Systemic Treatment of Triple Negative Breast Cancer

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University Vienna General Hospital, Vienna, Austria and

1 Systemic Treatment of Triple Negative Breast Cancer Christoph Zielinski Comprehensive Cancer Center Medical University Vienna General Hospital, Vienna, Austria and Central European Cooperative Oncology Group (CECOG,

2 COI Declaration Honoraria: BMS, MSD, AstraZeneca, Novartis, Roche

3 Breast cancer is a heterogeneous group of diseases Adapted from Sorlie T et al. Proc Natl Acad S 2001;98(19): OS DFS

4 Molecular Features of Luminal vs. Basal Epithelial Cells

5 Heterogeneity in the Nomenclature and Classification of TNBC

6 Gene Expressions in TNBC Subtype Gene Expression Profile / High Expression of Genes Basal-like 1 (BL-1) Basal-like 2 (BL.2) Immunomodulatory cell cycle progression, cell division, and DNA damage response pathways cell cycle progression, cell division and growth factor signalling immune processes and cell signaling Mesenchymal motility and extracellular matrix Mesenchymal stem-like motility, extracellular matrix, growth factor signalling (consistent with claudin-low) Luminal androgen receptor hormonally regulated pathways

7 Trials for TNBC ABC Trials Brightness Trial CALGB CREATE-X GeparSixto NRG-BR003 WSG-ADAPT TN WSG PlanB

8 Settings for Drug Testing in Breast Cancer Setting Endpoints Advantage Neoadjuvant Path. Response Shortness, Low Patient Numbers Adjuvant DFI, OS Endpoint-Driven Metastatic ORR, TtP, OS Risk- & Option-Driven

9 Pathological CR after Neoadjuvant Treatment Surrogate for Micrometastasis (?) P. Cortazar et al., Lancet 2014: CTNeoBC pooled analysis A. Berruti et al., J. Clin. Oncol., doi: /JCO Klinische Abteilung für Onkologie Klinik für Innere Medizin I Medizinische Univ. Wien Allgemeines Krankenhaus

10 Baseline

11 after three treatment courses

12 after six treatment courses

13 pcr vs. PFS by Subtype (N=4193) Luminal A Luminal B HER2-neg Luminal B HER2-pos HER2-pos (non-lum) TNBC von Minckwitz G et al, J Clin Oncol 2012

14 Carboplatin in TN BC Platinum constitutes the backbone of treatment in ovarian cancer due to molecular similarities of TN BC with ovarian cancer, it was speculated that Platinum would be also beneficial in TN BC

15 GEICAM Study 1 94 Patients with TN BC Treatment: EC x4 > Doce100 x4 versus Doce75 + Carbo AUC6 Primary Endoint: pcr (breast) Results: pcr (breast) 35% vs. 30% (p=0.61) pcr (breast and axilla) 30%, respectively Conclusion: No amelioration through the addition of Carboplatin (due to previous exposure to alkylating drug?) 1 Alba E at al. Breast Cancer Res Treat 2012;136:

GeparSixto 1 18 weeks N=131 / 600 pts with ct 2-4 or ct 1c if

750-1000 mg/d Paclitaxel 80 mg/ m² weekly NPLD (Myocet) 20 mg/

16 GeparSixto 1 18 weeks N=131 / 600 pts with ct 2-4 or ct 1c if N+ Triple neg. or HER2-pos. R Surgery Primary endpoint: pcr core biopsy blood collection TNBC: Her2 pos: Bevacizumab q3w Trastuzumab q3w Lapatinib mg/d Paclitaxel 80 mg/ m² weekly NPLD (Myocet) 20 mg/ m² weekly Carboplatin AUC 2 min/ml weekly 1 G. von Minckwitz et al., Proc. Am. Soc. Clin. Oncol. 2013

17 pcr Rates by Subtypes GeparSixto: pcr by Subtypes 1 [TITLE] 1 G. von Minckwitz et al., Proc. Am. Soc. Clin. Oncol. 2013

18 Efficacy of Carboplatin in TN BC Post-hoc Analyses from GeparSixto Additive effect of Carboplatin upon pcr in BRCA mutant, family (BRCA wt) and sporadic TN BC pcr Carboplatin Group vs. Control BRCA mut OR 2.75 familiy (BRCA wt) OR 2.29 sporadic TN BC OR 1.79 evidence from other phase II studies standard despite lack of a phase III study? 2, 4 1 von Minckwitz G et al. J Clin Oncol. 2014;32(Suppl.18):# Tamura K et al. J Clin Oncol 2014;32(Suppl 18):# Sikov WM et al. J Clin Oncol 2015;33: Sharma P et al. J Clin Oncol. 2014;32(Suppl.18):#1022.

