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CURRENT PARADIGMS in HER2-Positive Breast Cancer Neoadjuvant , A djuvant & Metastatic Settings

CURRENT PARADIGMS in HER2-Positive Breast Cancer Neoadjuvant , A djuvant & Metastatic Settings. Gunter von Minckwitz, MD, PhD Chairman of German Breast Group Germany. NEOADJUVANT SETTING. von Minckwitz et al . J Clin Oncol 2010 Untch M,, J Clin Oncol 2010. Eligibility Criteria.

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CURRENT PARADIGMS in HER2-Positive Breast Cancer Neoadjuvant , A djuvant & Metastatic Settings

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  1. CURRENT PARADIGMSin HER2-Positive Breast Cancer Neoadjuvant, Adjuvant & Metastatic Settings Gunter von Minckwitz, MD, PhD Chairman of German Breast Group Germany

  2. NEOADJUVANT SETTING

  3. von Minckwitz et al. J Clin Oncol 2010 Untch M,, J Clin Oncol 2010

  4. Eligibility Criteria Unilateral or bilateral untreated breast cancer Tumour 2 cm (palpation) or 1 cm (US) Given indication for chemotherapy, e.g.: cT3 or cT4 (including inflammatory) cT1-3 and ER/PgR negative cT1-3 and ER/PgR positive and cN+ (for cT2) or pNSLN+(for cT1) LVEF  55% No significant cardiac co-morbidity Untch M,, EBCC 2008 & J Clin Oncol 2010 Von Minckwitz G, J Clin Oncol 2010 ER, estrogen receptor; PgR, progesterone receptor LVEF, left ventricular ejection fraction

  5. Efficacy of TrastuzumabpCR % Untch M,, J Clin Oncol 2010

  6. Efficacy of Trastuzumabaccording to central HER2 status %

  7. Long-term LVEF in patients receiving 3xA60T150→3xT175CMFx4 ± Trastuzumab Gianni L, et al. NOAH study Lancet 2010

  8. PCR predicts survival in HER2-positive disease treated with EC-P+trastuzumabResults of the TECHNO-study M. Untch, personal communication

  9. Geparquinto – Decision Tree HER2 positive? no yes EC-Doc + Trastuzumab vs. EC-Doc + Lapatinib EC vs. EC + Bev Response assessment after 4xEC+/-Bev no yes 2nd randomisation: Pw vs. Pw + RAD001 Doc vs. Doc + Bev M. Untch, SABCS 2011, G. von Minckwitz SABCS 2011

  10. pCR(noinvasive/non-invasive residual in breast & nodes based on central pathology report review) M. Untch, SABCS 2011,

  11. Study Design Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 lapatinib lapatinib paclitaxel R A N D O M I Z E S U R GE R Y FEC X 3 trastuzumab trastuzumab paclitaxel • Stratification: • T ≤ 5 cm vs. T > 5 cm • ER or PgR + vs. • ER & PgR – • N 0-1 vs. N ≥ 2 • Conservative surgery • or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52weeks of anti-HER2 therapy J. Baselga, SABCS 2011

  12. Cumulative Incidence of Diarrhea Grade ≥ 3 J. Baselga, SABCS 2011 Safety Population

  13. Efficacy – pCR and tpCR L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response J. Baselga, SABCS 2011

  14. Comparison of pCR-rates Neo-Sphere Neo-Altto G5 HER2+ G5 TNBC Duration 12 12+6 24 24 Mono-Tx Doc+H Pw+H EC-Doc+H EC-Doc+B ypT0/isypN0 21.5 27.6 45.0 40.1* Combo-Tx Doc+HP Pw+HL n.a. n.a ypT0/isypN0 39.3 46.9 *without pCRs in non-responders

  15. CALGB 40601: HER2+ Neoadjuvant Trial Paclitaxel x 16 wks Paclitaxel x 16 wks Paclitaxel x 16 wks Trastuzumab SURGERY N=400 HER2+ Stage II-III Trastuzumab x 1y (recommended) Dose-dense AC (recommended) Lapatinib Endocrine Rx and RT prn Trastuzumab + lapatinib Breast imaging Blood MUGA Tumor Biopsy - required Breast imaging Blood MUGA Planned cross-validation with NeoALTTO

  16. GeparSixtoEffect of Carboplatin in HER2+/triple neg BC 18 weeks N=600 Paclitaxel weekly + Myocet weekly T4 or T3 orT>1cm, Triple neg. or HER2 pos. R* Surgery Paclitaxel weekly + Myocet weekly + Carboplatin Trastuzumab+Lapatinib in HER2 positive pts. Bevacizumab in TNBC pts. *stratified according to HER2/ER and Ki-67

  17. Conclusions Trastuzumab (H) doubles pCR-rates pCR after H is a surrogate for survival Combination with anthracyclines appears to be safe Double blockage of HER2 combined with a few CT cycles reaches comparable pCR rates as longer CT+Trastuzumab Double blockage of HER2 opens the window for CT-free regimen.

