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

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Presentation on theme: "19 th Annual NOCR Meeting Session I: Breast Cancer HER-2+ Disease Christy A Russell, MD Keck School of Medicine University of Southern California."— Presentation transcript:

1 19 th 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 Hudis C. N Engl J Med. 2007;357: Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab

4 Metastatic Breast Cancer Front-line Options

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

6 Trastuzumab in MBC: The Pivotal Trial TreatmentObjective Response Rate, % Median TTP, MosMedian OS, Mos Chemo Chemo + Trastuzumab Slamon DJ, et al. N Engl J Med. 2001;344: P <.001 for all comparisons.

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 ORR (%) H + Carbo + T H + V + T H + E90 + C H + E60 + C H + Carbo + T H + V + X H + G + P H + G + Carbo H + G + P H + E + T H + Carbo + P every 3 wks H + Carbo + P every wk H + TLC D-99 + P H + Carbo + T H + Cisplatin + T H + Carbo + P H + X + T Forbes et al, 2006 (N = 130) Wardley et al, 2006 (N = 111) Robert et al, 2006 (N = 92) Pegram et al, 2004 (N = 62) Pegram et al, 2004 (N = 59) Yardley et al, 2002 (N = 61) Cortes et al, 2004 (N = 54) Perez et al, 2005 (N = 48) Perez et al, 2005 (N = 43) Venturini et al, 2006 (N = 45) Miller et al, 2002 (N = 45) Yardley et al, 2006 (N = 41) Fountzilas et al, 2004 (N = 40) Chan et al, 2007 (N = 34) Dirix et al, 2006 (N = 34) Untch et al, 2004 (N = 26) Untch et al, 2004 (N = 25) Yardley et al, 2004 (N = 24)

9 Hormonal Therapy in HER2+ MBC RegimenORR, %PFS, Mos Trastuzumab (N = 79) [1] Anastrozole + trastuzumab (N = 103) [2] Anastrozole (N = 104) [2] 72.4 Lapatinib + letrozole (N = 642) [3] Letrozole (N = 644) [3] Lapatinib (N = 138) [4] 24NA 1. Vogel C, et al. J Clin Oncol. 2002;20: Mackey JR, et al. SABCS Abstract Johnston S, et al. J Clin Oncol. 2009;27: Gomez HL, et al. J Clin Oncol. 2008;26:

10 12 Downstream signaling pathways Cell proliferation Cell survival Trastuzumab T Lapatinib LLLLLL Erb receptors Mechanism of Action of Lapatinib Compared to Trastuzumab

11  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) Lapatinib as First-line Treatment for HER2- Amplified LABC or MBC EndpointLapatinib 1500 mg/day (n = 69) Lapatinib 500 mg BID (n = 69) 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, % Gomez HL, et al. J Clin Oncol. 2008;26:

12 Trastuzumab vs Lapatinib First-Line Therapy for MBC

13 MA.31/EGF108919: Design ClinicalTrials.gov. NCT 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+) Gelmon, ASCO 2012

14 [TITLE]

15 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

16 Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with T4 lesion and unlimited previous therapies*  Primary endpoint: TTP  Secondary endpoints: OS, PFS, ORR  Primary endpoint: TTP  Secondary endpoints: OS, PFS, ORR Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m 2 /day on Days 1-14 every 21 days Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m 2 /day on Days 1-14 every 21 days Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days *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: EGF Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer

17 Lapatinib + Capecitabine in HER2+ MBC: TTP Cameron D, et al. Oncologist. 2010;15: TTP With 1 Previous Trastuzumab RegimenTTP With > 1 Previous Trastuzumab Regimen Capecitabine Lapatinib + capecitabine Cumulative Progression Free (%) Wks Wks Cumulative Progression Free (%) Capecitabine Lapatinib + capecitabine 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.