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic

19 Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB (Alliance) 1 Randomized Phase II Study 1 W.M. Sikov et al., J Clin Oncol :1, 13-21

20 1 W.M. Sikov et al., J Clin Oncol :1, CALGB : Results 1

21 Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial Prof Sibylle Loibl, MD, Joyce O'Shaughnessy, MD, Prof Michael Untch, MD, William M Sikov, MD, Prof Hope S Rugo, MD, Mark D McKee, MD, Prof Jens Huober, MD, Mehra Golshan, MD, Prof Gunter von Minckwitz, MD, David Maag, PhD, Danielle Sullivan, PhD, Prof Norman Wolmark, MD, Kristi McIntyre, MD, Jose J Ponce Lorenzo, MD, Otto Metzger Filho, MD, Priya Rastogi, MD, Prof W Fraser Symmans, MD, Xuan Liu, PhD, Prof Charles E Geyer, MD The Lancet Oncology DOI: /S (18)

22 Rationale for the Use of Platin plus PARP Inhibition

23 Figure 1 BrighTNess: Study Design The Lancet Oncology DOI: ( /S (18) )

24 Figure 2 BrighTNess: Responses The Lancet Oncology DOI: ( /S (18) )

25 Figure 3 BrighTNess: Results in Subgroups The Lancet Oncology DOI: ( /S (18) )

26 Carboplatin in TN BC Conclusion: there is certain evidence of a benefit of the addition of Carboplatin to chemotherapy in the neoadjuvant treatment of TN BC, BUT: also other interventions may be efficacious...

27 BUT: Which Evidence for Other Chemotherapy? ABC Trials: 4 Year invasive-disease-free Survival Docetaxel plus Cyclophosphamide: 88.2% vs. Anthracycline and Cyclophosphamide plus a Taxane: 90.7% Blum IL et al., J Clin Oncol 35: , 2017

28 Overcoming Resistance to Neoadjuvant Chemotherapy N. Masuda et al., N Engl J Med 376: 2147, 2017

29 Overcoming Chemotherapy Resistance: Capecitabine after Neoadjuvant Chemotherapy N. Masuda et al., N Engl J Med 376: 2147, 2017

30 Which Adjuvant Chemotherapy? Conclusions Germline BRCA-1 Mutated Disease: Platinum-Based Regimen BRCA-1 wildtype Disease: Combinations Containing Anthracyclines and Taxanes In the case of Treatment Resistance: Capecitabine

31 Settings for Drug Testing in Breast Cancer Setting Endpoints Advantage Neoadjuvant Path. Response Shortness, Low Patient Numbers Adjuvant DFI, OS Endpoint-Driven Metastatic ORR, TtP, OS Risk- and Option- Driven

32 Overall survival from MBC in dependence on molecular characteristics patients Median observation: 14.8 years Median OS from MBC: Luminal A: 2.2 years Her-2 positive: 0.7 years (remark: pre-trastuzumab) Basal: 0.5 years (p<0.001) Kennecke H et al. J Clin Oncol 2010;28:

33 First-Line Taxane or Carboplatin in TN MBC 1 Kein Unterschied bei corebasal-like und brcaness 1 A. Tutt et al., SABCS 2014: S3-01

34 Doublet Chemotherapy in TN MBC Median PFS: nab-paclitaxel + Carboplatin: 7.4 months nab-paclitaxel + Gemcitabine: 5.4 months Gemcitabine + Carboplatin: 6.0 months Yardley D et al., SABCS, Abstr. 874, 2016

35 Multifactoral Contributions of Activated/Recruited Stromal Cells to the Hallmarks of Cancer Douglas Hanahan, Lisa M. Coussens Cancer Cell 2012, 31:

36 CECOG TURANDOT Study: Multicentre Randomised Phase III Trial 51 centres, 12 countries (Europe and Israel) HER2-negative measurable/non-measurable LR/mBC ECOG PS 0 2 BEV PAC (n=285): BEV 10 mg/kg d1 & 15 + PAC 90 mg/m 2 d1, 8 & 15 q4w No prior chemotherapy for LR/mBC Prior (neo)adjuvant chemotherapy and/or radiotherapy permitted only if completed 6 months before randomisation a R BEV CAP (n=279): BEV 15 mg/kg + CAP 1000 mg/m 2 bid d1 14 q3w Treat to PD or toxicity Stratification factors: ER/PgR status Country Tumour and QoL assessment q12 weeks in both arms Safety assessment at every cycle Menopausal status C. Zielinski et al., Lancet Oncol. 2016

37 CECOG TURANDOT Study: OS (PP population, n=533) BEV PAC (n=268) BEV CAP (n=265) Events, n (%) 89 (33) 92 (35) Estimated probability year OS rate: BEV PAC: 81% BEV CAP: 79% BEV PAC BEV CAP Median, months (95% CI) HR, stratified (97.5% repeated CI) 30.5 (26.2 NR) ( to 1.686) p-value b month OS rate: BEV PAC: 68% BEV CAP: 70% 2-year OS rate: BEV PAC: 60% BEV CAP: 55% 26.0 (22.2 NR) Time (months) No. at risk BEV PAC BEV CAP C. Zielinski et al., Lancet Oncol. 2016

38 CECOG TURANDOT Study: PFS (ITT population) Estimated probability BEV PAC BEV CAP BEV PAC (n=285) BEV CAP (n=279) Events, n (%) 177 (62) 214 (77) Median, months (95% CI) HR, stratified (95% CI) ( ) 1.36 ( ) p-value a a 2-sided log-rank test adjusted by stratification factors Time (months) No. at risk BEV PAC BEV CAP C. Zielinski et al., Lancet Oncol ( )

