AGO e. V. in der DGGG e.v. sowie in der DKG e.v.

AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de

Disease-Free and Overall Survival in Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR An increase in survival over time in MBC has 2a been shown in some retrospective analyses However, patients with MBC today have received 2a more adjuvant treatment and have therefore considered more drug resistant Multiple lines of sequential therapy are 1b beneficial (at least same efficacy, less toxicity) Especially targeted drugs in combination with 1b chemotherapy can induce substantial survival benefits

Treatment of Metastatic Breast Cancer Predictive Factors AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 Therapy Factor Oxford / AGO LoE / GR www.ago-online.de Endocrine therapy ER / PR (primary tumor, metastasis) 1a A ++ previous response 2b B ++ Chemotherapy previous response 1b A ++ Anti-HER2-drugs HER2 (primary tumor, better metastasis) 1a A ++ Bone modifying drugs bone metastasis 1a A ++ Any therapy CTC monitoring 1b A +* (other potentially biological factors see chapter Predictive factors ) *within clinical trials

Turner NC, et al. ASCO 2015 (abs LBA502)

Turner NC, et al. ASCO 2015 (abs LBA502)

Study Design N=800 pts. with HR+/HER2- breast cancer no pcr and CPS-EG score 3 : Palbociclib 125 mg once daily p.o. d1-21, q28d for 13 cycles Neoadjuvant Chemotherapy Surgery +/- Radiotherapy R Placebo d1-21, q28d for 13 cycles All patients will receive concomitantly endocrine therapy according to local standards

Cytotoxic Therapy Goals AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford LoE: 1b GR: A AGO: ++ Mono-Chemotherapy: Favourable therapeutic index Indicated in case of Slow, not life-threatening progression Insensitive to or progression during endocrine therapy Poly-Chemotherapy: Unfavourable therapeutic index Indicated to achieve rapid remission in the case of Extensive symptoms Imminent life-threatening metastases Survival benefit in comparison to sequential singleagent therapies with the same compounds not proven Therapeutic index evaluates overall efficacy, toxicity and impact on quality of life

Chemotherapy for MBC General Considerations: Drug Selection AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de AGO: ++ The choice of cytotoxic drugs to be used depends on: ER / PR, HER2; combination with biologicals Previous treatments (and their toxicities) Disease-free interval after end of adjuvant treatment Aggressiveness of disease and localization of metastases Estimated life expectancy Co-morbidities (including organ dysfunctions) Patients preference and expectations

ESMO Guidelines ABC: Update on HER-2-negative Advanced Breast Cancer Sequential monotherapy is the preferred choice for MBC. Combination CT should be reserved for patients with rapid clinical progression, lifethreatening visceral metastases, or need for rapid symptom and/or disease control (LoE 1A) Although taxanes can be used as first-line therapy, they have not shown superior benefit to anthracyclines in a meta-analysis carried out in a mostly taxane-naive, anthracycline-pre-treated patient population HELIOS Klinikum Berlin-Buch 15.06.2015 10

MBC HER2-negative/HR-positive Cytotoxic 1 st -Line Therapy* AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 Oxford / AGO LoE / GR Monotherapy: Paclitaxel (q1w), Docetaxel (q3w) 1b A ++ Doxorubicin, epirubicin, mitoxantrone (A) Peg. liposomal doxorubicin (A lip ) 1b A ++ Vinorelbine 3b B + Capecitabine 2b B + Nab-paclitaxel 2b B + www.ago-online.de Polychemotherapy: A + T 1b A ++ T + gemcitabine after adj. A 2b B ++ A + C or A lip + C 1b B ++ Paclitaxel + capecitabine 2b a B + Docetaxel + capecitabine after adj. A 1b A + *In ER pos. disease only if endocrine therapy is not or not anymore indicated

MBC HER2-negative/HR-pos: Cytotoxic Therapy after Anthracycline Treatment* AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR Paclitaxel q1w 1a A ++ Docetaxel q3w 1a A ++ Capecitabine 2b B ++ Nab-paclitaxel 2b B ++ Peg-liposomal doxorubicin 2b B + Eribulin 1b B + Vinorelbine 2b B + Docetaxel + Peg-liposomal Doxo 1b B +/- *independent whether anthracyclines were used in adjuvant or 1 st line metastatic situation

MBC HER2-negative/HR-positive: Cytotoxic Therapy after adjuvant Taxane and Anthracycline Treatment AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR Experimental therapies within studies ++ Capecitabine 2b B ++ Eribulin 1b B ++ Vinorelbine 2b B ++ (Peg)-liposomal Doxorubicin 2b B + Gemcitabine + Cisplatin / Carboplatin 2b B +/- Gemcitabine + Capecitabine 2b B +/- Gemcitabine + Vinorelbine* 1b B - *Cave neutropenia / therapeutic index!

