Presentation on theme: "Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic settings Christy A Russell, MD Keck School of Medicine University."— Presentation transcript:
1Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic settingsChristy A Russell, MDKeck School of MedicineUniversity of Southern California
3Chemotherapy Plus Trastuzumab in Metastatic Disease Slamon et aln = 469Marty et aln = 186Treatment ArmsAC or T*vsAC or T→H†DocetaxelDocetaxel →H†Time to Disease Progression (mos)4.67.4P value6.111.7< 0.0010.0001Response Rate32%50%34%61%0.0002Median Overall Survival (mos)20250.04623310.0325*T = paclitaxel; †H = trastuzumab.Hudis CA. N Engl J Med. 2007;357:36-51; Slamon DJ, et al. N Engl J Med. 2001;344: ; Marty M, et al. J Clin Oncol. 2005;23:
5Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 EpitopesPertuzumab-HER2 ComplexTrastuzumab-HER2 ComplexPertuzumabDimerization domainIIIIIIIIIIIITrastuzumabIVIVADCC, antibody-dependent cell-mediated cytotoxicity.Like trastuzumab, pertuzumab was among the first-line anti-HER2 antibodies tested preclinically in vitro and in vivo that showed that antibodies against the HER2 extracellular domain could growth-inhibit these tumors preclinically. Although they are both HER2-targeting agents, pertuzumab and trastuzumab have some distinct differences, listed here. The most important difference is that pertuzumab binds to a different epitope in the HER2 extracellular domain that inhibits the HER2 dimerization with other HER family receptors. In particular, pertuzumab more strongly inhibits the most effective signaling dimerization partner complex, HER2 plus HER3.Inhibits HER2 dimerization with other HER family receptors (particularly HER3)Activates ADCCInhibits multiple HER-mediated signaling pathwaysActivates ADCCInhibits HER-mediated signaling pathwaysPrevents HER2 domain cleavageHubbard SR. Cancer Cell. 2005;7:
6Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and May Have Synergistic Activity Subdomain IV of HER2Dimerization domain of HER2Trastuzumab does not inhibit HER2 dimerization, thus blocking HER2:HER3Trastuzumab prevents HER2 receptor sheddingTrastuzumab blocks HER2 signaling and flags cells for destruction by the immune systemPertuzumab inhibits HER2 from forming dimer pairsFlags cells for destruction by the immune systemPertuzumab does not prevent HER2 receptor shedding6
7CLEOPATRA Study Design Docetaxel (≥ 6 cycles recommended)Centrally confirmed HER2-positive locally recurrent, unresectable or MBC≤ 1 hormonal regimen for MBCPrior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mosBaseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumabN = 406TrastuzumabPlaceboR1:1Docetaxel (≥ 6 cycles recommended)TrastuzumabN = 402PertuzumabPrimary endpoint: Independently assessed PFSBaselga J, et al. N Engl J Med. 2012;366:
8CLEOPATRA: PFS Assessed at an IRF 100Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos)90807060PFS (%)5040HR: 0.62 (95% CI: ; P < .001)302010510152025303540MosPts at Risk, n Pertuzumab Control139 9383 4232 1710 70 00 0Baselga J, et al. N Engl J Med. 2012;366:
9Adding Pertuzumab to Trastuzumab and Chemotherapy
11NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure Preferred regimensDocetaxel + trastuzumab + pertuzumab (category 1)Paclitaxel + trastuzumab + pertuzumabOther regimensTrastuzumab with:Paclitaxel ± carboplatinDocetaxelVinorelbineCapecitabineNCCN. Clinical practice guidelines in oncology: breast cancer. V
12NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure Preferred agentsAdo-trastuzumab emtansine (T-DM1)Other agentsLapatinib + capecitabineTrastuzumab + capecitabineTrastuzumab + lapatinib (without cytotoxic therapy)Trastuzumab + other agentsNCCN. Clinical practice guidelines in oncology: breast cancer. V
15EMILIA 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 diseaseT-DM1 3.6 mg/kg by IV every 3 wks (n = 495)Patients with HER2-positive locally advanced or MBC* (N = 980)PDCapecitabine 1000 mg/m2 orally twice daily on Days 1-14, every 3 wks + Lapatinib 1250 mg/day orally continuously (n = 496)*All pts received previoustaxane and trastuzumabPrimary endpoint: PFS by IRF, OS, safetySecondary endpoints: QoL (FACT B), DOR, PFS by investigator assessmentVerma S, et al. NEJM 2012;367:
16T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS Median, MosEvents, n1.0Capecitabine/lapatinib T-DM13042650.8Stratified HR: (95% CI: ; P < .0001)0.6Proportion Progression Free0.4T-DM1Capecitabine/ lapatinib0.224681012141618202224262830MosVerma S, et al. NEJM 2012;367:
