2 blockade Chemotherapy + trastuzumab Trastuzumab + lapatinib Capecitabine + lapatinib NCCN. Clinical practice guidelines in oncology: breast cancer. v National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.

16 EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer
1250 mg/day PO + Capecitabine mg/m2/day on Days 1-14 every 21 days Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with T4 lesion and unlimited previous therapies* Capecitabine 2500 mg/m2/day on Days 1-14 every 21 days Primary endpoint: TTP Secondary endpoints: OS, PFS, ORR *No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant). Geyer C, et al. N Engl J Med. 2006;355:

17 Lapatinib + Capecitabine in HER2+ MBC: TTP
TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab Regimen 100 100 80 80 Capecitabine Lapatinib + capecitabine Capecitabine Lapatinib + capecitabine 60 60 Cumulative Progression Free (%) Cumulative Progression Free (%) 40 40 20 20 20 40 60 80 20 40 60 80 Wks Wks Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc. Cameron D, et al. Oncologist. 2010;15:

18 Lapatinib + Capecitabine in HER2+ MBC: Efficacy
Result Capecitabine (n = 201) Capecitabine + Lapatinib (n = 207†) HR P Value Median TTP, wks[1] 18.6 31.3 0.50 < .001 OS, wks[1] 56.6 71.4 0.79 .077 ORR, %[2] 13.9 23.7 -- .017 Brain mets as site of first progression,* n (%)[2] 13 (6) 4 (2) .045 † n=198 in 2008 study. *Exploratory analysis. 1. Cameron D, et al. Oncologist. 2010;15: Cameron D, et al. Breast Cancer Res Treat. 2008;112:

19 Combining Lapatinib and Trastuzumab Increases Antitumor Activity
1600 Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse model Effect was durable: no tumor relapse observed at 8 mos after treatment Lapatinib induced accumulation of inactive HER2 at plasma membrane Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells In vivo activity was consistent with in vitro data demonstrating the combination as synergistic 1400 1200 Control Trastuzumab Lapatinib Trastuzumab + lapatinib 1000 Tumor Volume (mm3) 800 * 600 * 400 †‡ 200 13 16 19 21 23 Days After Injection *P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab. Scaltriti M, et al. Oncogene. 2009;28: Konecny GE, et al. Cancer Res. 2006;66: Xia W, et al. Oncogene. 2004;23: Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28: , copyright 2009.

20 Pivotal Trial EGF104900 R Lapatinib 1500 mg/day PO Patient Population
HER2+ MBC Multiple lines of trastuzumab Progression on trastuzumab at study entry R Crossover at the time of progressive disease Lapatinib 1000 mg/day PO + trastuzumab 4 mg/kg then 2 mg/kg IV q wk Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR Blackwell KL, et al. J Clin Oncol. 2012;30:

21 Lapatinib ± Trastuzumab in MBC: PFS
Outcome Lapatinib (n = 145) Lapatinib/ Trastuzumab (n = 146) HR (95% CI) P Value 6-mos PFS, % 13 28 0.73 ( ) .008 Progressed or died, n 128 127 -- Median PFS, wks 8.1 12.0 Blackwell KL, et al. J Clin Oncol. 2010;28:

22 Mos From Randomization
EGF104900: Overall Survival L + T (n = 148) L (n = 148) n 146 145 Median OS, mos 14.0 9.5 HR (95% CI) 0.74 ( ) Stratified log-rank P value .026 100 Survival(%) 80% 80 70% 60 56% 6-mo OS 52% of patients in the L arm crossed over to L + T 40 41% 12-mo OS 20 5 10 15 20 25 30 35 Mos From Randomization Pts at risk, n Lap 1000/Tras Lap 1500 87 64 63 46 42 28 25 13 1 Blackwell KL, et al. J Clin Oncol. 2012;30:

23 Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial
6 mg/kg every 3 wks + Capecitabine 2500 mg/m2/day on Days 1-14 every 21 days (n = 78) Patients with progressive MBC or LABC, HER2 overexpression, previous trastuzumab within 6 wks, and LVEF ≥ 50 (N = 156*) Capecitabine 2500 mg/m2/day on Days 1-14 every 21 days (n = 78) Primary endpoint: TTP Secondary endpoints: OS, ORR, safety *Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication. von Minckwitz G, et al. J Clin Oncol. 2009;27: 23