18 ResultCapecitabine (n = 201) Capecitabine + Lapatinib (n = 207 † ) HRP Value Median TTP, wks [1] <.001 OS, wks [1] ORR, % [2] Brain mets as site of first progression,* n (%) [2] 13 (6)4 (2) † 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: Lapatinib + Capecitabine in HER2+ MBC: Efficacy

19 Combining Lapatinib and Trastuzumab Increases Antitumor Activity Scaltriti M, et al. Oncogene. 2009;28: Konecny GE, et al. Cancer Res. 2006;66: Xia W, et al. Oncogene. 2004;23: Tumor Volume (mm 3 ) Days After Injection *P <.05; † P <.01 vs control; ‡ P <.05 vs trastuzumab; § P <.01 vs both lapatinib and trastuzumab. Control Trastuzumab Lapatinib Trastuzumab + lapatinib * * †‡ † † § Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28: , copyright  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

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

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

22 EGF104900: Overall Survival L + T (n = 148) L (n = 148) n Median OS, mos HR (95% CI)0.74 ( ) Stratified log-rank P value % of patients in the L arm crossed over to L + T Mos From Randomization Survival(%) 12-mo OS 6-mo OS 41% 70% 80% 56% Pts at risk, n Lap 1000/Tras Lap Blackwell KL, et al. J Clin Oncol. 2012;30:

23 Trastuzumab Beyond Progression in HER2+ MBC: BIG Phase III Trial Patients with progressive MBC or LABC, HER2 overexpression, previous trastuzumab within 6 wks, and LVEF ≥ 50 (N = 156*)  Primary endpoint: TTP  Secondary endpoints: OS, ORR, safety  Primary endpoint: TTP  Secondary endpoints: OS, ORR, safety Trastuzumab 6 mg/kg every 3 wks + Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Trastuzumab 6 mg/kg every 3 wks + Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) *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:

24 BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. von Minckwitz G, et al. J Clin Oncol. 2009;27: PFS Probability of PFS Mos X XH Censored Log-rank P =.0338 Pts at Risk, n X XH OS Probability of OS Mos X XH Censored Log-rank P =.2570 Pts at Risk, n X XH

25 New Option in the Front-Line: Pertuzumab

26 HER1/3/4 Pertuzumab HER2 Trastuzumab Subdomain IV Dimerization domain 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: Pertuzumab and Trastuzumab: Mechanisms of Action

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

28 Baselga J, et al. N Engl J Med. 2012;366: 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 Trastuzumab Docetaxel (≥ 6 cycles recommended) Trastuzumab Docetaxel (≥ 6 cycles recommended) Placebo Pertuzumab 1:1 N = 406 N = 402 R Primary endpoint: Independently assessed PFS CLEOPATRA Study Design

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

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

31 Select Adverse Events (Grade ≥ 3), %Pertuzumab (n = 407) Placebo (n = 397) Neutropenia Febrile neutropenia Leukopenia Diarrhea Peripheral neuropathy Left ventricular systolic dysfunction CLEOPATRA: Safety Results 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

33 Second-line and Further Therapy TDM-1

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

35 EMILIA Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC  Primary endpoint: PFS by IRF, OS, safety  Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment Verma S, et al. NEJM 2012;367: T-DM1 3.6 mg/kg by IV every 3 wks (n = 495) Capecitabine 1000 mg/m 2 orally twice daily on Days 1-14, every 3 wks + Lapatinib 1250 mg/day orally continuously (n = 496) Patients with HER2-positive locally advanced or MBC* (N = 980) PD Stratified by world region, number of previous chemotherapy regimens for MBC or unresectable locally advanced breast cancer, presence of visceral disease *All pts received previous taxane and trastuzumab

36 T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS Proportion Progression Free Mos Median, MosEvents, n Capecitabine/lapatinib T-DM Stratified HR: (95% CI: ; P <.0001) T-DM1 Capecitabine/ lapatinib 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 Adverse Event, % T-DM1 (n = 490) Capecitabine + Lapatinib (n = 488) All GradesGrades ≥ 3 All Grades Grades ≥ 3 Nonhematologic  Diarrhea  Hand-foot syndrome  Vomiting  Hypokalemia  Fatigue  Nausea  Mucosal inflammation  Increased AST  Increased ALT Hematologic  Neutropenia  Febrile neutropenia001.0  Anemia  Thrombocytopenia 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 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 PD Trastuzumab + Taxane (n = 364) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) Patients with HER2+, previously untreated MBC (N = 1092)

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

43 BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab  Everolimus in HER2+ MBC 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/m 2 on Days 1, 8, 15 + Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22 Paclitaxel 80 mg/m 2 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 Stratification by previous adjuvant or neoadjuvant trastuzumab and presence of visceral metastases ClinicalTrials.gov. NCT :1 28-day cycle

