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:
19 th Annual NOCR Meeting Session I: Breast Cancer HER-2+ Disease Christy A Russell, MD Keck School of Medicine University of Southern California
HER-2+ Breast Cancer Adjuvant and Neoadjuvant Therapy Combining Trastuzumab with other HER2- directed agents Second generation choices Novel agents and conjugates
Hudis C. N Engl J Med. 2007;357: Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab
Metastatic Breast Cancer Front-line Options
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:
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.
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
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)
12 Downstream signaling pathways Cell proliferation Cell survival Trastuzumab T Lapatinib LLLLLL Erb receptors Mechanism of Action of Lapatinib Compared to Trastuzumab
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:
Trastuzumab vs Lapatinib First-Line Therapy for MBC
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
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
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
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.
ResultCapecitabine (n = 201) Capecitabine + Lapatinib (n = 207 † ) HRP Value Median TTP, wks  <.001 OS, wks  ORR, %  Brain mets as site of first progression,* n (%)  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
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
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:
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:
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:
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:
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
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
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
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
Pertuzumab, % (n = 402) Placebo, % (n = 406) HRP Value Median OS, mos NR Swain SM, et al. SABCS Abstract P CLEOPATRA: Overall Survival (Confirmatory Analysis)
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
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
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:
Overall Survival – Second Interim Analysis Verma S, et al. NEJM 2012;367:
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:
Ongoing Clinical Trials for Metastatic Breast Cancer
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)
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
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
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.
Early Stage HER-2+ Breast Cancer
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)
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.
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.
Study Design Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
Efficacy – pCR and to tpCR Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
pCR by Hormone Receptor Status Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
*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].
NeoSphere Study Design and Objectives Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NeoSphere pCR Rates: ITT Population Summary Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NeoSphere: pCR and Hormone Receptors Status Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
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
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.
Adjuvant HER-2 Targeted Therapy
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
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
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
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
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
DFS by Nodal Status at Randomization
Role of Anthracyclines?
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.
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.
Duration of Trastuzumab
Pending Clinical Trials
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
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).
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
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
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.