24 BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC
1.0 PFS 1.0 OS X XH Censored Log-rank P = .0338 X XH Censored Log-rank P = .2570 0.8 0.8 0.6 0.6 Probability of PFS Probability of OS 0.4 0.4 0.2 0.2 10 20 30 40 10 20 30 40 Mos Mos Pts at Risk, n Pts at Risk, n X XH 74 77 40 55 15 29 8 12 5 4 3 3 2 1 1 1 1 1 X XH 74 77 66 68 50 59 33 47 21 27 10 15 3 6 3 1 2 1 Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. von Minckwitz G, et al. J Clin Oncol. 2009;27:

25 New Option in the Front-Line: Pertuzumab

26 Pertuzumab and Trastuzumab: Mechanisms of Action
HER2 Trastuzumab HER1/3/4 Dimerization domain Subdomain IV Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC Ferguson KM, et al. Mol Cell. 2003;11: Olayioye MA, et al. EMBO J. 2000;19: Hynes NE, et al. Nat Rev Cancer. 2005;5: Rowinsky EK. Annu Rev Med. 2004;55:

27 Phase II Trial of Pertuzumab + Trastuzumab in HER2+ MBC: Efficacy
SD Responses were durable: Median duration of response: 5.8 mos Median PFS (all patients): 5.5 mos 60 PR CR 50 40 Patients (%) 30 20 10 All Patients (N = 66) Baselga J, et al. J Clin Oncol. 2010;28:

28 CLEOPATRA Study Design
Docetaxel (≥ 6 cycles recommended) Centrally confirmed HER2-positive locally recurrent, unresectable or MBC ≤ 1 hormonal regimen for MBC Prior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mos Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumab N = 406 Trastuzumab Placebo R 1:1 Docetaxel (≥ 6 cycles recommended) Trastuzumab N = 402 Pertuzumab Primary endpoint: Independently assessed PFS Baselga J, et al. N Engl J Med. 2012;366:

29 CLEOPATRA: Progression-Free Survival
Independently Assessed Pertuzumab, Mos (n = 402) Placebo, Mos (n = 406) HR P Value Median PFS 18.5 12.4 0.62 < .001 Baselga J, et al. N Engl J Med. 2012;366:

30 CLEOPATRA: Overall Survival (Confirmatory Analysis)
Pertuzumab, % (n = 402) Placebo, % (n = 406) HR P Value Median OS, mos NR 37.6 0.66 .0008 Swain SM, et al. SABCS Abstract P

31 CLEOPATRA: Safety Results
Select Adverse Events (Grade ≥ 3), % Pertuzumab (n = 407) Placebo (n = 397) Neutropenia 48.9 45.8 Febrile neutropenia 13.8 7.6 Leukopenia 12.3 14.6 Diarrhea 7.9 5.0 Peripheral neuropathy 2.7 1.8 Left ventricular systolic dysfunction 1.2 2.8 Baselga J, et al. N Engl J Med. 2012;366:

32 NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure
Preferred regimens Docetaxel + trastuzumab + pertuzumab (category 1) Paclitaxel + trastuzumab + pertuzumab Other regimens Chemotherapy + trastuzumab NCCN. Clinical practice guidelines in oncology: breast cancer. V National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v2.2006; Breast Cancer. At: Accessed December 2005.

33 Second-line and Further Therapy TDM-1

34 Trastuzumab/Emtansine: Novel Antibody–Drug Conjugate
Monoclonal antibody: trastuzumab Target expression: HER2 Trastuzumab Highly potent cytotoxic agent Cytotoxic agent: emtansine (DM1) MCC DM1 Systemically stable Linker: SMCC T-DM1 Average drug:antibody ratio ≅ 3.5:1

35 EMILIA Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC
Stratified by world region, number of previous chemotherapy regimens for MBC or unresectable locally advanced breast cancer, presence of visceral disease T-DM1 3.6 mg/kg by IV every 3 wks (n = 495) Patients with HER2-positive locally advanced or MBC* (N = 980) PD Capecitabine 1000 mg/m2 orally twice daily on Days 1-14, every 3 wks + Lapatinib 1250 mg/day orally continuously (n = 496) *All pts received previous taxane and trastuzumab Primary endpoint: PFS by IRF, OS, safety Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment Verma S, et al. NEJM 2012;367:

