High dose chemotherapy in Ewing sarcoma. Nathalie Gaspar Gustave Roussy Cancer Campus, Villejuif (France)

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1 High dose chemotherapy in Ewing sarcoma Nathalie Gaspar Gustave Roussy Cancer Campus, Villejuif (France)

2 Principles of high-dose chemotherapy Log-linear dose/efficacy relation of alkylating agents - Increased efficacy (?) - Increased toxicity : hematologic +++ Rescue by autologous stem cell transplatation : Peripheral stem cells > bone marrow stem cells Porrata et al. BJC 2001

3 High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW HDC in newly diagnosed multimetastatic EW HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now

4 HDC in recurrent or progressive EW Small heterogenous Retrospectives studies HDC might benefit patients with Lung only EW recurrence EW Late recurrence > 2years Who achieved CR or PR before HDC EFS 20% vs 0% GASPAR et al. JCO 2015

5 High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now

6 HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons GASPAR et al. JCO 2015

7 HDC in newly diagnosed multimetastatic EW +/-RADIOTHERAPY CD IE Bu/Mel CSP EW93/97 CT S CT +/-RT CT S CHD +/-RT EW88 EW93/ Oberlin, BJC 2001 Localised disease (n=141) 58 % 17 % Metastatic disease (n=28) % 38 % Localized tumors Metastatic tumors 3 Oberlin, JCO 2006

8 HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Various induction chemotherapies Various HDC regimens +/- Total body irradiation GASPAR et al. JCO 2015

9 HDC in newly diagnosed multimetastatic EW Importance of Busulfan 1.0 EWING TUMOURS EBMT 99 No relapse before MGT/SCR psu Busulfan HDC regimen Other HDC regimens years Busulfan n=139 5 yrs. psu = 0.54 ± 0.05 others n=120 5 yrs. psu = 0.26 ± 0.04 p<0.001

10 HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Two very different populations of newly diagnosed metastatic EW EW with lung metastasis only EW with metastasis other than lung only EW93/97 97 patients ( ) GASPAR et al. JCO 2015

11 EE99-R3: multimetastatic EW TTT VIDE x6 loc Med FUP 3.8 years Large prospective European non randomised trial 281 patients Med Age 15.3y Limb PT 31% ITV>200ml 65% VAIx1 R3 Bu/Mel 60% did recevied CHD - 16 PD before CHD - 24%? Status before HDC OS 34% EFS 27% Median survival time 19.2 months Ladenstein, JCO 2010

12 EE99-R3: multimetastatic EW CR Age HR Score Age - 14 ans - > 14 ans Volume tumoral initial -<200ml - 200ml BM VTI Métastases osseuses > Métastases MO -non -oui Méta pulmonaires -non -oui Not really used Ladenstein, JCO 2010

13 Multimetastatic EW EE99-R3 VIDE x6 C H I R VAIx1 Bu/Mel Experience Monocentrique Gustave Roussy VIDE x6 C H I R Thio HD Bu/Mel 3y-EF 11% 3y-OS 22% N=18 patients To improve the CR rate before HDC Loschi, BMT 2015

14 Multimetastatic EW To improuve induction CT PR 15 SD 2 PD 2 ISG up-front window melphalan N=19 patients Patients <40 years All Met 2y-OS 21% Cisplatinum (Luksch PBC 2017) N=8 Luksch, ECJ 2007 n=102 n=97 n=79 n=57 /65 with Lung Mets Luksch, Ann Oncol Gy 12 Gy <14y ISG/SSG IV N=102 patients Patients <40 years All Met 5y-EFS 44% 5y-OS 52% To improuve lung mets control

15 Multimetastatic EW To improuve MRD control by maintenance treatment Oral metronomic cyclophosphamide Celocoxib Vinblastine PI: Valérie Laurence, France ONOING

16 Multimetastatic EW Ewing 2008 A HDC randomised trial in multimetastatic EW There are no data to support equivalent efficacy with treosulfan, which, although closely related to busulfan, is less radiosensitizing. PI: Utah Dirksen, Germany ONOING

17 High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now

18 HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Two very different popuations of metastatic EW at diagnosis EW with lung metastasis only EW with metastasis other than lung only EW93/97 97 patients ( ) GASPAR et al. JCO 2015

