HER2-positive Breast Cancer

Transcription

1 HER2-positive Breast Cancer Multiple choices what to use when? Thomas Ruhstaller Brustzentrum St. Gallen

2 Adjuvant setting

3 NCIC MA5 N Engl J Med 06, x CEF can 6 x CMF oral HER2 + pg schlecht in allen Subgruppen HER2+: CEF>CMF RFS p= OS p= 0.06 HER2-: CEF = CMF

4 CALGB: N Engl J Med 2007;357: Versch. Anthracyclin-Dosen +/- Paclitaxel HER2+ Subgruppe profitiert von Taxanen

5 Adjuvant Trastzumab

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7 For how long do we need to treat?

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12 Anthracyclines replaced by carboplatin?

13 BCIRG 006 AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 Her 2+ (Central FISH) N+ or high risk N- N=3,222 Stratified by Nodes and Hormonal Receptor Status AC TH TCH 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 1 Year Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab Slamon D., SABCS 2006

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15 Dual HER2-targeted adjuvant therapies

16 On September 9, 2011, The independent data monitoring committee has indicated that the lapatinib alone arm is unlikely to meet the prespecified criteria to demonstrate non-inferiority to trastuzumab alone with respect to disease-free survival.

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21 Small HER2-pos tumor: How much chemotherapy is necessary?

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36 Chemotherapy Anthracyclines > CMF Taxanes added benefit to anthracyclines Trastuzumab Combined with chemotherapy 1y = standard (several studies ongoing) Timing of trastuzumab according to CT unclear Accepted: start with anthracyclines, then taxanes combined with trastuzumab Delayed trastuzumab still effective (HERA) Lapatinib not non-inferior compared to trastuzumab Dual HER2-targeted therapies awaiting results of ongoing trials Small HER+ tumors - some low risk tumors <2cm need less Adjuvant treatment in summary concomittant chemotherapy (12 weeks Paclitaxel) - unclear remains the relevance of the ER-status

37 Metastastic disease

38 38 Trastuzumab first approved on these results Referent / Bereich

39 Hernata: Trast/Doc versus Trast/Vin M. Andersson et al., J Clin Oncol 2011; 29, Ph-lll, first line HER2+ Doc: 100mg/m 2 Nav: 30-35mg/m 2 More patients in the docetaxel arm discontinued therapy due to toxicity (P <.001). The study failed to demonstrate superiority of any drug in terms of efficacy, but the vinorelbine combination had significantly fewer adverse effects.

40 Progression-free survival (%) DESO 2014 St. Gallen Management des HER2+ Mammakarzinoms Doc/Trast + Pertuzumab (Cleopatra) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Docetaxel-Trastuzumab-Pertuzumab vs Docetaxel-Trastuzumab-Plazebo PFS n at risk Ptz + T + D Pla + T + D D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months Time (months) = 6.1 months HR = % CI p< Stratified by prior treatment status and region Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 9 PFS: 12 vs 18ms

41 Herceptin kombiniert mit Chemotherapie: T-DM1 HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res

42 Second-line: T-DM1 versus Lap /Cap

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44 TH3RESA Study Schema HER2-positive (central) advanced BC a (N=600) 2 T-DM1 3.6 mg/kg q3w IV (n=400) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice (TPC) b (n=200) PD T-DM1 c (optional crossover) Stratification factors: World region, number of prior regimens for advanced BC, d presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety a Advanced BC includes MBC and unresectable locally advanced/recurrent BC. b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. c First patient in: Sep Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD. d Excluding single-agent hormonal therapy. BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks.

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46 HER2+ and ER+: opposing forces or potential collaboraters? 50% of all HER2+ tumors express ER/PgR Neoadjuvant pcr rate:

47 47 AI alone nearly no effect! AI + HER2-directed therapy is effective (ph-lll and ph-ll trials) TAnDEM (Kaufman, JCO 09): Anastrozole +/- Trastuzumab Phase-lll: n=208 and an appropriate first-line therapy EGF30008 (Johnston, JCO 09): Letrozole +/- Lapatinib Subgroup phase-lll: n=219 Cross-over 70% Referent / Bereich

48 48 Dual HER2-targeted therapy alone Pathologic CR Rates in Neo-Sphere: Doc + T Doc + TP TP pcr 29% 46% 17% ER+ ER- 20% 37% 26% 63% 6% 29% Referent / Bereich

49 49 Some thoughts from E. Winer in SA 2014: Referent / Bereich

50 HER2-positive metastatic or locally advanced breast cancer first line Therapy Regimens and schedules Trastuzumab + Pertuzumab* T-DM1 Physicians discretion Progression Progression Trastuzumab + Pertuzumab + Chemotherapy (paclitaxel, vinorelbine) * T-DM1 Physicians discretion Paclitaxel: 80 /90 mg/m2 d1,8,15; q 4w // weekly tbd Vinorelbine 25 mg/m2 d1,8,15; q 4w // weekly tbd Trastuzumab: 6 mg/kg/q3w Loading dose 8mg/kg Pertuzumab: 420 mg/q3w loading dose 840 mg *Patients with hormone receptor positive disease will/may receive endocrine treatment when treated without chemotherapy

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