36 T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS
Median, Mos Events, n 1.0 Capecitabine/lapatinib T-DM1 304 265 0.8 Stratified HR: (95% CI: ; P < .0001) 0.6 Proportion Progression Free 0.4 T-DM1 Capecitabine/ lapatinib 0.2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Verma S, et al. NEJM 2012;367:

37 Overall Survival – Second Interim Analysis
Verma S, et al. NEJM 2012;367:

38 T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events
Capecitabine + Lapatinib (n = 488) All Grades Grades ≥ 3 Nonhematologic Diarrhea 23.3 1.6 79.7 20.7 Hand-foot syndrome 1.2 58.0 16.4 Vomiting 19.0 0.8 29.3 4.5 Hypokalemia 8.6 2.2 4.1 Fatigue 35.1 2.4 27.9 3.5 Nausea 39.2 44.7 2.5 Mucosal inflammation 6.7 0.2 19.1 2.3 Increased AST 22.4 4.3 9.4 Increased ALT 16.9 2.9 8.8 1.4 Hematologic Neutropenia 5.9 2.0 Febrile neutropenia 1.0 Anemia 10.4 2.7 8.0 Thrombocytopenia 28.0 12.8 Verma S, et al. NEJM 2012;367:

39 T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Expert Perspectives
T-DM1 showed improved efficacy vs capecitabine plus lapatinib Significant PFS improvement (HR: 0.650; P < .0001) OS benefit (HR: 0.68; P =<0.001) Favorable safety profile T-DM1 is an important new therapeutic option for patients with HER2+ MBC that has been previously treated with trastuzumab. Verma S, et al. NEJM 2012;367:

40 Ongoing Clinical Trials for Metastatic Breast Cancer

41 Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC
PD Trastuzumab + Taxane (n = 364) Patients with HER2+, previously untreated MBC (N = 1092) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) Primary endpoints: PFS as assessed by IRF, AEs Superiority design with a noninferiority analyses Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR ClinicalTrials.gov. NCT 41

42 mTOR Inhibition May Overcome Trastuzumab Resistance
Increased signaling through IGF-1R IGF-1R EGFR/HER2 Nutrients Truncated HER2 PI3K PTEN Constitutive PI3K/AKT activation LKB1 AKT Absent or low PTEN AMPK TSC1 TSC2 Elevated AKT or pAKT RHEB mTOR mTOR inhibitor Downstream inhibition with mTOR inhibitor counters these resistance mechanisms Synergy of mTOR inhibition and trastuzumab in vitro and in vivo Growth & proliferation Angiogenesis Cell metabolism Widakowich C, et al. Anticancer Agents Med Chem. 2008;8: Miller TW, et al. Clin Cancer Res. 2009;15:

43 BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab  Everolimus in HER2+ MBC
Stratification by previous adjuvant or neoadjuvant trastuzumab and presence of visceral metastases 28-day cycle 2:1 Patients with HER2-overexpressing, unresectable locally advanced or metastatic breast cancer, no previous trastuzumab or chemotherapy within 12 mos for advanced disease (N = 717) Everolimus 10 mg/day PO + Paclitaxel 80 mg/m2 on Days 1, 8, 15 + Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22 Paclitaxel 80 mg/m2 on Days 1, 8, 15 + Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22 + Placebo PO daily Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, PK, biomarkers ClinicalTrials.gov. NCT

44 Conclusions Multiple effective and available options in HER2+ MBC
Trastuzumab Pertuzumab Lapatinib Preferred first-line regimens include dual HER2 inhibition with pertuzumab and trastuzumab Other HER2 inhibition agents continue to have a role outside the first-line setting including the new availability of TDM-1.

