Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic - PowerPoint Presentation

Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic settings Christy A Russell, MDKeck School of MedicineUniversity of Southern California

Metastatic Breast Cancer

Chemotherapy Plus Trastuzumabin Metastatic Disease Slamon et al n = 469 Marty et aln = 186Treatment ArmsAC or T*vsAC or T→H†DocetaxelvsDocetaxel →H†Time to Disease Progression (mos)4.67.4P value6.111.7P value< 0.0010.0001Response Rate32%50%< 0.00134%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;344:783-792 ; Marty M, et al. J Clin Oncol. 2005;23:4265-4267.

Anti-HER2 Targeted Therapy:Pertuzumab

Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes Hubbard SR. Cancer Cell. 2005;7:287-288. Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex Pertuzumab Dimerization domain Trastuzumab III II I Inhibits HER2 dimerization with other HER family receptors (particularly HER3) Activates ADCC Inhibits multiple HER-mediated signaling pathways Activates ADCC Inhibits HER-mediated signaling pathways Prevents HER2 domain cleavage III II I IV IV

Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and May Have Synergistic Activity HER2 Trastuzumab Pertuzumab Subdomain IV of HER2 Trastuzumab 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 shedding Dimerization domain of HER2 HER3

Baselga J, et al. N Engl J Med. 2012;366:109-119. 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 mosBaseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumabTrastuzumabDocetaxel (≥ 6 cycles recommended)TrastuzumabDocetaxel (≥ 6 cycles recommended)PlaceboPertuzumab1:1N = 406N = 402RPrimary endpoint: Independently assessed PFSCLEOPATRA Study Design

CLEOPATRA: PFS Assessed at an IRF Baselga J, et al. N Engl J Med. 2012;366:109-119 100 90 80 7060 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 Mos PFS (%) Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos) HR: 0.62 (95% CI: 0.51-0.75; P < .001) Pts at Risk, n Pertuzumab Control 402 406 345 311 267 209 139 93 83 42 32 17 10 7 0 0 0 0

Adding Pertuzumab to Trastuzumab and Chemotherapy Pertuzumab Pertuzumab

CLEOPATRA: Safety Baselga J, et al. N Engl J Med. 2012;366:109-119. Adverse Events , %Trastuzumab + Docetaxel + Pertuzumab(n = 407)Trastuzumab + Docetaxel + Placebo (n = 397)All GradesGrade 3/4All GradesGrade 3/4Diarrhea66.87.946.35.0Alopecia60.9NR60.5NRNeutropenia52.848.949.645.8Nausea42.3NR41.6NRFatigue37.62.236.8 3.3Rash 33.7NR24.2 NR Decreased appetite 29.2 NR 26.4 NR Mucosal inflammation 27.8 NR 19.9 NR Asthenia 26.0 2.5 30.2 1.5 Peripheral edema 23.1 NR 30.0 NR Constipation 15.0 NR 24.9 NR Febrile neutropenia 13.8 13.8 7.6 7.6 Dry skin 10.6 NR 4.3 NR Leukopenia NR 12.3 NR 14.6

NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure Preferred regimensDocetaxel + trastuzumab + pertuzumab (category 1) Paclitaxel + trastuzumab + pertuzumab Other regimens Trastuzumab with: Paclitaxel ± carboplatinDocetaxelVinorelbineCapecitabineNCCN. Clinical practice guidelines in oncology: breast cancer. V.1.2014.

NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure Preferred agentsAdo-trastuzumab emtansine (T-DM1)Other agents Lapatinib + capecitabine Trastuzumab + capecitabine Trastuzumab + lapatinib (without cytotoxic therapy) Trastuzumab + other agentsNCCN. Clinical practice guidelines in oncology: breast cancer. V.1.2014.

Second-line and Further Therapy TDM-1

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

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;367:1783-91. T-DM1 3.6 mg/kg by IV every 3 wks(n = 495)Capecitabine 1000 mg/m2 orally twice dailyon Days 1-14, every 3 wks +Lapatinib 1250 mg/day orally continuously(n = 496)Patients withHER2-positivelocally advancedor MBC*(N = 980)PDStratified by world region, number of previous chemotherapy regimens for MBC or unresectable locally advanced breast cancer, presence of visceral disease*All pts received previoustaxane and trastuzumab

T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS 1.0 0.8 0.6 0.4 0.2 0 Proportion Progression Free Mos 0 30 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Median, Mos Events, n Capecitabine/lapatinib T-DM1 6.4 9.6 304 265 Stratified HR: 0.650 (95% CI: 0.55-0.77; P < .0001) T-DM1 Capecitabine / lapatinib Verma S, et al. NEJM 2012;367:1783-91.