Triple Negative Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR Experimental therapies within studies ++ Cytotoxic therapy as for patients with HR pos / HER2 neg. mbc + Carboplatin (vs. Docetaxel) 1b a B +/- in gbrca mutation 1b a B + Gemcitabine/Cisplatin (vs. GemPac) 1b a A + Bevacizumab added to first line cytotoxic therapy 2b B +

Untch M, et al. Presented at: San Antonio Breast Cancer Symposium; 9-13 December 2014: San Antonio, Texas. Abstract PD2-6. San Antonio Breast Cancer Symposium, December 9-13, 2014 pcr in Stratified Subgroups Parameter Subgroup pcr (%) P-value SPARC SPARC negative 28.8 vs 37.7.003 SPARC positive 29.8 vs 48.3.074 Ki67 Ki67<=20% 19.6 vs 26.1.137 Ki67>20% 33.1 vs 44.0.001 Biological subtype HER2-, HR+ 12.0 vs 16.0.183 HER2-, HR- 25.7 vs 48.2 <.001 HER2+, HR+ 50.0 vs 56.4.275 HER2+, HR- 66.7 vs 74.6.371 HER2 HER2-17.7 vs. 27.0 <.001 HER2+ 54.1 vs 61.8.120 HR-status HR- 36.1 vs. 56.1 <.001 HR+ 25.6 vs. 29.9.169

Bevacizumab Treatment in HER2-neg. Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR 1 st line in combination with: Paclitaxel (q1w) 1b B + Capecitabine 1b B + Anthracyclines 2b B +/- Nab-Pac 2b B +/- Docetaxel (q3w) 1b B +/- Cap+Bev as maintenance after Doc+Bev 1b B +/- 2 nd line as treatment through multiple lines 1b B +/- 2 nd line in combination with: Taxanes 1b B +/- Capecitabine 1b B +/- Gemcitabine or vinorelbine 1b B -

Paclitaxel (P) + Bevacizumab (B) ± B 1L MBC (N=314) PFS, OS mpfs: 18.5 vs. 10.2 mo mos: 55.5 vs. 38.7 mo Mentuccia L, et al. ASCO 2015 (abs 549)

PARP inhibition and tumor-selective synthetic lethality DNA damage (SSBs) DNA replication (accumulation of DNA DSBs) PARP PARP inhibition Normal cell with functional HR pathway HR-deficient tumor cell (e.g. BRCA 1/2 -/- ) HR-mediated DNA repair Cell survival Tumor-selective cytotoxicity Cell death Impaired HRmediated DNA repair DSB, double-strand break; HR, homologous recombination SSB, single-strand break Farmer H et al. Nature 2005;434:917 921 Bryant HE et al. Nature 2005;434:913 917 McCabe N et al. Cancer Res 2006;66:8109 8115

A randomized, placebo- controlled, double blind, phase III study evaluating safety and efficacy of the addition of veliparib plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy versus in subjects with early stage triple negative breast cancer (TNBC) GBG 81 Brightness Heilung durch Innovation, Kompetenz und Partnerschaft

Prediction of pathological complete response (pcr) by Homologous Recombination Deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC Results from GeparSixto. Gunter von Minckwitz, Kirsten Timms, Michael Untch, Eric P. Elkin, Eric Hahnen, Peter A. Fasching, Andreas Schneeweiss, Christoph T. Salat, Mahdi Rezai, Jens U. Blohmer, Dirk M. Zahm, Christian Jackisch, Bernd Gerber, Peter Klare, Sherko Kümmel, Holger Eidtmann, Stefan Paepke, Rita Schmutzler, Julia Reid, Valentina Nekljudova, Karsten Weber, Anne-Renee Hartman, Sibylle Loibl for the GBG/AGO-B study groups Slides are the property of the authors. For permission to reuse contact sibylle.loibl@germanbreastgroup.de

100% pcr Rates by Treatment and According to HR Deficiency Status (ypt0/is ypn0) HR non-deficient OR 2.75 (0.85-8.94) P=0.086 100% HRD score high tbrca intact OR 2.97 (1.19-7.42) P=0.018 100% tbrca mutant OR 1.64 (0.51-5.27) P=0.406 20.0% 40.7% 36.6% 63.2% 61.9% 72.7% 75% Mean 29.8% Δ 20.7% 75% Mean 49.4% Δ 26.6% 75% Mean 68.5% Δ 10.8% 50% 50% 50% 25% 25% 25% 0% 0% PM PM+Cb PM PM+Cb N=30 N=27 N=41 N=38 0% PM PM+Cb N=21 N=33 by Gunter von Minckwitz, M.D.. Slides and presented data is the property of GBG. Permission required for reuse.

