IntensifiedCT with stemcellrescue for high-riskprimary breastcancer

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1 IntensifiedCT with stemcellrescue for high-riskprimary breastcancer Paolo PEDRAZZOLI SC Oncologia

Trend of HDC BC in Europe: 1992-2012: data from the EBMT registry Phase III NEG Phase

2 Trend of HDC BC in Europe: : data from the EBMT registry Phase III NEG Phase III POS Meta-analyses Curtesy, M. Bregni Preclinical models/phase II 2012: inclomplete data

3 Rodenhuis et al HER2- Nitz et al. 2005

5 Trial design: intense dose-dense sequential CT vs conventional Moebus V et al. JCO 2010;28: by American Society of Clinical Oncology

6 Event-free survival (EFS) and overall survival (OS) by treatment arm Moebus V et al. JCO 2010;28: by American Society of Clinical Oncology

7 German Adjuvant Intensified CT trials DD > 3 LN+ HD > 9 LN+

8 Individual patient data

9 Patient characteristics Chacteristics SDC HDC Sample size Age Premenopausal 70% 70% HR positive 66% 66% HER2 positive 26% 25% Tumor size 3.5 cm 3.5 cm Nodes pos High grades 52% 54%

10 Background

11 Relapse-Free Survival ALL patients HDC SDC HR=0.87 (0.81, 0.94)

12 Overall Survival ALL patients HDC SDC HR=0.94 (0.87, 1.02)

13 HDC with ASCT for HRBC does not produce sufficient benefit to be worthwhile, also in view of the toxicity of the procedure.

15 TOXICITY DOSE-INTENSITY SUBGROUP ANALYSIS

16 TOXICITY DOSE-INTENSITY SUBGROUP ANALYSIS

17 In clinical decision making, any benefit in survival must be clearly weighted against the greater toxicities of a treatment modality Everybody, from Hippocrates on

18 Mortality of early studies Tallman et al TRM=4.9% Peters et al TRM=7% CSE midollari, HD BCNU

19 Mortality of «modern» studies Nitz et al TRM=0% Rodenhuis et al TRM=1%

20 Overall acute treatment-related mortality HDC: 2,4% SDC: 0,6% myelodysplastic syndrome and/or acute myelogenous leukemia (data from 6 of the 15 trials) HDC: 17 SDC: 16

21 Overall Survival excluding death due to toxicity HDC = 3046 SDC = 3075 HR = % CI, 0.83 to 0.99 P =.011 Berry et al, JCO 2011

22 Mortality: Italian Registry Overall acute treatment-related mortality 9/1272 (0.7%) Long-term mortality (not BC) Cardiac failure 2/1272 (0.15%) Secondary malignancies: 14/1272 (1.1%) Pedrazzoli et al, submitted

23 Intensified CT does not seem detrimental to the chances of giving subsequent lines of CT in case of recurrence Siena S, et al. Ann Oncol. 1994;5(10): Korbling M, Fliedner TM. Bone Marrow Transplant. 1996;17(5): Bengala C, et al. Br. J Cancer. 2006;94(7):

24 TOXICITY DOSE-INTENSITY SUBGROUP ANALYSIS

25 Trial # Pts F/U (Yrs) HDC Regimen Control Arm Hortobagyi C, 1200 Et, 165 P, 2 cycles FAC x 8 Tallman C, 800 T FAC x 6 Rodenhuis C, 480 T, 1600 Cb FEC100 x 5 Zander C, 600 T, 40 M AC x 4, CMF 1-8 x 3 Coombes C, 500 T, 800 Cb FEC x 6 Nitz C, 90E 400 T, 2 cycles Dose dense EC x 4, CMF x 3 Bergh C, 500 T, 800 Cb Tailored FEC Gianni C, 8000 M, 240 E, 600 T, 180 A E 120 x 3, CMF x 6 Peters C, 165 P, 600 BCNU FAC x 4, ID CPB Tokuda C, 600 T FEC x 6 Schrama C, 480 T, 1600 Cb FEC120 x4 Roché C (mg/kg), 45 M, 140 A FEC x 4 Leonard C, 800 T ADM x 4, CMF 1-21 x 6 Basser C, 200 E, 3 cycles EC x 4, CMF 1-8 x 3 Moore STAMP I/STAMP V Dose dense ADM /Pacli/C Total HDC and SDC regimens