OS: Second Interim Analysis Data cutoff July 31, 2012; median follow-up: 18.6 mos. Verma S, et al. N Engl J Med. 2012;367:1783-1791. 100 806040200 0 OS (%) 2 4 8 10 12 14 16 30 Mos 6 18 20 22 24 26 28 T-DM1 Lapatinib-capecitabine Lapatinib-capecitabine T-DM1 Median No. of Mos 25.1 30.9 No. of Events 182 149 Stratified HR: 0.68 (95% CI: 0.55-0.85; P < .001) Pts at Risk, n Lapatinib- capecitabine T-DM1 496 495 471 485 453 474 435 457 403 439 368 418 297 349 240 293 204 242 159 197 133 164 86 111 63 86 17 28 7 13 4 5 36 32 34 Efficacy stopping boundary P = .0037 or HR: 0.73 110 136 27 38 45 62 51.8% (95% CI: 45.9-57.7) 78.4% (95% CI: 74.6-82.3) 85.2% (95% CI: 82.0-88.5) 64.7% (95% CI: 59.3-70.2)

T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events Adverse Event, % T-DM1 (n = 490) Capecitabine + Lapatinib (n = 488)All GradesGrades ≥ 3All GradesGrades ≥ 3NonhematologicDiarrhea23.31.679.720.7Hand-foot syndrome1.2058.0 16.4 Vomiting19.0 0.8 29.3 4.5 Hypokalemia 8.6 2.2 8.6 4.1 Fatigue 35.1 2.4 27.9 3.5 Nausea 39.2 0.8 44.7 2.5 Mucosal inflammation 6.7 0.2 19.1 2.3 Increased AST 22.4 4.3 9.4 0.8 Increased ALT 16.9 2.9 8.8 1.4 Hematologic Neutropenia 5.9 2.0 8.6 4.3 Febrile neutropenia 0 0 1.0 1.0 Anemia 10.4 2.7 8.0 1.6 Thrombocytopenia 28.0 12.8 2.5 0.2 Verma S, et al. NEJM 2012;367:1783-91.

Ongoing Clinical Trials for Metastatic Breast Cancer

Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC Primary endpoints: PFS as assessed by IRF, AEsSuperiority design with a noninferiority analyses Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR ClinicalTrials.gov. NCT01120184. PDTrastuzumab + Taxane(n = 364)T-DM1 + Pertuzumab(n = 364)T-DM1 + Placebo(n = 364)Patients with HER2+, previously untreated MBC(N = 1092)

Phase III Trial of Everolimus in Combination With Trastuzumab and Paclitaxel as Frontline Therapy for HER2+ MBC (BOLERO-1) RANDOMIZATION Primary Endpoint: PFS Available at: www.clinicaltrials.gov/NCT 00876395.

Other Trials With Completed or Ongoing Accrual in MBC T-DM1 vs investigator’s choice (TH3RESA) Addition of pertuzumab to vinorelbine and trastuzumab (VELVET)

Neoadjuvant Therapy

Trastuzumab + Lapatinib Trials

pCR Rates (breast and LN) with Trastuzumab (H) and/or Lapatinib (L) Study/Neoadjuvant Regimen Total pCR Trastuzumab Total pCR LapatinibTotal pCRH + 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 406013(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;18:633-640. 2. Robidoux, et al Lancet Oncol; pub online Oct 4, 20133. Carey, et al. ASCO 2013, abst 500. 4. Guarneri, et al. JCO 2012;31.