  18. Case 1 with Locally Advanced Breast Cancer

  19. 1) Preop AC-T + trastuzumab (9 weeks) 2) Preop AC-T + trastuzumab (T completed up to 52 weeks including adjuvant) 3) Preop TCH 4) Preop AC-T with no trastuzumab 5) Preop trastuzumab without CT 6) Primary surgery Case 1 : What is your treatment option?

  20. Treatment approach according to AGO’s perspective: AC-TH → Surgery →H (up to 1 year) Case 1 with Locally Advanced Breast Cancer

  21. Any question or contribution?...

  22. METASTATIC SETTING

  23. Single-Institution Retrospective Analysis on 2091 patients with MBC Dawood et al. J Clin Oncol 2010

  24. First Randomized Phase III Study to Investigate Continuation of Trastuzumab Capecitabine 2,500 mg/m² d 1–14 q3w (n=78) R Capecitabine 2,500 mg/m² d 1–14 q3w + Continuation of trastuzumab 6 mg/kg q3w (n=78) von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009 R, randomization

  25. Clinical Response (RECIST) OR: 27.0% CB: 54.1% OR: 48.0% CB: 75.3% OR: 0.0115 CB: 0.0068 (2-sided p) CR: 7.7% CR: 2.7% PR: 40.4% PR: 24.3% NC: 27.1% NC: 27.2% OR = Overall response = CR+PR CB = Clinical benefit = CR+PR+NC>24wks von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009

  26. Time To Progression at median Follow up of 15.6 months • X : 5.6 (4.2 - 6.3) mos • XH : 8.2 (7.3 - 11.2) mos • HR=0.69 (two-sided p=0.034; one-sided p=0.017) P<0.0467 Progression to CNS: X: 8.3% XH: 13.8% PFS X: 5.6 mos XH: 8.2 mos P=0.026 two sided von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009

  27. Lapatinib + Capecitabine Capecitabine No. of pts 198 201 Progressed or died* 82 (41%) 102 (51%) Median TTP, months 4.3 6.2 Hazard ratio (95% CI) 0.57 (0.43, 0.77) p-value 0.00013 Capecitabine + Lapatinib vs Capecitabine 70 * due to breast cancer Cameron et al, Breast Cancer Res Treat 2008

  28. Final Overall Survival Analysis(N=151) • X : 20.6 (18.6 – 27.4) mos • XH : 24.9 (20.3 – 30.7) mos • HR=0.94 (two-sided p=0.74) von Minckwitz G, et al. SABCS 2010 poster presentation

  29. Overall survival after 2nd progressioncont of trast vs not (N=140) von Minckwitz G, et al. SABCS 2010 poster presentation

  30. ….Trastuzumab and lapatinib beyond trastuzumab K. L. Blackwell et al, JCO Mar 2010: 1124–1130

  31. Phase II Trastuzumab / Pertuzumab Study (BO17929) Baselga et al. J Clin Oncol 20010

  32. Beyond trastuzumab…T-DM1 IRF - Independent Review Facility *including unconfirmed partial remissions

  33. Conclusion • ADCC is an antibody specific key mechanism for the action of trastuzumab • Trastuzumab is synergistic to various other agents • In vivo data and clinical evidence support the concept of “trastuzumab beyond progression”; representing a paradigm shift • HER2 blockade throughout all stages of MBC should be considered !

  34. Case 2 with Metastatic Breast Cancer

  35. Case 2: What is your treatment of choice? 1) Trastuzumab + Paclitaxel 2) Trastuzumab + Vinorelbine 3) Trastuzumab + Capecitabine 4) Lapatinib + Capecitabine 5) Trastuzumab + Lapatinib 6) CT without anti-Her2-agent

  36. Case 2 with Metastatic Breast Cancer • Treatment approach according to AGO’s perspective: Paclitaxel + Trastuzumab

  37. Case 3 with Metastatic Breast Cancer

  38. 1) Vinorelbine + Trastuzumab 2) Capecitabine + Trastuzumab 3) Capecitabine + Lapatinib 4) Trastuzumab + Lapatinib Case 3: What is your treatment option in 2nd line?

  39. Case 3 with Metastatic Breast Cancer • Treatment approach according to AGO’s perspective: Capecitabine+Trastuzumab

  40. Option 1 2nd Line Treatment for Case 3

  41. WBRT followed by 1) Vinorelbine +Trastuzumab 2) Cisplatin+ Trastuzumab 3) Lapatinib + Capecitabine (if not used as 2nd line) 4) Trastuzumab + Lapatinib Case 3: What is your treatment option in 3rd line?

  42. Case 3 with Metastatic Breast Cancer • Treatment approach according to AGO’s perspective: Trastuzumab + Lapatinib

  43. Any question or contribution?...

  44. ADJUVANT SETTING

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