45 Early Stage HER-2+ Breast Cancer

46 Neo-Adjuvant Therapy

47 GeparQuinto: HER2-Positive (n=615)
Core biopsy (d21-d35 after last infusion) Surgery Doc R Doc* EC Trastuzumab (T) Lapatinib (L) E: Epirubicin 90 mg/m² C: Cyclophosphamide 600 mg/m² Doc: Docetaxel 100mg/m² *+ G-CSF T for 6 mos T for 12 mos T: Trastuzumab 6 (8) mg/kg L: mg/d p.o. (all 3 week cycles) This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.

48 pCR Rates According to Other Definitions
No invasive residual in breast & nodes P<0.05 in breast This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.

49 Neo-ALTTO Trial José Baselga, Ian Bradbury, Holger Eidtmann, Serena DiCosimo, Claudia Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh, Karine Fauria, Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang, Istvan Lang, Michael Untch, Richard D. Gelber and Martine Piccart-Gebhert on behalf of the Neo-ALTTO Study Team December 10, 2010 *FDA approved in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.

50 Study Design Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.

51 Efficacy – pCR and to tpCR
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.

52 pCR by Hormone Receptor Status
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.

53 *Pertuzumab is not approved by the FDA for treatment of breast cancer.
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

54 NeoSphere Study Design and Objectives
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

55 NeoSphere pCR Rates: ITT Population Summary
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

56 NeoSphere: pCR and Hormone Receptors Status
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

57 NSABP B-41: Lapatinib in Neoadjuvant Treatment of HER2+ Breast Cancer
Tissue biopsy for biomarker analysis Doxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery (n = 178) Tissue biopsy for biomarker analysis Patients with HER2+, operable breast cancer (N = 529) Doxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Lapatinib 1250 mg/day until 1 day before surgery (n = 173) Surgery Trastuzumab 1 yr Doxorubicin/Cyclophosphamide 60/600 mg/m2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery + Lapatinib 750 mg/day until 1 day before surgery (n = 173) Primary endpoint: pCR Secondary endpoints: pCR in N0, toxicity, cCR, RFS, OS Robidoux A, et al. ASCO Abstract LBA506.

58 Lapatinib in Neoadjuvant Treatment of HER2+ Breast Cancer (NSABP B-41): pCR
Regimen n pCR*, % P Value† AC → WP + T 176 49.4 AC → WP + L 171 47.4 .78 AC → WP + T + L 60.2 .056 *Absence of invasive tumor in resected breast specimen and histologically negative axillary nodes. †Relative to AC → WP + T regimen. Robidoux A, et al. ASCO Abstract LBA506.

59 Adjuvant HER-2 Targeted Therapy

60 NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
Group A AC T R A N D O M I Z E Group B HER2 positive (FISH+ or IHC 3+) AC T H Group C n=3,505 AC T H = AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) Romond et al. N Engl J Med. 2005;353:1673. Herceptin® (trastuzumab) PI. November 2006.

61 NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy
Group 1 AC T R A N D O M I Z E Node positive HER2 positive (FISH+ or IHC 3+) Group 2 N=2,006 AC T H = AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) Romond et al. N Engl J Med. 2005;353:1673. Herceptin® (trastuzumab) PI. November 2006.

62 Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N9831 + B-31
Control Group (n=1,979): AC  T AC T N9831 Group A AC T B-31 Group 1 Trastuzumab Group (n=1,989): AC  T+H AC T N9831 Group C H AC T B-31 Group 2 H = AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) Herceptin® (trastuzumab) PI. November 2006. Data on file. Genentech, Inc.

63 N9831 and NSABP B-31 Update

64 Kaplan-Meier estimates of (A) event-free survival and (B) overall survival.
HR 0.52 P < .001 HR 0.61 Perez E A et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology

65 N9831 and NSABP B-31 Update Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology

66 Events Per Year From Randomizaton
Perez E A et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology

67 BCIRG 006 Update

68 Breast Cancer International Research Group (BCIRG) 006 Trial: Treatment Schema
D O M I Z E AC T (n=1073) SURGERY HER2-positive tumor (FISH+); node-positive or high-risk node-negative disease AC TH (n=1074) 52 weeks TCH (n=1075) 52 weeks Endpoints 1°: Disease-free survival (DFS) 2°: Overall survival, toxicity, pathologic and molecular markers = H = Trastuzumab 4 mg/kg loading dose = H = Trastuzumab 2 mg/kg qw = H = Trastuzumab 6 mg/kg q3w = AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w = T = docetaxel 100 mg/m2 q3w = TC = docetaxel 75 mg/m2/carboplatin target AUC 6 mg/mL· min Radiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicated Slamon et al. 29th Annual San Antonio Breast Cancer Symposium, 2005; Herceptin® (trastuzumab) PI. March 2009. Herceptin® (trastuzumab) PI. March 2009.