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 Core biopsy (d21-d35 after last infusion) Surgery Doc R Doc* ECEC ECEC 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. GeparQuinto: HER2-Positive (n=615)

48 No invasive residual in breast & nodes P<0.05 No invasive residual in breast P<0.05 pCR Rates According to Other Definitions 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 Primary endpoint: pCRSecondary endpoints: pCR in N0, toxicity, cCR, RFS, OS Robidoux A, et al. ASCO Abstract LBA506. Patients with HER2+, operable breast cancer (N = 529) Doxorubicin/Cyclophosphamide 60/600 mg/m 2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m 2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery (n = 178) Doxorubicin/Cyclophosphamide 60/600 mg/m 2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m 2 q28d x 4 cycles + Trastuzumab weekly until 1 wk before surgery + Lapatinib 750 mg/day until 1 day before surgery (n = 173) Doxorubicin/Cyclophosphamide 60/600 mg/m 2 q21d x 4 cycles → Weekly Paclitaxel 80 mg/m 2 q28d x 4 cycles + Lapatinib 1250 mg/day until 1 day before surgery (n = 173) Tissue biopsy for biomarker analysis Surgery Trastuzumab 1 yr Tissue biopsy for biomarker analysis

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

59 Adjuvant HER-2 Targeted Therapy

60 NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy CP RANDOMIZERANDOMIZE HER2 positive (FISH+ or IHC 3+) Group A Group C Group B AC T T H H T = AC(doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T(paclitaxel 80 mg/m 2 /wk × 12) = H(trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) n=3,505

61 NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy CP RANDOMIZERANDOMIZE Node positive HER2 positive (FISH+ or IHC 3+) Group 1 Group 2 AC T H T = AC(doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T(paclitaxel 175 mg/m 2 q3w × 4 or 80 mg/m 2 /wk × 12) = H(trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) N=2,006

62 Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N B-31 CP Control Group (n=1,979): AC  T N9831 Group A B-31 Group 1 Trastuzumab Group (n=1,989): AC  T+H N9831 Group C B-31 Group 2 = AC(doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T(paclitaxel 80 mg/m 2 /wk × 12) = T(paclitaxel 175 mg/m 2 q3w × 4 or 80 mg/m 2 /wk × 12) = H(trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) AC T H T T H T

63 N9831 and NSABP B-31 Update

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

65 N9831 and NSABP B-31 Update Perez E A et al. JCO 2011;29: ©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 68 Slamon et al. 29th Annual San Antonio Breast Cancer Symposium, 2005; Herceptin ® (trastuzumab) PI. March 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 HER2-positive tumor (FISH+); node-positive or high-risk node-negative disease RANDOMIZERANDOMIZE SURGERYSURGERY AC T (n=1073) TCH (n=1075) AC TH (n=1074) 52 weeks = AC = doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w = T = docetaxel 100 mg/m 2 q3w = TC = docetaxel 75 mg/m 2 /carboplatin target AUC 6 mg/mL· min Radiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicated

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

72 Overall Survival

73 DFS by Nodal Status at Randomization

74

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

93 Women with centrally determined HER2- positive invasive breast cancer (N = 8381 accrued) Trastuzumab 8 mg/kg IV (loading dose)*  6 mg/kg every 3 wks for 1 yr  Paclitaxel 80 mg/m 2 IV once wkly x 12 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/m 2 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/m 2 IV once wkly x 12 (This arm closed in 9/2011 due to inferiority) Trastuzumab 4 mg/kg IV (loading dose)  2 mg/kg once wkly x 11  Paclitaxel 80 mg/m 2 IV once wkly x 12 Surgery, adjuvant anthracycline- based therapy for 4 cycles; LVEF ≥ 50 6-week wash-out ALTTO Trial Design *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).

94 N = 3806 SURGERYSURGERY Central confirmation of HER2 status Randomization within 7 wks of surgery Start treatment within 1 wk F O L O W U P 10 Y R S RANDOMIZATIONRANDOMIZATION Chemotherapy + trastuzumab and pertuzumab Anthracycline or non-anthracycline–based chemotherapy allowed Chemotherapy + trastuzumab and placebo Anthracycline or non-anthracycline–based chemotherapy allowed 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 APHINITY: Study Schema N = 3806 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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