39 TURANDOT: Baseline characteristics of the TNBC Subgroup Characteristic BEV PAC (n=63) BEV CAP (n=67) Median age, years (range) 54 (29 84) 56 (28 77) Premenopausal, n (%) 17 (27) 18 (27) ECOG performance status, n (%) 0 47 (75) 40 (60) 1 13 (21) 24 (36) 2 3 (5) 3 (4) Disease-free interval, n (%) 12 months 9 (14) 2 (3) >12 months 42 (67) 45 (67) None (metastatic at first diagnosis) 12 (19) 20 (30) Metastatic sites, n (%) Visceral 41 (65) 46 (69) Liver 17 (27) 29 (43) Lung 35 (56) 28 (42) Bone 22 (35) 25 (37) Lymph node status, n (%) Positive 33 (52) 44 (66) Negative 25 (40) 18 (27) Unknown 5 (8) 5 (7) Prior (neo)adjuvant chemotherapy, n (%) 45 (71) 42 (63) Taxane 19 (30) 14 (21) Anthracycline 39 (62) 33 (49) Neither anthracycline nor taxane 4 (6) 6 (9)

40 CECOG TURANDOT Study: PFS of the TNBC Subgroup PFS BEV PAC (n=63) BEV CAP (n=67) Events, n (%) 50 (79) 54 (81) 1.00 Median, months (95% CI) 9.0 ( ) 5.6 ( ) Estimated probability Hazard ratio a (95% CI) 1.37 ( ) p-value b BEV PAC BEV CAP No. at risk BEV PAC Time (months) BEV CAP a Univariate Cox proportional hazards model. b Two-sided log-rank test.

41 CECOG TURANDOT Study: ORR in the TNBC Subgroup Patients (%) 70 p= a BEV PAC (n=63) BEV CAP (n=67) Objective response rate 0 Complete response Partial response Stable disease Progressive disease Not evaluable a Pearson chi-square test.

42 Estimated probability CECOG TURANDOT Study: OS of the TNBC Subgroup BEV PAC BEV CAP a Univariate Cox proportional hazards model. b Two-sided log-rank test. OS BEV PAC (n=63) BEV CAP (n=67) Events, n (%) 28 (44) 34 (51) Hazard ratio a (95% CI) 1.33 ( ) p-value b year OS rate, % (95% CI) 78 (68 88) No. at risk BEV PAC BEV CAP (51 75) Time (months)

43 Treatment Options in BC

44 Examples for Novel Approaches to TNBC Molecular interventions (PI3K, AKT, mtor, BRCA) Antihormal Interventions (target: AR) Stroma-Directed

45 OlympiAD Trial in Triple-Negative, Germline BRCA-Mutated Advanced Breast Cancer Robson M et al. N Engl J Med DOI: /NEJMoa

46 OlympiAD Trial in Triple-Negative, Germline BRCA-Mutated ABC Robson M et al. N Engl J Med DOI: /NEJMoa

47 Examples for Novel Approaches to TNBC A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer Lee S. Schwartzberg, et al.: DOI: / CCR Published January 2017

49 Enzalutamide in TN MBC: PFS in the (A) intent-to-treat (ITT) population and (B) evaluable subgroup and of OS in the (C) ITT population and (D) evaluable subgroup. Published in: Tiffany A. Traina; Kathy Miller; Denise A. Yardley; Janice Eakle; Lee S. Schwartzberg; Joyce O Shaughnessy; William Gradishar; Peter Schmid; Eric Winer; Catherine Kelly; Rita Nanda; Ayca Gucalp; Ahmad Awada; Laura Garcia-Estevez; Maureen E. Trudeau; Joyce Steinberg; Hirdesh Uppal; Iulia Cristina Tudor; Amy Peterson; Javier Cortes; JCO 2018, 36, DOI: /JCO

56 Signalling pathways and involved entities that are unravelling experimental therapeutic targets for TNBC. Depicted molecular landscape of TNBC confers an insight of novel and investigational targeted therapeutic strategy which are directly unlocking its heterogeneous biology. Ji Hyun Park et al. ESMO Open 2018;3:e Copyright European Society for Medical Oncology. All rights reserved.

57 Future aspects of therapeutic strategies in patients with TNBC based on its chemosensitivity and immune-molecular heterogeneity. Ji Hyun Park et al. ESMO Open 2018;3:e Copyright European Society for Medical Oncology. All rights reserved.

58 Systemic Treatment of Triple Negative Breast Cancer: Conclusions TN BC remains a major challenge regarding our understanding of its biology and consequently its treatment. Platinum-based therapies seem to have certain efficacy in the neoadjuvant setting. In advanced disease, there might be a place for Bevacizumab-based treatment if ORR is required. PARP inhibition seems to have various efficacy at various stages of the disease. Further analyses of disease biology will certainly lead to ameliorated treatment options in this diversified disease. Enzalutamide exerts promising activity in AR+ disease ICPI treatment might have a certain place in selected patients.

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