NeoSphere Study design and pcr results Patients with operable or locally advanced/ inflammatory HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) TD (n=107) Trastuzumab (8! 6 mg/kg) Docetaxel (75!100 mg/m²) PTD (n=107) Pertuzumab (840!420 mg) Trastuzumab (8! 6 mg/kg) Docetaxel (75!100 mg/m²) PT (n=107) Pertuzumab (840!420 mg) Trastuzumab (8! 6 mg/kg) PD (n=96) Pertuzumab (840!420 mg) Docetaxel (75!100 mg/m²) Study dosing: q3w x 4 S U R G E R Y bpcr, % ± 95% CI pcr, % ± 95% CI 60 45 30 15 0 80 60 40 20 0 p=0.0198 bpcr p=0.0141 p=0.003 tpcr TD PTD PT PD HR-positive HR-negative 2036,8 2663,2 5,927,3 17,430 TD PTD PT PD Mod. Gianni L et al. ASCO 2015, Oral Abstract Session Breast Cancer-HER2/ER, Abstract No. 505

First Line Therapy of HER2 Overexpressing Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR Docetaxel + trastuzumab + pertuzumab 1b A ++ (nab)paclitaxel + trastuzumab + pertuzumab 2b B + T-DM 1 (relapse within 6 months after taxane and trastuzumab-pretreatment) 2b B + 1 st line chemotherapy* + trastuzumab 1b B + Trastuzumab mono 2b B +/- Taxanes + lapatinib 1b a B - Taxanes + trastuzumab + everolimus 1b a B - Trastuzumab + aromatase inhibitors (if ER+) 2b B +/-** Lapatinib + aromatase inhibitors (if ER+) 2b B +/-** *Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel **see chapter Endocrine +/- targeted

2 nd line Therapy of HER2-positive mbc (If Pretreatment with Trastuzumab) AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 www.ago-online.de Oxford / AGO LoE / GR T-DM 1 1b A ++ TBP: 2 nd line chemotherapy + trastuzumab 2b D + Capecitabine + lapatinib 1b B + Trastuzumab + lapatinib (HR neg. disease) 2b B + Taxane + trastuzumab + pertuzumab 5 D + Any other 2 nd line chemotherapy* + trastuzumab + pertuzumab 5 D +/- Trastuzumab + aromatase inhibitors (if ER+) 3b B + Lapatinib + aromatase inhibitors (if ER+) 3b B + *e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel (toxicity!)

Further Lines of Therapy of HER2-Positive Metastatic Breast Cancer AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2015.1 Oxford / AGO Pretreatment with Trastuzumab LoE / GR T-DM 1 1b A ++ Capecitabine + lapatinib 1b B + Trastuzumab + lapatinib (HR neg. disease) 2b B + Chemotherapy + trastuzumab + ( treatment beyond progression ) 2b B + Trastuzumab + pertuzumab 2b B + Vinorelbine + trastuzumab + everolimus 1b B +/- www.ago-online.de There is no data for patients pretreated with trastuzumab and pertuzumab Experimental anti-her2-regimen 5 D + For patients pretreated with trastuzumab and pertuzumab 5 D treatment according to the recommendations above. There is no data for treatment beyond progression for pertuzumab.

Efficacy and Safety Results From a Phase III Trial of Nivolumab Alone or Combined With Ipilimumab vs. Ipilimumab Alone in Treatment-naïve Patients With Advanced Melanoma (CheckMate 067) Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

1.( CLEVER) CHEMOTHERAPY IS HERE TO STAY 2.THE ERA OF TARGETED THERAPY HAS STARTED

MARIANNE T-DM1 ± Pertuzumab vs. Trastuzumab + Taxan in 1L HER2 + (N=3.425) Ellis PA, et al. ASCO 2015 (abs 507)

MARIANNE T-DM1 ± Pertuzumab vs. Trastuzumab + Taxan in 1L HER2 + (N=3.425) Ellis PA, et al. ASCO 2015 (abs 507)