Updates from the San Antonio Breast Cancer Symposium 2013 HER2+ Breast Cancer Julie R. Gralow, M.D. Director and Jill Bennett Professor of Breast Medical Oncology Professor of Global Health University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance

 HER-2 Over-Expressing Breast Cancer cell division HER-2 nucleus cancer cell Trastuzumab Anti-HER-2 Antibody HER-2 Oncogene: amplified and overexpressed in % of breast cancer Lapatinib Dual HER-1/HER-2 Tyrosine Kinase Inhibitor Pertuzumab Anti-HER-2 Antibody T-DM1 Antibody-Drug Conjugate

APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast Cancer Tolaney SM et al, SABCS 2013, abstract #S1-04 Randomized adjuvant HER2+ trials included few small, lymph node negative breast cancers Patients: 406 pts with node-negative, HER2+ breast cancer, < 3 cm – –2/3 ER+, 20% < 0.5 cm Treatment: Paclitaxel and trastuzumab weekly x 12, followed by 9 months of single agent trastuzumab Results: 3.6 years median follow-up –): 2 distant, 4 locoregional, 3 contralateral breast cancers, 1 non- breast cancer death (ovarian ca) –10 recurrences/deaths (2.5%): 2 distant, 4 locoregional, 3 contralateral breast cancers, 1 non- breast cancer death (ovarian ca) –3 year DFS 98.7%

APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast Cancer Tolaney SM et al, SABCS 2013, abstract #S1-04 Toxicity: – –2 symptomatic CHF (resolved on stopping trastuzumab) – –13 asymptomatic declines in LVEF (able to resume trastuzumab in 11) Conclusion: Paclitaxel plus trastuzumab can be considered a reasonable approach for majority of patients with small, lymph node negative, HER2+ breast cancer

HER2 Therapy Combinations Neo ALTTO: Preop HER2+ Baselga J et al, Lancet 379: , 2012 Invasive, operable HER2+ breast cancer T > 2 cm N=450 lapatinib trastuzumab lapatinib trastuzumab FECX3FECX3 SURGERYSURGERY RANDOMIZERANDOMIZE Lapatinib 1500 mg/d Trastuzumab weekly Lapatinib 1000 to 750 trastuzumab paclitaxel 80 mg/m2 paclitaxel paclitaxel pCR

Neo ALTTO: Survival Follow-up Analysis Piccart M et al, SABCS 2013 abstract #S1-01 Lapatanib + Trastuzumab TrastuzumabLapatinib 3 yr EFS (all)84%78% HR+83%80%86% HR-86%72%70% 3 yr OS (all)95%90%93% HR+97%94%93% HR-93%87%93% None statistically significant

Neo ALTTO: EFS and OS by pCR Piccart M et al, SABCS 2013 abstract #S1-01

Neo ALTTO Survival Follow-up Analysis: Conclusions Underpowered to detect moderate EFS and OS differences, await results of ALTTO adjuvant trialUnderpowered to detect moderate EFS and OS differences, await results of ALTTO adjuvant trial Patients who achieved pCR had significantly better EFS and OS compared with no pCRPatients who achieved pCR had significantly better EFS and OS compared with no pCR HER2+/ER- disease different from HER2/ER+ diseaseHER2+/ER- disease different from HER2/ER+ disease

Combined HER-2 Targeted Therapy BIG 2.06/N063D Adjuvant HER2+ Trial (ALTTO) – Soon to Report PIs: M Piccart, E Perez HER2+ BC Tumors  1 cm after completion of anthracycline based therapy with LVEF  50% RANDOMIZERANDOMIZE (paclitaxel) trastuzumab (trast for 1 yr) (paclitaxel) lapatinib (lap for 1 yr) (paclitaxel) trastuzumab+ lapatinib (trast + lap for 1 yr) (paclitaxel) trastuzumab (12 weeks), 6-week wash out, lapatinib (34 weeks) N= 8,000

TRIO Trial: Phase II Trial of Preoperative Trastuzumab, Lapatinib or Combination Hurvitz S et al, SABCS 2013, abstract #S1-02 Lapatinib 21 days Trastuzumab 1 dose Lapatinib 21 days Trastuzumab 1 dose TCH x 6 cycles TCL x 6 cycles TCHL x 6 cycles surgery biopsy HER2+ invasive breast cancer Stage I- III N=130

