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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

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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 20- 25% of breast cancer Lapatinib Dual HER-1/HER-2 Tyrosine Kinase Inhibitor Pertuzumab Anti-HER-2 Antibody T-DM1 Antibody-Drug Conjugate

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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%

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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

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HER2 Therapy Combinations Neo ALTTO: Preop HER2+ Baselga J et al, Lancet 379:633-640, 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

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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

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

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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

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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

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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

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

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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

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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

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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

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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