26 DOSE-INTENSITY Trial # Pts HDC SDI SDIP Control Arm SDI SDIP Difference SDI SDIP Hortobagyi Tallman Rodenhuis Zander Coombes Nitz Bergh Gianni Peters Tokuda Schrama Roche Leonard Basser Moore

27 Survival excluding trials with SDIP HDC < SDC (ACCOG, SWOG, SBG, MCG and IBCSG 2500 pts) OS RFS

28 TOXICITY DOSE-INTENSITY SUBGROUP ANALYSIS

29 Overall Survival - HER2 neg only 27% of the tumors had HER2 status available

30 Overall Survival - Triple negative Year

31 A positive effect of HDC in HER2- population, particularly in TN tumors, is biologically plausible and supported by clinical evidence Rodenhuis S,et al. Ann Oncol. 2006;17, Gluz O, et al. Ann Oncol. 2008;19: Diallo-Danebrock R, et al. Clin Cancer Res. 2007;13: Nieto Y, et al. J Clin Oncol. 2002;20: De Giorgi U, et al. High-dose chemotherapy for triple negative breast cancer. Ann Oncol 2007;18:202-3.

32 Gluz O et al. Ann Oncol 2008;19: Event-free survival (EFS) Overall survival (OS).

33 statistical analys is not «often» utilized in med oncology: Karapetis CS, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;23;359(17):

34 OS, Single vs Multiple TX Multiple (n=230) p = Single (n=937) Monts from transplant Pedrazzoli et al, submitted

35 Forward look Careful consideration of the potential contribution of both dose density and higher dose (High dose-dense) may be the way to improve results Ad hoc prospective studies taking into account the clinical and biological information we currently have (and that are rapidly improving), may well be useful in selecting target pts populations more likely to benefit from CT given safely at intensified doses

36 HD-TNBC-TRIAL: A phase II randomized, open-label neo-adjuvant study of standard chemotherapy regimen compared to high dose chemotherapy regimen with autologous stem cell transplantation in patients with triple negative BC TNBC Diagnosis R ARM A: EC for4 CyclesfollowedbyT for4 Cycles ARM B: ET for 4 cycles+ ETC with AHST for 2 cycles EC intended dose: epirubicin 75 mg/m(2) plus cyclophosphamide 600 mg/m(2), q 21 T intended dose: docetaxel 75 mg/m2,q21 ETintende dose: epirubicina75 mq/mq plus docetaxel75 mg/mq q21 ETC + AHST: epirubicin90 mg/m(2) plus cyclophosphamide3000 mg/m(2) +thiotepa400 mg/m2, q2 + peripheral blood progenitor cells Tx BIOLOGICAL STUDIES Curtesy, D. Generali

37 German vs Cremona HD arms E T E T E T E T HD-TNBC- CREMONA TRIAL

38 447 (HDC) vs 410 (SDC) Patients A statistically significant advantage in progression-free survival (HR, 0.76; P.001) did not translate into survival benefit TRM=not reported

40 Survival of patients undergoing HDC after obtaining complete or partial response by conventional-dose chemotherapy OS PFS Martino et al BMT 2012

41 Survival of patients converted in complete remission by HDC and of patients never achieving complete remission Converted in CR Never in CR Martino et al BMT 2012

42 Thank you for your attention

High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High- Risk Primary Breast Cancer

J Natl Cancer Inst Monogr (2015) 2015(51): lgv010 doi:10.1093/jncimonographs/lgv010 High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High- Risk Primary Breast Cancer Paolo