KLINISCH RELEVANTE NEUIGKEITEN. FRÜHES MAMMAKARZINOM Nadia Harbeck. Brustzentrum der Universität München. Prof. Nadia Harbeck

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1 CAMPUS GROSSHADERN CAMPUS INNENSTADT KLINIK UND POLIKLINIK FÜR FRAUENHEILKUNDE UND GEBURTSHILFE DIREKTOR: PROF. DR. MED. SVEN MAHNER KLINISCH RELEVANTE NEUIGKEITEN VOM ASCO 2017: FRÜHES MAMMAKARZINOM Nadia Harbeck Brustzentrum der Universität München Leitung: Prof. Nadia Harbeck

2 ASCO 2017 Prof. Harbeck KLINISCH RELEVANTES VOM ASCO 2017 PRIMÄRES MAMMAKARZINOM HER2+: Eskalation und De-Eskalation Duale Blockade jetzt auch adjuvant? APHINITY Trastuzumab für weniger als 1 Jahr? Update APT Studie: 12x Paclitaxel + Trastuzumab HER2-: : Adjuvante Chemotherapie: Anthrazykline notwendig? WSG PlanB TNBC: PARPi und/oderplatin?brightness Ausblick in die Zukunft: Immuntherapie: I-SPY and beyond KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

3 ASCO 2017 Prof. Harbeck Therapiestrategie beim frühen Mammakarzinom Harbeck & Gnant, Lancet 2017 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

4 APHINITY: Trial Design S U R G E R Y Central confirmation of HER2 status (N = 4805) R Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Randomisation and treatment Anti HER2 therapy for a total of 1 year (52 weeks) within 8 weeks of surgery (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy *A number of standard anthracycline taxane sequences or a non anthracycline (TCH) regimen were allowed F O L L O W U P 10 Y E A R S The slides are the property of BIG. Permission required for reuse 4

5 APHINITY: Randomization i Stratification i Factors by Treatment Pertuzumab Placebo n=2400 n=2404* Nodal status, n (%) 0 positive nodes and T 1 cm* 0 positive nodes and T >1 cm* 90 (3.8) 807 (33.6) 84 (3.5) 818 (34.0) 1 3 positive nodes 4 positive nodes 907 (37.8) 596 (24.8) 900 (37.4) 602 (25.0) Adjuvant chemotherapy regimen (randomised), n (%) Anthracycline containing tii regimen 1865 (77.7) 7) 1877 (78.1) Non anthracycline containing regimen 535 (22.3) 527 (21.9) Hormone receptor status (central), n (%) Negative (ER and PgR negative) 864 (36.0) 858 (35.7) Positive (ER and/or PgR positive) 1536 (64.0) 1546 (64.3) Geographical region, n (%) USA Canada/Western Europe/Australia New Zealand/South Africa 296 (12.3) 1294 (53.9) 294 (12.2) 1289 (53.6) Eastern Europe Asia Pacific Latin America Protocol Version, n (%) Protocol A Protocol Amendment B 200 (8.3) 550 (22.9) 60 (2.5) 1828 (76.2) 572 (23.8) 200 (8.3) 557 (23.2) 64 (2.7) 1827 (76.0) 577 (24.0) The slides are the property of BIG. Permission required for reuse * One patient was excluded from the ITT population due to her falsification of personal information 5

6 APHINITY: Intent to Treat Primary Endpoint Analysis Invasive Disease free Survival expected: 89.2% Number needed to treat: 112 The slides are the property of BIG. Permission required for reuse 6