CALGB 40601 Schema Carey L, et al ASCO 2013 Abstr # 500

Breast pCR Rate by HR Status Carey L, et al ASCO 2013 Abstr # 500HR+ (N=173) HR- (N=123)

Basal-like(N=11) pCR Rate by Arm and Subtype Carey L, et al ASCO 2013 Abstr # 500HER2-E(N=52)Lum-A(N=51)Lum-B(N=35)

Neoadjuvant Trastuzumab + Pertuzumab Trials

NeoSphere: study design THP (n=107)docetaxel + trastuzumab + pertuzumab HP (n=107) trastuzumab + pertuzumab TP (n=96)docetaxel + pertuzumab SURGERYdocetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17FEC q3w x 3trastuzumab q3w cycles 5–17FEC q3w x 3trastuzumab q3w cycles 5–17FEC q3w x 3trastuzumab q3w cycles 5–21Study dosing: q3w x 4TH (n=107)docetaxel + trastuzumab Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) BC, 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, M0H, trastuzumab; P, pertuzumab; T, docetaxel 3

H, trastuzumab; P, pertuzumab; T, docetaxel NeoSphere pCR rates: ITT population summary p = 0.0141 50 40 3020100THTHPHPTPpCR, %  95% CI p = 0.0198 p = 0.003 29.0 45.8 16.8 24.0

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

NeoSphere Trial: pCR in Breast and Nodes HR+ HR- n %pCR n%pCRTrastuzumab + docetaxel5012%5729.8%Trastuzumab + docetaxel + pertuzumab5022%5754.4%Trastuzumab + pertuzumab512%5520%Docetaxel + pertuzumab468.7%5026%

TRYPHAENA Study: TCH + pertuzumab 225 patients with locally advanced, operable, or inflammatory breast cancer (T2-T4d)Trial was designed to assess cardiac safety Schneeweiss , et al. Ann Oncol 2013;24

TRYPHAENA pCR Neoadjuvant Regimen HR+ HR- %pCR%pCRTCH + 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

FDA 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.

Adjuvant HER-2 Targeted Therapy

NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy CP1270832-44 R A N DOMIZEHER2 positive (FISH+ or IHC 3+)Group AGroup CGroup BACTACTHHACT = 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) n=3,505

NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy CP1270832-45 R A N DOMIZENode positiveHER2 positive (FISH+ or IHC 3+)Group 1Group 2ACTHACT = 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)N=2,006

Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N9831 + B-31CP1270832- 46 Control Group (n=1,979) : AC  TN9831 Group AB-31 Group 1Trastuzumab Group (n=1,989): AC  T+HN9831 Group CB-31 Group 2 = 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)ACTHACTACTH ACT

Kaplan-Meier estimates of (A) event-free survival and (B) overall survival. Perez E A et al. JCO 2011;29:3366-3373 ©2011 by American Society of Clinical Oncology P < .001 HR 0.52 P < .001HR 0.61

Events Per Year From Randomization Perez E A et al. JCO 2011;29:3366-3373 ©2011 by American Society of Clinical Oncology

B reast Cancer I nternational R esearch Group (BCIRG) 006 Trial: Treatment SchemaSlamon et al. NEJM 2011;365.Endpoints1°: 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 q3wHER2-positive tumor (FISH+); node-positive or high-risk node-negative diseaseRANDOMIZESURGERYAC T (n=1073)TCH (n=1075) AC TH (n=1074) 52 weeks 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=0.04DFSOSAC-TH vs AC-THR .63 p<0.001TCH vs AC-THR .77 p=0.04

Overall Survival Overall Survival

Trials to be Reported

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/m2 IV once wkly x 12Trastuzumab 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 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)Trastuzumab 4 mg/kg IV (loading dose)  2 mg/kg once wkly x 11 Paclitaxel 80 mg/m2 IV once wkly x 12Surgery, adjuvant anthracycline-based therapy for 4 cycles;LVEF ≥ 506-week wash-outALTTO 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 S U R G ERYCentral confirmationof HER2 statusRandomizationwithin 7 wksof surgeryStarttreatmentwithin1 wkFOLLOWUP10YRS RAN DOMIZATI O N 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 N = 3806 ClinicalTrials.gov Identifier: NCT01358877

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 anthracyclinesDefinition of “high-risk”Role of additional biologic agents to trastuzumab

“Low-Risk” HER2+ Breast Cancer

Background The 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.

[TITLE] Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

[TITLE] Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

Treatment of T1a/b N0 Tumors: NCCN Luis IV, et al ASCO 2013 Abstr # 1006

[TITLE] Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

APT Trial Tolaney SM, et. Cancer Res 2013;73:Abst S1-04.

Conclusions Metastatic 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 doublets Identify “low-risk” patients for alternative trastuzumab + chemotherapy regimens.