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71 Disease-Free Survival Among all Study Patients
DFS AC-TH vs AC-T HR .64 p<0.001 TCH vs AC-T HR .75 p=0.04 OS AC-TH vs AC-T HR .63 p<0.001 TCH vs AC-T HR .77 p=0.04

72 Overall Survival Overall Survival

73 DFS by Nodal Status at Randomization

74 DFS by Nodal Status at Randomization

75 Role of Anthracyclines?

76 Controversies in Use of Anthracyclines
Authors suggest TCH should not be a preferred regimen for HER2+ early breast cancer. BCIRG 006 not powered to show equivalence or non-inferiority between the two H-based regimens Numerically fewer recurrences and deaths in the ACTH arm than TCH.

77 Controversies in Use of Anthracyclines
Authors encourage use of anthracycline-based adjuvant trastuzumab regimens as a mainstay of therapy for women with higher-risk HER2+ tumors. TCH should only be considered for women with lower-risk HER2+ tumors or in women with clinical reasons to avoid anthracyclines.

78 Duration of Trastuzumab

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91 Pending Clinical Trials

92 BETH Phase III Study: Chemotherapy + Trastuzumab ± Bevacizumab
6 x docetaxel and carboplatin TCH (Group 1A) RT HER2+, N+ or high-risk N- Stratified by Ns and HRS (N ~ 3500) 1 yr of trastuzumab 6 x docetaxel and carboplatin TCHB (Group 1B) RT 1 yr of trastuzumab Primary endpoint: IDFS Secondary endpoints: DFS, OS, RFI, DRFI, toxicity 1 yr of bevacizumab ClinicalTrials.gov. NCT

93 ALTTO Trial Design Trastuzumab 8 mg/kg IV (loading dose)*  6 mg/kg every 3 wks for 1 yr  Paclitaxel 80 mg/m2 IV once wkly x 12 Women with centrally determined HER2-positive invasive breast cancer (N = 8381 accrued) Surgery, adjuvant anthracycline-based therapy for 4 cycles; LVEF ≥ 50 6-week wash-out Trastuzumab 4 mg/kg IV (loading dose)  2 mg/kg once wkly x 11  Paclitaxel 80 mg/m2 IV once wkly x 12 Lapatinib 1500 mg orally once daily x 34 wks Lapatinib 1500 mg/kg orally once daily x 51 wks  Paclitaxel 80 mg/m2 IV once wkly x 12 (This arm closed in 9/2011 due to inferiority) *For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose). Trastuzumab 8 mg/kg (loading dose)  6 mg/kg every 3 wks for 1 yr Lapatinib 1000 mg orally once daily x 51 wks  Paclitaxel 80 mg/m2 IV once wkly x 12

94 APHINITY: Study Schema
S U R G E R Y R A N D O M I Z T F O L W U P 10 Y R S Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline–based chemotherapy allowed N = 3806 N = 3806 Central confirmation of HER2 status Chemotherapy + trastuzumab and placebo Anthracycline or non-anthracycline–based chemotherapy allowed 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 ClinicalTrials.gov Identifier: NCT

95 Conclusions Trastuzumab in addition to chemotherapy remains the standard for all “high-risk” HER-2+ early breast cancer. Controversies exist regarding the following: Use of anthracyclines Definition of “high-risk” Role of additional biologic agents to trastuzumab Optimal duration of trastuzumab

96 Final Thoughts The addition of anti-HER2 therapy has changed the natural history of HER2+ early and metastatic breast cancer. Combining different anti-HER2 agents in these settings also appears to have an improved outcome. Pertuzumab and TDM-1 are newly approved for women with HER2+ metastatic breast cancer. Their role in the adjuvant/neoadjuvant setting depends upon the maturation of current clinical trials.


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