19 EE99-R2pulm : EW lung metastasis Historical comparison: Bu/Mel vs CT+ total lung irradiation (TLI) EW93/ WITH CHD Paulussen, JCO 1998 CESS81, CESS86, EICESS WithOUT CHD RT bipulm 15-18Gy n=75; 5y-EFS 36% No RT pulm Oberlin, JCO 2006 Paulussen, JCO 1998 Rational for the EE99- R2pulm randomised trial VIDE x6 Loc TTT VAIx1 R2pulm Bu/Mel VAIx7 + TLI

20 EURO-E.W.I.N.G 99 stratification All newly diagnosed Ewing Sarcoma up to age 50 years Surgery after VIDE Histological response Localised disease Other local treatment Initial tumour volume Initial surgery Pre-op RT Exclusive RT Metastatic disease <10% >10% <200ml >200ml Standard risk Localised High risk Pulmonary metastases Other metastases R1 R2Loc R2Pulm R3 Le Deley et al, JCO 2014 Whelan et al. ASCO 2016 Dirksen et al. ASCO2016 Ladenstein et al, JCO 2010 JCO 2018

21 Med FUP 7,8 ans Randomisation rate 55% 132 assigned to VAI & WLI rando 131 eligible for R2pulm trial 1 not eligible for R2pulm trial 120 started assigned intervention 2 received BuMel 6 early stop of Tx due to progression 4 no information EE99-R2pulm : EW lung metastasis 3327 patients assessed for eligibility 592 pulmonary met. patients 480 pts with documented eligibility criteria 265 pts included in the R2pulm trial from 144 centres, 14 countries - One pulmonary/pleural nodule of > 1 cm - or more than one nodule of > 0.5 cm - A solitary nodule of 0.5- <1 cm or multiple nodules of cm was questionable evidence of metastatic disease, pathologic confirmation was recommended. 133 assigned to BuMel rando 130 eligible for R2pulm trial 3 not eligible for R2pulm trial 100 received assigned intervention 30 did not receive BuMel HD 1 received another HD 2 received BuMel + WLI 2735 pts other than pulmonary met. disease 112 pmets pts did not meet eligibility criteria 215 pts not included 128 because of refusal 87 for miscellaneous reasons 132 in the intention-to-treat analysis 133 in the intention-to-treat analysis Dirksen, ASCO 2016

22 EE99-R2pulm : EW lung metastasis Hypothesis: detection of a 15%-EFS improvement at 3 years in Bu/mel arm (EFS 55% vs. 40%, HR=0.65), 2-sided alpha=0.05; power=80% Sample size calculation: 188 events, 326 patients No advantage of Bu/Mel No survival benefit ITT analysis BuMel, 3-y EFS= 55% VAI+TLI, 3-y EFS=51% HR = 0.82 (95%CI, ) p= 0.24 BuMel, 3-y OS= 68% VAI+TLI, 3-y OS=68% HR = 0.96 (95%CI, ) p= 0.82 Stable results in per-protocol analysis Dirsksen, ASCO 2016

23 EE99-R2pulm : EW lung metastasis Cumulative incidence of secondary metastase (competing risk approach) No major heterogeneity across subgroups Dirsksen, ASCO 2016

24 EE99-R2pulm : EW lung metastasis Late effect analysis not done Dirsksen, ASCO 2016

25 High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW: no BU/Mel advantage HDC in newly diagnosed localised high-risk EW up to now

26 HDC in newly diagnosed localised high-risk EW Société Française des Cancers de l Enfant; 1993 to 1999; prospective study of 48 (PHR) HDC added to CyDoxo is feasable and show historical improve EFS compared to EW88 without HDC Homogenous induction Chemotherapy And HDC regien Gaspar et al. GASPAR et al. JCO 2015

27 HDC in newly diagnosed localised high-risk EW CT S CT +/-RT CT S CHD +/-RT EW88 EW93 Oberlin, BJC 2001 Gaspar, EJC 2012 Residual tumour cells 5% Initial tumoral volume 200ml Residual tumour cells 30% Initial tumoral volume 200ml Rational for the randomised EE99-R2loc trial VIDE x6 TTT loc VAIx1 R2loc VAIx7 Bu/Mel

28 EURO-E.W.I.N.G 99 stratification Histological response is the main prognostic factor in patients with localised disease undergoing surgery after induction chemotherapy Disease-free survival Joint SFOP-GPOH study Le Deley et al, SIOP 2001