7 APHINITY: IDFS Forest Plot by Subgroups No. of Patients Events // No. of Patients Events Unstratified 3 year IDFS Rate, % Interaction Hazard Ratio Subgroup Pertuzumab Placebo Pertuzumab Placebo test p value (95%CI) All patients 171 / / ( ) NA Nodal status 0 positive nodes, tumor 1cm 2 / 90 4 / ( ( ) ) positive nodes, tumor >1cm 30 / / ( ) positive nodes 55 / / ( ) positive nodes 84 / / ( ) positive nodes 32 / / ( ) positive nodes 139 / / ( ) 0.96) Adjuvant chemotherapy regimen Anthracycline 139 / / ( ) Non anthracycline 32 / / ( ) Central hormone receptor status Positive (ER and/or PgR positive) 100 / / ( ) Negative (ER and PgR negative) 71 / / ( ) Protocol version Protocol A 120 / / ( ) Protocol Amendment B 51 / / ( ) Menopausal status at screening Pre menopausal 93 / / ( ) Post menopausal 78 / / ( ) Age group (years) <40 30 / / ( ) / / ( ) / / ( ) / / ( ) Tumor size (cm) <2 41 / / ( ( ) 092) <5 108 / / ( ) / / ( ) Sex 1/5 1/ Female 171 / / 2396 Pertuzumab better Placebo better 0.82 ( ) NA 7

8 APHINITY: Node positive Subgroup Number needed to treat: 56 The slides are the property of BIG. Permission required for reuse 8

9 APT Paclitaxel Mono + Trastuzumab (Deeskalation Anthrazykline bei HER2-pos.) Primary Outcome: DFS DFS Events DFS Event N (%) Time to event [months; mean (range)] Any recurrence or death 23 (5.7) Local/Regional Recurrence* Ipsilateral axilla (HER2-) Ipsilateral breast (HER2+) New Contralateral Primary Breast Cancer 6 (1.5) Her2+ 1 HER2-3 Unknown 2 5 (1.2) 3 29 (12 54) 2 51 (37 65) (12 59) 87 (84 90) DFS by HR Status val Stratu m Disease- -Free Survi No. of event s 7-yr DFS 95% Conf. Interval Negative % 84.6% to 97.2% Positive % 91.8% to 97.5% Number at HRrisk HR Distant Recurrence 4 (1.0) 49 (27 53) 73 Death Non-breast cancer related 8 (2.0) 58 (13 71) 9 Mod. Tolaney S et al. ASCO 2017, Poster Session Breast Cancer - Local/Regional/Adjuvant, Abstract No. 511

10 Short-HER: Study Design EUDRACT number: NCI ClinicalTrials.gov number: NCT Pts 65 yrs received Docetaxel 80 mg/sqm 11% of the pts in the long arm received paclitaxel 175 mg/sqm Stratification factors: HR status, Nodal status Rdith Radiotherapy and hormonal ltherapy started t at the completion of ChemoRx, when indicated d LVEF evaluation Presented by: PierFranco Conte

11 Short-HER: Disease Free Survival Number at risk A long B short Months from randomization A long B short Presented by: PierFranco Conte

12 DFS Subgroup analysis Events/randomized HR (90% CI) Age <60 years 123/ years 66/ (0.85, 1.54) 1.18 (0.78, 1.76) Stage I 52/509 II 81/549 III 56/191 Nodal status N0 73/670 N1 56/385 N2+N3 60/ (0.57, 1.44) 0.96 (0.66, 1.38) 1.76 (1.11, 2.80) 0.91 (0.62, 1.33) 0.93 (0.60, 1.45) 2.07 (1.33, 3.22) Stage III vs I+II Nodal status N2+N3 vs N0+N1 Ratio of HRs (90%CI) p-value 2.30 (1.35, 3.94) < (1.33, 3.83) < Hormone-receptor Negative 71/398 Positive 118/ ( (0.81, 178) 1.78) 1.12 (0.83, 1.52) Favouring SHORT Favouring LONG Presented by: PierFranco Conte

13 Disease Free Survival (Bayesian Approach) Presented by: PierFranco Conte

14 Short-HER: Overall Survival Long (N=627) Short (N=626) OS events # y OS % HR 1.06 (90% CI) ( ) Number at risk A long B short Months from randomization A long B short Presented by: PierFranco Conte

