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Updates from the San Antonio Breast Cancer Symposium 2013 HER2+ Breast Cancer

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

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Updates from the San Antonio Breast Cancer Symposium 2013 HER2+ Breast Cancer

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  1. 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

  2. HER-2 Over-Expressing Breast Cancer HER-2 Oncogene: amplified and overexpressed in 20-25% of breast cancer Pertuzumab Anti-HER-2 Antibody HER-2 Trastuzumab Anti-HER-2 Antibody cancer cell nucleus Lapatinib Dual HER-1/HER-2 Tyrosine Kinase Inhibitor T-DM1 Antibody-Drug Conjugate cell division

  3. APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast CancerTolaney 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 • 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%

  4. APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast CancerTolaney 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

  5. HER2 Therapy CombinationsNeo ALTTO: Preop HER2+Baselga J et al, Lancet 379:633-640, 2012 R A N D O M I Z E lapatinib Lapatinib 1500 mg/d Invasive, operable HER2+ breast cancer T > 2 cm N=450 paclitaxel 80 mg/m2 FEC X 3 S U R GE R Y Trastuzumab weekly trastuzumab paclitaxel Lapatinib 1000 to 750 lapatinib trastuzumab trastuzumab paclitaxel pCR

  6. Neo ALTTO: Survival Follow-up AnalysisPiccart M et al, SABCS 2013 abstract #S1-01 None statistically significant

  7. Neo ALTTO: EFS and OS by pCRPiccart M et al, SABCS 2013 abstract #S1-01

  8. Neo ALTTO Survival Follow-up Analysis: Conclusions • Underpowered 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 pCR • HER2+/ER- disease different from HER2/ER+ disease

  9. (paclitaxel) trastuzumab (trast for 1 yr) RANDOMIZE HER2+ BC Tumors 1cm after completion of anthracycline based therapy with LVEF 50% (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) Combined HER-2 Targeted TherapyBIG 2.06/N063D Adjuvant HER2+ Trial (ALTTO) – Soon to ReportPIs: M Piccart, E Perez N= 8,000

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

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

  12. TRIO Trial: Phase II Trial of Preoperative Trastuzumab, Lapatinib or CombinationHurvitz S et al, SABCS 2013, abstract #S1-02 • pCR 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 therapy • Molecular analyses ongoing to evaluate profiles of non-responders

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

  14. BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast CancerSlamon D et al, SABCS 2-13, abstract #S1-03 Median Follow-up 38 months 1 year of adjuvant bevacizumab added to chemo and trastuzumab does not improve IDFS or OS

  15. BETH: Randomized Phase III Trial of Adjuvant Bevacizumab in HER2+ Breast CancerSlamon D et al, SABCS 2-13, abstract #S1-03 Adverse Events (grade 3, 4)

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

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

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

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

  20. Adjuvant Pertuzumab and T-DM1SOON TO OPEN: KAITLIN StudyPhase III Trial of Adjuvant Trastuzumab + Pertuzumab + Taxane vs TDM1 + Pertuzumab in HER2+ Breast Cancer T-DM1 + Pertuzumab HER2+, non-metastatic breast cancer (n=2500) Co-Primary endpoints: invasive DFS & OS Anthracycline-based regimen Taxane + Trastuzumab + Pertuzumab

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

  22. 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 N= 3,260 Randomization Docetaxel + Cyclophosphamide x 6 or AC x 4 + Paclitaxel x 12 (MD Choice) Docetaxel + Cyclophosphamide x 6 or AC x 4 + Paclitaxel x 12 (MD Choice) + Trastuzumab x 1 yr

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