TRIO Trial: Phase II Trial of Preoperative Trastuzumab, Lapatinib or Combination Hurvitz S et al, SABCS 2013, abstract #S1-02

pCR similar in TCH and TCHL armspCR similar in TCH and TCHL arms –Differs from other preop studies –Numbers in each arm very small Addition of lapatinib increased toxicity, limiting ability of patients to receive planned therapyAddition of lapatinib increased toxicity, limiting ability of patients to receive planned therapy Molecular analyses ongoing to evaluate profiles of non- respondersMolecular analyses ongoing to evaluate profiles of non- responders

BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast Cancer Slamon D et al, SABCS 2-13, abstract #S1-03 Cohort 1 Non-Anthracycline TCH H Cohort 2 Anthracycline TH FEC H Node positive or high-risk node negative HER2+ Arm 1A TCH H Arm 1B TCHBev HBev Arm 2A TH FEC H Arm 2B THBev FEC HBev N= 3231 N= 278

BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast Cancer Slamon D et al, SABCS 2-13, abstract #S1-03 IDFSOS No Bevacizumab92%96% + Bevacizumab92%97% Median Follow-up 38 months 1 year of adjuvant bevacizumab added to chemo and trastuzumab does not improve IDFS or OS

BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast Cancer Slamon D et al, SABCS 2-13, abstract #S1-03 Chemo/TrastuzumabChemo/Trastuzumab /Bevacizumab Hypertension4%19% Thromboembolic event 2%3% Bleeding<1%2% CHF<1%2.1% GI perforation1 event11 events Adverse Events (grade 3, 4)

TH3RESA Trial: T-DM1 in Later Line Metastatic Disease Wildiers H et al, European Cancer Congress 2013, Abstract LBA15 T-DM1 q3wks Physician’s Choice HER2+ MBCHER2+ MBC Prior anthracycline, taxane, capecitabine, lapatinib, trastuzumabPrior anthracycline, taxane, capecitabine, lapatinib, trastuzumab Progression on at least 2 HER2 RxsProgression on at least 2 HER2 Rxs N=795N=795 2:1 randomization2:1 randomization R

TH3RESA Trial: T-DM1 in Later Line Metastatic Disease Wildiers H et al, European Cancer Congress 2013, Abstract LBA15

Metastatic T-DM1 and Pertuzumab CLOSED: MARIANNE Phase III 1 st -Line HER2+ Metastatic Breast Cancer Trastuzumab + Taxane T-DM1 + Pertuzumab T-DM1 + Placebo HER2+ recurrent locally advanced or untreated MBC n=1092 Primary endpoint: OS Rx until progressive disease

Adjuvant Pertuzumab CLOSED: APHINITY Trial Phase III Trial of Adjuvant Pertuzumab added to Standard Chemo and Trastuzumab N=4800N=4800 Operable HER2+ breast cancerOperable HER2+ breast cancer Primary endpoint: IDFSPrimary endpoint: IDFS Standard chemotherapy (6-8 cycles) + Trastuzumab q3 wks x 52 weeks + Pertuzumab q3 wks x 52 weeks Standard chemotherapy (6-8 cycles) + Trastuzumab q3 wks x 52 weeks + Placebo q3 wks x 52 weeks R

Adjuvant Pertuzumab and T-DM1 SOON TO OPEN: KAITLIN Study Phase III Trial of Adjuvant Trastuzumab + Pertuzumab + Taxane vs TDM1 + Pertuzumab in HER2+ Breast Cancer T-DM1 + Pertuzumab Taxane + Trastuzumab + Pertuzumab HER2+, non- metastatic breast cancer (n=2500) Co-Primary endpoints: invasive DFS & OS Anthracycline- based regimen

Residual Disease after Preop Therapy OPEN KATHERINE Trial: Phase III Trial of T-DM1 vs Trastuzumab in Patients with HER2+ Breast Cancer with Residual Disease after Preop Therapy T-DM1 q3 wks x 14 Trastuzumab q3 wks x 14 HER2+, non- metastatic breast cancer T1-4, N0-3 at presentation (n=1484) Primary endpoints: invasive DFS Preop Therapy: At least 6 cycles, including at least 9 weeks of taxane and trastuzumab Surgery: Residual tumor in breast or axilla

Adjuvant HER2 Therapy Low HER2 Expression Tumors ONGOING NSABP B-47: Adjuvant Trastuzumab in Breast Cancer with Normal HER2 Expression Primary Breast Cancer HER2 IHC 1+ or 2+ FISH Negative Docetaxel + Cyclophosphamide x 6 or AC x 4 + Paclitaxel x 12 (MD Choice) Randomization Docetaxel + Cyclophosphamide x 6 or AC x 4 + Paclitaxel x 12 (MD Choice) + Trastuzumab x 1 yr N= 3,260