15 Cardiac Adverse Events 0.15 Time to 1 st Cardiac Adverse Event > G HR= 0.32 (95% CI 0.21;0.50) p< P< Months from randomization Number of cardiac events Grade Long Short N(%) N(%) 2 70 (11.2) 22 (3.5) 3 17 (2.7) 7 (1.1) 4 3 (0.5) 3 (0.5) Total 90 (14.4) 32 (5.1) Cumulative hazard estimates t A Long B Short Presented by: PierFranco Conte

16 ASCO 2017 Prof. Harbeck Therapiestrategie beim frühen Mammakarzinom Harbeck & Gnant, Lancet 2017 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

17 Prospective WSG Phase III PlanB trial: Final analysis on adjuvant 4xEC 4xDoc vs. 6xDocetaxel/Cyclophosphamide in high clinical and intermediate/high genomic risk HER2- negative early breast cancer Nadia Harbeck, Oleg Gluz, Michael Clemens, Wolfram Malter, Toralf Reimer, Benno Nuding, Bahriye Aktas, Andrea Stefek, Anke Pollmanns, Fatemeh Lorenz-Salehi, Christoph Uleer, Petra Krabisch, Sherko Kuemmel, Cornelia Liedtke, Steven Shak, Rachel Wuerstlein, Matthias Christgen, Ronald E. Kates, Hans H. Kreipe, and Ulrike Nitz, on behalf of the WSG PlanB investigators Presented by: Nadia Harbeck, MD

18 PlanB: Design HER2-negative early breast cancer HR- R Age<75 years Doc x6* A 75 C 600 cm0 N R D free margins E O C 0-3 LN and pn+ M pn0 high risk pt>2 G2-3 upa/pai-1 HR+ U R R E N C E S C O R E RS>11 or >/= 4 LN 0-3 LN and RS<11 Recurrence Score: after early amendment HR- age <35 years C: Cyclophosphamide I Z A T I O N Presented by: Nadia Harbeck, MD E 90 C 600 x4 Doc 100 x4* Endocrine therapy* * Endocrine Therapy and RT according to national guidelines E: Epirubcin; Doc: Docetaxel; 18

19 PlanB: Translational subprotocol 5-year DFS in per-protocol population (no chemotherapy in pn0-1 and Recurrence Score 0-11) 5-Y DFS 94.2% 5-Y DFS 94% 94% 5-Y DFS 94.5% N0 5-Y DFS 95% N1 94% 5-Y DFS 85.5% 5-Y DFS 88% 84% Gluz et al, EBCC 2016, plenary lecture Presented by: Nadia Harbeck, MD 19

20 PlanB: Disease-free survival (DFS) by chemotherapy arm (ITT population) HR (TC vs. EC-Doc) = %CI: [ ] 5y DFS 90% 90% Presented by: Nadia Harbeck, MD 20

21 PlanB: Disease-free survival (DFS) according to Recurrence Score (HR+)* RS<25 RS>25 5y DFS 5y DFS TC: 94% TC: 86% EC-Doc 95% EC-Doc 85% *ITT patients with RS measured; after early amendment Presented by: Nadia Harbeck, MD 21

22 PlanB: DFS in subgroups (ITT population) Presented by: Nadia Harbeck, MD 22

23 PlanB: Overall survival (OS) by chemotherapy arm (ITT population) HR (TC vs. EC-Doc) = %CI: [ ] 5y OS 95% 95% Presented by: Nadia Harbeck, MD 23