29 EURO-E.W.I.N.G 99 stratification All newly diagnosed Ewing Sarcoma up to age 50 years Surgery after VIDE Histological response Localised disease Other local treatment Initial tumour volume Initial surgery Pre-op RT Exclusive RT Metastatic disease <10% >10% <200ml >200ml Standard risk Localised High risk Pulmonary metastases Other metastases R1 R2Loc R2Pulm R3 Le Deley et al, JCO 2014 Whelan et al. ASCO 2016 Dirksen et al. ASCO2016 Ladenstein et al, JCO 2010 JCO sept 2018

30 EE99 and Ewing2008 R2loc trial 5% February 2000 and December 2015 Recruitment was stopped before reaching this target because of low accrual. 40% Whelan, JCO 2018

31 EE99 and Ewing2008 R2loc trial median age was 17.1 years (range, 11 months to 44.7 years). Whelan, JCO 2018

32 EE99 and Ewing2008 R2loc trial Hypothesis: detection of a 15%-EFS improvement at 3 years in Bu/mel arm (3-y EFS 70% vs. 55%, HR=0.60), 2-sided alpha=0.05; power=80% The initial target sample size was 328 patients (124 events) Advantage of Bu/Mel 69.0% (95% CI, %) 60.7% (95% CI, %) 56.7% (95% CI, %) 47.1% (95% CI, %). Stable results in per-protocol analysis EFS HR, 0.64 (95% CI, 0.43 to 0.95; P =.026) Whelan, JCO 2018

33 EE99 and Ewing2008 R2loc trial Benefit due to the prevetion of the metastasis Cumulative incidence of metastases (competing risk approach) Translates into better OS 78.0% (95% CI, %) 64.5% (95% CI, %) VAI Bu/Mel HR = 0.59 (95%CI, ) p= 0.02 OS 72.2% (95% CI, %) 55.6% (95% CI, %) HR, 0.63 (95% CI, 0.41 to 0.95; P =.028) Whelan, JCO 2018

34 EE99 and Ewing2008 R2loc trial Patients with an intermediate poor response may benefit more than those with a very poor response (10% to 29% v 30% viable cells; interaction test, P =.06), as well as younger patients ( 25 v >25 years of age; P =.12). Whelan, JCO 2018

35 EE99 and Ewing2008 R2loc trial Acute toxicity one course of BU/Mel vs 7 cours of VAI The effect of BuMel on the risk of severe acute toxicity did not differ between patients older than 25 years and younger patients Radiosensitizeing effect of Busulfan when primary tumour itrrdiation involved - Large digestive tract - Spinal cord Whelan, JCO 2018

36 Euro-EWING 2012 Random1: quelle backbone de CT? VIDE vs VDC-IE Random2: renforcement du TE? +/- acide zoledronique PI: Bernadette Brenan, UK

37 High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW: no BU/Mel advantage HDC in newly diagnosed localised high-risk EW: BU/Mel advantage up to now

38 HDC in Ewing sarcoma In newly diagnosed high-risk localised EW FIRST Proof concept of HDC efficacy in a randomised trial HDC does prevent metastasis and increase survival In newly diagnosed lung metastatic EW : HDC no better than conventional CT + TLI In newly diagnosed multimetastatic and reccurent EW : no clear proof of concept, only historical data

39 Thanks to all te actors of the Ewing community in Europe and across the world

40 COG studies : EW loc, VDC-IE INT-0154 N=478 patients, Randomisation rate? AEWS0031 N=568 patients, Randomisation rate? Standard Compressed Granowetter, JCO 2009 Wormer, JCO 2012

41 AEWS0031 : EW loc, VDC-IE Compressed > standard mean hospital days per cycle identical in both arms (around 5 days) 5y-EFS 73% vs 65% (P=0.048) HR 0.74 (95% CI, 0.54 to 0.99) 5y-OS 83% vs 77% (P=0.056) HR 0.69 (95% CI, 0.47 to 1.0) No prospective evaluation of the hisological response = no direct possible comparison to the EE99 results Wormer, JCO 2012

42 HDC in newly diagnosed multimetastatic EW INT-0091 N=60 patients Bone EW only; All mets Standard VDC-IE Week 13 Bi-Pulm RT 15 Gy If lung metastasis AEWS02P1 N=35 patients Patients <50 years BM/bone Met VAC VDC VAC IE VDC IE VAC HD IE VDC VAC HD D1C-D21C14 Vinblastine 1 mg/m2/dose IV push 3x/week Celecoxib 250 mg/m2/bid 1y-OS 35% (19 51%) Lung toxicities grade>2 7/21 pts irradiated (2 died) 3y-EFS 28% Without CHD