17OS: Second Interim Analysis Median No. of MosNo. of Events10085.2% (95% CI: )Lapatinib-capecitabine T-DM1Stratified HR: 0.68 (95% CI: ; P < .001)8064.7% (95% CI: )Efficacy stopping boundary P = or HR: 0.736078.4% (95% CI: )T-DM1OS (%)4051.8% (95% CI: )Lapatinib-capecitabine2024681012141618202224262830323436Pts at Risk, n Lapatinib- capecitabine T-DM1Mos63 8645 6227 3817 287 134 5Data cutoff July 31, 2012; median follow-up: 18.6 mos.Verma S, et al. N Engl J Med. 2012;367:
18T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events Capecitabine + Lapatinib(n = 488)All GradesGrades ≥ 3NonhematologicDiarrhea23.31.679.720.7Hand-foot syndrome1.258.016.4Vomiting19.00.829.34.5Hypokalemia22.214.171.124Fatigue35.12.427.93.5Nausea126.96.36.199Mucosal inflammation188.8.131.52.3Increased AST184.108.40.206Increased ALT220.127.116.11.4HematologicNeutropenia5.92.0Febrile neutropenia1.0Anemia10.42.78.0Thrombocytopenia28.012.8Verma S, et al. NEJM 2012;367:
19Ongoing Clinical Trials for Metastatic Breast Cancer
20Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC PDTrastuzumab + 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, AEsSuperiority design with a noninferiority analysesInterim futility analysis: option to drop experimental armSecondary endpoints: OS, TTF by IRF, ORR, CBR, DORClinicalTrials.gov. NCT20
21Phase III Trial of Everolimus in Combination With Trastuzumab and Paclitaxel as Frontline Therapy for HER2+ MBC (BOLERO-1)RANDOMIZATIONHER+ MBCNo prior anthracycline/taxane-based chemotherapy in the metastatic setting(N = 719)Everolim us 10 mg PO +Paclitaxel 80 mg/m2 qwk d 1, 8, 15+ Trastuzu mab 2 mg/kg d 1, 8, 15, 22Placebo +Primary Endpoint: PFSAvailable at:
22Other Trials With Completed or Ongoing Accrual in MBC T-DM1 vs investigator’s choice (TH3RESA)Addition of pertuzumab to vinorelbine and trastuzumab (VELVET)
25pCR Rates (breast and LN) with Trastuzumab (H) and/or Lapatinib (L) Study/Neoadjuvant RegimenTotal pCRTrastuzumabLapatinibH + LNeoALTTO1(6 week H and/or L (WP) x 12 plus H and/or L)N=45527.6%20.0%46.8%NSABP B-412(AC x 4 WP x 12 plus H and/or L)N=51949.4%47.4%60.2%CALGB(WP x 16 plus H and/or L)N=29943%29%52%CHER-LOB4(WP x 12 FEC x 4 plus H and or L throughoutN=12125%26.3%46.7%WP=weekly paclitaxel; AC=doxorubicin/cyclophosphamide; FEC=5-FU, epirubicin, cyclophosphamideBaselga J, et al. Lancet 2012;18: Robidoux, et al Lancet Oncol; pub online Oct 4, 20133. Carey, et al. ASCO 2013, abst Guarneri, et al. JCO 2012;31.
36NeoSphere: study design TH (n=107) docetaxel + trastuzumabSURGEYFEC q3w x 3trastuzumab q3w cycles 5–17trastuzumab q3w cycles 5–21Patients with operable or locally advanced /inflammatory* HER2-positive BCChemo-naïve & primary tumors >2cm (N=417)THP (n=107) docetaxel + trastuzumab + pertuzumabHP (n=107) trastuzumab + pertuzumabdocetaxel q3w x 4→FEC q3w x 3trastuzumab q3w cycles 5–17TP (n=96) docetaxel + pertuzumabStudy dosing: q3w x 4BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel3
37NeoSphere pCR rates: ITT population summary 50p = 0.00340pCR, % 95% CI45.8302029.024.01016.8H, trastuzumab; P, pertuzumab; T, docetaxelTHTHPHPTP
38NeoSphere: pCR and Hormone Receptors Status Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
39NeoSphere Trial: pCR in Breast and Nodes HR+HR-n%pCRTrastuzumab + docetaxel5012%5729.8%Trastuzumab + docetaxel + pertuzumab22%54.4%Trastuzumab + pertuzumab512%5520%Docetaxel + pertuzumab468.7%26%
40TRYPHAENA Study: TCH + pertuzumab 225 patients with locally advanced, operable, or inflammatory breast cancer (T2-T4d)Trial was designed to assess cardiac safetySchneeweiss, et al. Ann Oncol 2013;24
41TRYPHAENA pCR Neoadjuvant Regimen HR+ HR- %pCR TCH + Pertuzumab (76) 47.5%81.1%FEC (75)P + T + Docetaxel45.7%62.5%Pertuzumab + Trastuzumab41.0%73.5%FEC (72)DocetaxelSchneeweiss, et al. Ann Oncol 2013;24
42FDA Approval in Neoadjuvant Setting Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage breast cancer (either >2 cm or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pCR rate. No data are available demonstrating improvement in EFS or OS.Limitations of Use:The safety of pertuzumab as part of a doxorubicin-containing regimen has not been established.The safety of pertuzumab administered for > 6 cycles for early breast cancer has not been established.
44NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy Group AACTRANDOMIZEGroup BHER2 positive (FISH+ or IHC 3+)ACTHGroup Cn=3,505ACTH= 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)
45NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy Group 1ACTRANDOMIZENode positiveHER2 positive (FISH+ or IHC 3+)Group 2N=2,006ACTH= 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)
46Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N9831 + B-31 Control Group (n=1,979): AC TACTN9831 Group AACTB-31 Group 1Trastuzumab Group (n=1,989): AC T+HACTN9831 Group CHACTB-31 Group 2H= 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)
49Breast Cancer International Research Group (BCIRG) 006 Trial: Treatment Schema DOMIZEAC T (n=1073)SURGERYHER2-positive tumor (FISH+);node-positive or high-risk node-negative diseaseAC TH (n=1074)52 weeksTCH (n=1075)52 weeksEndpoints1°: 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· minRadiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicatedSlamon et al. NEJM 2011;365.Herceptin® (trastuzumab) PI. March 2009.
50Disease-Free Survival Among all Study Patients DFSAC-TH vs AC-THR .64 p<0.001TCH vs AC-THR .75 p=0.04OSAC-TH vs AC-THR .63 p<0.001TCH vs AC-THR .77 p=0.04
53ALTTO Trial DesignTrastuzumab 8 mg/kg IV (loading dose)* 6 mg/kg every 3 wks for 1 yr Paclitaxel 80 mg/m2 IV once wkly x 12Women with centrally determined HER2-positiveinvasive breast cancer(N = 8381 accrued)Surgery, adjuvant anthracycline-based therapy for 4 cycles;LVEF ≥ 506-week wash-outTrastuzumab 4 mg/kg IV (loading dose) 2 mg/kg once wkly x 11 Paclitaxel 80 mg/m2 IV once wkly x 12Lapatinib1500 mg orally once daily x 34 wksLapatinib 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 yrLapatinib 1000 mg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12
54APHINITY Chemotherapy + trastuzumab and pertuzumab S U R G E R YRANDOMIZTFOLWUP10YRSChemotherapy + trastuzumab and pertuzumabAnthracycline or non-anthracycline–based chemotherapy allowedN = 3806N = 3806Central confirmationof HER2 statusChemotherapy + trastuzumab and placeboAnthracycline or non-anthracycline–based chemotherapy allowedRandomization within 7 wks of surgeryStart treatment within 1 wkAnti-HER2 therapy for a total of 1 yr (52 wks)Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapyClinicalTrials.gov Identifier: NCT
55ConclusionsTrastuzumab in addition to chemotherapy remains the standard for all “high-risk” HER-2+ early breast cancer.Controversies exist regarding the following:Use of anthracyclinesDefinition of “high-risk”Role of additional biologic agents to trastuzumab
57BackgroundThe three randomized adjuvant trials of HER2+ early breast cancer included limited patients with stage I disease, and virtually no patients with tumors < 1 cm.Many patients with stage I, HER2+ EBC will have a sufficiently high risk of recurrence to justify administration of adjuvant therapy, but they will likely derive a smaller absolute benefit.The development of regimens with lower degrees of toxicity is important for this population.Tolaney SM, et al. Cancer Res 2013;73:Abst S1-04.
58[TITLE]Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting
59[TITLE]Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting
60Treatment of T1a/b N0 Tumors: NCCN Luis IV, et al ASCO 2013 Abstr # 1006
61[TITLE]Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting
62APT TrialTolaney SM, et. Cancer Res 2013;73:Abst S1-04.
68ConclusionsMetastatic breast cancer: The landscape of drug choices has changed with the addition of pertuzumab in the front-line and TDM-1 in the second-line.Neoadjuvant therapy: The landscape has changed with the approval of pertuzumab in the neoadjuvant setting.Adjuvant therapy:We await adjuvant trial data on anti-HER2 doubletsIdentify “low-risk” patients for alternative trastuzumab + chemotherapy regimens.