24 TNBC: BRIGHTNESS Study Design Segment weeks Segment weeks Arm A Veliparib 50 mg BID + Carboplatin + Paclitaxel Screening Day -28 Informed Consent Arm B Arm C Randomization 2:1:1 Placebo BID Doxorubicin + + Carboplatin + Paclitaxel Cyclophosphamide Placebo BID + Placebo + Paclitaxel Pre-Op Visit a Surgery b = First day of treatment with Veliparib/Placebo + Carboplatin/Placebo + Paclitaxel = Last dose of Veliparib/Placebo + Carboplatin/Placebo + Paclitaxel a Performed at least 2 weeks after last chemotherapy treatment. b Surgery (+/- radiotherapy) was recommended approximately 2-8 weeks after last chemotherapy treatment. 24 Mod. Geyer CE et al. ASCO 2017, Poster Discussion Session Breast Cancer Local/Regional/Adjuvant, Abstract No. 520

25 TNBC: BRIGHTNESS Efficacy Pathologic Complete Response ypt0/tis ypn0 p=0.001 p=0.38 atients % Pa 25 Mod. Geyer CE et al. ASCO 2017, Poster Discussion Session Breast Cancer Local/Regional/Adjuvant, Abstract No. 520

26 I-SPY 2 TRIAL Schema: HER2- Signatures Presented By Rita Nanda at 2017 ASCO Annual Meeting

27 Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Presented By Rita Nanda at 2017 ASCO Annual Meeting

28 Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE 173 Peter Schmid, presented at 2017 ASCO Annual Meeting, Abstract #556

29 KEYNOTE-173: Ergebnisse Peter Schmid, presented at 2017 ASCO Annual Meeting, Abstract #556

30 ASCO 2017 Prof. Harbeck AKTUELLE STUDIEN ZUR IMMUNTHERAPIE BEIM FRÜHEN MAMMAKARZINOM: TNBC Phase 3 Patient Population Locally advanced, centrally confirmed TNBC T > 2 cm Bilateral and multiple BC are allowed Inflammatory BC is allowed No chest wall involvement 2:1 Pembro 200mg q3w + Carboplatin x 4 cycles + Paclitaxel 80 mg/m2 weekly x 12 wks Pembro 200 mg + Adriamycin i 60 mg/m2 + Cyclophosphamide 600 mg/m2 q3w x 4 cycles Placebo + Carboplatin 4 cycles + Paclitaxel 80 mg/m2 x 12 wks Placebo + Surgery KEYNOTE-522 Pembro 200 mg q3w x 6 months Estimated t enrollment = 855 Surgery Placebo Adriamycin 60 mg/m2 + Cyclophosphamide 600 mg/m2 q3w x 4 cycles Stratification tifi ti factors: Nodal status: t Positive vs. Negative, Tumor size: T1/2 vs. T 3/4 KLINIKUM DER UNIVERSITÄT MÜNCHEN Dual Primary Endpoints pcr (ypt0/tis ypn0) EFS Secondary Endpoints pcr (ypt0 ypn0) ORR DCR DoR OS Safety Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

31 ASCO 2017 Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

32 ASCO 2017 Prof. Harbeck ZUSAMMENFASSUNG ASCO 2017 PRIMÄRES MAMMAKARZINOM HER2+: Eskalation und De-Eskalation Duale Blockade adjuvant bei Risikosituation (APHINITY) nach Zulassung neoadjuvanter Therapiebeginn bleibt Standard Niedriges Risiko (pt1 pn0): 12x Paclitaxel + Trastuzumab HER2-: Adjuvante Chemotherapie mit 6xTC ist Alternative zu EC- Pac weekly bei mittlerem klinischem Risiko (WSG PlanB) TNBC: Neoadjuvant ist Standard Hinzunahme von Carboplatin sinnvoll (BRIGHTNESS) ) Neoadjuvante Studien mit Immuntherapie anbieten KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

33 ASCO 2017 Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

34 EVIDENZBASIERTE, PATIENTENORIENTIERTE BRUSTKREBS-THERAPIE Das digitale Tagebuch für jede Patientin Jährlich aktualisierte, evidenzbasierte Empfehlungen zur Diagnostik und Therapie AGO (DKG, DGGG) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe