Sarcomes des tissus. Axel Le Cesne

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1 Sarcomes des tissus Axel Le Cesne Gustave Roussy, Villejuif, France French Sarcoma Group Chairman systemic treatment, EORTC Board of directors, CTOS Académie de Médecine GR, 18 janvier2017

2 Les sarcomes: une famille de maladies rares et hétérogènes Titre du diagramme Sarcomes Sarcomes osseux Sarcomes des tissus mous Sarcomes viscéraux 1 % des cancers de l'adulte 4000 nouveaux cas/an en France 2/100 tuméfaction des parties molles Taille médiane au diagnostic: 8 cm Tous les âges, âge médian: 53 ans Sex ratio équilibré Groupe de tumeurs hétérogènes Membre supérieur 15% Tête et cou 10% Tronc, rétropéritoine 30 % Membre inférieur 45%

3 Un sarcome peut se développer partout dans le corps

4 Histological sub-type of Sarcoma 2% 2% 6% 2% 3% 3% 11% Leiomyosarcomas Unclassifiable 16% 5% 8% Bone Liposarcomas 4% 3% GIST 18% 15% Bone primary (osteosarcoma/ chondrosarcoma) (8%) GIST (18%) Liposarcoma (15%) Soft-tissue Ewing sarcoma/pnet (4%) Kaposi sarcoma (3%) Dermatofibrosarcoma (5%) Unclassified sarcoma (16%) Leiomyosarcoma (11%) Rhabdomyosarcoma (3%) Angiosarcoma (3%) Myxofibrosarcoma (2%) Synovial sarcoma (2%) Endometrial stromal sarcoma (2%) Other very rare subtypes (6%) PNET, primitive neuroectodermal tumor. Ducimetiere F, et al. PLoS ONE. 2011;6(8):e20294.

5 21 st century: to understand our mistakes and sarcoma complexity A Rainbow Of Different Sarcoma Subtypes At least 106 entities (malignant 77), multiple sites, size, grade: 100 patients included in trials = 100 different diseases!!

6 Lipome Hématome Sarcome

7 Sarcomes des tissus mous - constat Masse > 5 cm et profonde dans les tissus mous Dans les centres experts Suspicion sarcome Imagerie ad-hoc centre expert RCP Biopsie initiale diag de sarcome Traitement d induction Chirurgie planifiée Traitements adjuvants adaptés En dehors des centres experts Suspicion kyste / tumeur bénigne Absence imagerie, RCP, biopsie Chirurgie inadaptée diag de sarcome Centre expert RCP Chirurgie de sauvetage Traitement adjuvant au cas par cas Rechute locale et RCP avant chirurgie Sans RCP Avec RCP Ray-Coquard et al La perte de chance se situe en amont de la RCP Rechute et conformité de la chirurgie Chir non conforme Derbel et al, PloS ONE 2016 Chir conforme aux recommandations

8 Réseaux de référence Sarcomes ( ) RRePS Pr Jean-Michel COINDRE BERGONIE Réseau de Référence en Pathologie des Sarcomes RESOS Pr François GOUIN CHU Nantes Pr Gonzague DE PINIEUX CHU Tours Tumeurs osseuses NetSarc Pr Jean-Yves BLAY CENTRE LEON BERARD Réseau de Référence Clinique des Sarcomes Relecture diagnostic obligatoire Revue collégiale cas discordants Base de données partagée via Internet Structuration des RCP sarcome en France Organisation RCP de recours Evaluation des pratiques -activité, -discordances, -délais, -techniques utilisées, -matériel congelé/paraffine 350 KE /an pendant 5 ans Evaluation des pratiques -activité RCP, -nouveaux pat. / Pat. en suivi -description traitements phase locale phase avancée, -inclusions essais, 400 KE /an pendant 5 ans

9 Rate of discrepancies for advice and reviewing (RRePS network) % of tumor category change RRePS Network (95% of incidence cases reviewed!)

10 Sarcoma reference networks ( ) Radiology before treatment Biopsy before surgery Surgery inside Netsarc Yes 86% No 3% Yes 80% No 17% Discussion in MTB Before surgery 56% After surgery 41% Surgery outside NetSarc Yes 59% No 11% Yes 36% No 54% Before surgery 10% After surgery 81% First discussion in MTB Sarcomas / GIST / desmoïds 2011 N= N= N= N=3247 Yes 48% 47% 45% 41% 54% 50% 48% 48% No 5% 5% 4% 4% 75% of incidence cases in 2014 Avant chirurgie Après chirurgie Rechute

11 NETSARC French Network of reference centers Relapse free survival n=13454 pts ( ) Patients whose primary surgery was performed in Netsarc centers had R0, R1, R2 surgery in 49%, 27%, 7% vs 24%, 31%, 21% in centers outside Netsarc (p< ) LRFS P<0.001 R0 in 50% of pts R2 in 7% R0 in 25% of pts R2 in 21% Logrank p= Inside vs outside NETSARC referal centers J.Y. Blay et al, ASCO 2016, ESMO 2016, NEJM 2017 submitted

12 «Operable» STS Take home messages (ESMO 2014) Surgery is the standard treatment of all patients with an adult type, localized STS. It must be carried out by a surgeon specifically trained in the treatment of this disease [III, A]. The standard surgical procedure is a wide excision with negative margins (R0)

13 Règles carcinologiques STM - Chirurgie Discussion pluridisciplinaire avant chirurgie Exérèse large monobloc R0 x mm (rechute < 20%) R1: résidus microscopiques (rechute > 50%) R2: résidus macroscopiques (rechute 100%) Cicatrice dans l axe du membre! Reprise systématique si exérèse marginale (si possible!) Exérèse monobloc enlevant les cicatrices de la biopsie «Le chirurgien ne doit pas voir la tumeur»: un chirurgien qui voit la tumeur est une exérèse R1 par définition: «énucléation» Une exérèse fragmentaire est une exérèse R2 par définition: «sarcomatose du lit tumoral» (risque métastatique augmenté)

14 STM - Traitement loco-régional Recommandations: chirurgie large conservatrice + RTE 50 Gy + complément 10 Gy - STM membres: chirurgie exclusive (amputation ou ex compartim.) - STM bon pronostic (petite T, superf, bas gde): chirurgie exclusive - STM extremité, compartimental - stade I à III (T1a exclus), grade 1 à 3 - à distance des nerfs, os et vsx - exérèse monobloc R0 (> 5 mm) - reprise sans reliquat tumoral R RTE adjuvante pas de RTE Arrêt de l étude en 2016.

15 Adjuvant systemic treatment in STS in high grade STS (grade 2-3) A never ending issue?

16 Localized resectable STS Adjuvant CT? N: 351 in 9 years (2/95-12/03) (years) Observation Overall survival Overall Logrank test: p=0.891 Adjuvant Patients benefiting the most from adjuvant CT: Male Extremity 5-10 cm High grade P. Woll, Lancet Oncol 2012 For who?? Tierney et al, Lancet 1997

17 EORTC adjuvant trials in STS Predictive factor of resection on OS by treatment Overall survival N = 819 Primary endpoint for each localized STS: R0 en bloc resection! R1 resection with CT R1 resection no CT R0 resection +/- CT Cntrl-Marginal Adjuv-Marginal Cntrl-Radical Adjuv-Radical (years) Adjuvant chemotherapy should never be intended to rescue inadequate surgery Le Cesne et al, Annals of Oncol 2014

18 STS Adjuvant CT ESMO CPGs / IGR algorythm (2017) Adjuvant CT R1 resection (even after salvage surgery) grade 3 specially in males. Discussion if margins unknown No adjuvant CT R0 resection, male/female grade 2-3 R1 resection, grade 2. All grade 1 Superficial STS, all grade, all age All retroperitoneal sarcomas All STS > 70 yrs Induction CT R2, R1 fragmentated resection before salvage surgery Adjuvant CT is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient for a shared decision-making with the patient

19 Neoadjuvant chemotherapy in STS A resolved question?

20 Neoadjuvant CT in STS Take home messages (ESMO 2014) If the decision is made to use CT as upfront treatment, it may well be used preoperatively. A local benefit may be gained, facilitating surgery Multi agent CT with adequate dose anthracyclines plus ifosfamide is the treatment of choice

21 R0 resection: prerequisite for cure! Stoeckle E, et al. EJSO 2006; 32: Primary endpoint for each localized STS: R0 en bloc resection!

22 Localized resectable STS Neo-adjuvant CT? 3 neoadjuvant EI cycles 3 neoadjuvant HTCT cycles Positive impact on metastases (OS) New standard in high risk grade 3 STS of extremity/trunk wall? (10-15% of our patients) Gronchi et al, ESMO 2016

23 Standard versus histotype-tailored CT ISG-STS 1001 Homogeneous group of STS Grade III, adult type STS Extremities and trunk wall Size > 5 cm R EI x 3 Surg + RT ht-ct x 3 Surg + RT MRC LipoS Trabectedin Synovial S HD-IFX LeiomioS GEM - DTIC UPS GEM TAX MPNST IFX + Etoposide Hypothesis: HT CT reduces by 30% the risk of relapse (40 to 27%, HR: 0.66) N random = 350, 500 registered Analysis: 150 events (relapses or deaths) with interim analysis for futility (IDMC) Gronchi et al, ESMO 2016

24 N = 287 pts RFS ISG-STS Results OS P= % 38% P= % 64 % Standard treatment in high grade «resectable» STS of extremities/trunk wall witth a high risk of relapse (50-70%)? Gronchi et al, ESMO 2016

25 Induction CT in STS Response rate with anthracyclins + ifosfamide N = 80 32% 57% Rate of non PD 94% 3% 16% Rate of non PD 97% 5% 6% 81% CR PR SD PD Very few PD during CT : no lost of chance for the vast majority of patients Ruiz et al, EJC 2011 Gronchi et al, ESMO 2016

26 Induction CT in STS Resection rate with anthracyclins + ifosfamide N = 80 Rate of R0 92% Rate of R0 90% N = % 81 % 16% R1 (10%) Locally advanced STS Resectable STS High level of R0 resection, pre-requisite for a better outcome in STS Ruiz et al, EJC 2011 Gronchi et al, ESMO 2016

27 Evolution of PFS overtime with EI regimen in the adjuvant and neoadjuvant setting in high grade STS of extremity 5 EI cycles in adjuvant EI induction +/- 2 in adjuvant 3 EI induction probability R0: 50% Arm A Arm B R0: 90% R0: 90% months 5 yrs RFS: 44% Frustaci, JCO yrs RFS: 60% Palassini, JCO yrs RFS: 62% Gronchi, ESMO 2016 Results mean: increasing the rate of R0 with CT could have an impact on PFS in localized operable STS of extremity

28 RFS by histology subtype HT-regimen Histological response EI Phase II trial - trabectedin in resectable MLPS N = 23 4 pcr, 10 ppr, no clinical PD A. Gronchi et al, Annals of Oncol 2011 Phase II trial - AI regimen - GR 100% 80% Survie sans progression en fonction de la réponse histologique logrank : chi2 à 1 ddl = 6.286, p = % 40% % nécrose <=70 % nécrose >70 A. Gronchi et al, ESMO 2016 A risque 20% 0% Années R. Ruiz et al, EJC 2011

29 Future of adjuvant/induction CT for non selected localized resectable STS Conventional CT with «molecular signature» FNCLCC Grade 3 Adjuvant/induction conventional CT AI regimen n=100 p=2,19x genes: Cinsarc signature Chibon et al, Nat Med 2010 FNCLCC Grade 2 Discussion during our French Sarcoma Group annual meeting in June 2017 n=42 p=0,05

30 Systemic treatment in advanced STS Front-line CT

31 General treatment algorithm in STS LOCAL DISEASE Surgery ± RT+/- CT 50-60% CURE LOCAL RELAPSE METASTASES LOCAL RELAPSE AND METASTASES Surgery ± RT+/- CT 1 st -line chemotherapy 2 nd -line chemotherapy 3 rd -line and beyond Paliative Anthracyclins Ifosfamide Trabectedin / Pazopanib gemcitabine + docetaxel (US) Trabectedin (US-L-STS) Eribulin? Clinical trials 80-90% Isolated lung mets Curative? Anthracycline-based multi-agent chemotherapy Trabectedin / Pazopanib gemcitabine + docetaxel (US) Trabectedin (US-L-STS) Eribuline? Clinical trials) 10-20% Surgery Surgery

32 Advanced STS Poly- vs monoct Authors Schedule N OR Survival Muss A/AC 104 NS NS Omura A/AD 146 NS NS Borden A/AD 186 AD = 30 % (p = 0.02) NS Lerner A/AD 66 AD : 44 % (leiomyo S) NS Santoro A/AI/CYVADIC 449 NS NS Borden A/AVd 295 NS NS Edmonson A/AI/APM 262 AI = 34 % (p = 0.03) NS Antman AD/MAID 340 MAID : 32 % (p = 0.002) NS Judson A/AI 415 AI: 26% (A: 13%) NS Ryan A/APal 447 APal: 28% (A: 19%) NS Multiagent chemotherapy with adequate dose anthracyclines plus ifosfamide may be the treatment of choice, particularly when a tumour response is felt to be potentially advantageous and PS is good. Doxorubicin alone remains the gold standard in palliative situation

33 GeDDiS phase III trial Gem-Tax vs Doxorubicin alone in front-line Seddon et al. J Clin Oncol (ASCO) Doxorubicin alone remains the gold standard in palliative situation

34 Doxorubicin plus Dacarbazine in leiomyosarcomas Total OR with HDI in trials: Leiomyosarcoma 7% Synovialosarcoma: 45% Ongoing data collection of Dox+DTIC in EORTC centers ASCO 2017 Doxorubicin plus dacarbazine is an option for multiagent first-line chemotherapy of leiomyosarcoma, where the activity of ifosfamide is far less convincing in available retrospective evidence, or solitary fibrous tumour [22] [V, B].

35 Weekly paclitaxel and gemcitabine in angiosarcomas Weekly taxol Weekly gemcitabine Median PFS: 4.0 months Median OS: 7.6 months Penel et al. J Clin Oncol 2008 Stacchiotti et al, Annals of Oncol 2012 In angiosarcoma, taxanes are an alternative option, given their high antitumour activity in this specific histological type [III,B]. An alternative option is gemcitabine ± docetaxel [V, B].

36 Doxorubicin +/- olaratumab (anti-pdgfra) in front-line CT for advanced STS Overall Survival (ITT) (Phase 2) Ongoing phase III W. Tap et al. Lancet oncol 2016 Ongoing phase III, closed for inclusion, results in 9/17

37 Systemic treatment in advanced STS Pre-treated STS: toward a personalized treatment?

38 Systemic TT in STS in pretreated pts Histological Sub-type Agents All sarcomas (Europe) Trabectedin in Europe (2007) All sarcomas (excepted LPS) Pazopanib (2012) All sarcomas (US) Gemcitabine +/- Docetaxel L-Sarcoma Trabectedin in US (2015) Translocation Related Sarcoma Trabectedin in Japan (2015) Liposarcoma Eribuline in US and Europe (2016) Leiomyosarcoma (Europe) Gemcitabine (option, ESMO2014) Gem + DTIC (option, ESMO 2014) Alveolar soft tissue sarcoma Anti-angiogenic agents (ESMO 2014) Angiosarcoma Taxol, gemcitabine (ESMO 2014) All sarcomas Ifosfamide HD (ESMO 2014, SS/UPS) DTIC (ESMO 2014, specially leiomyos)

39 L-STS - Trabectedin vs dacarbazine A Phase III study (SAR 3007) - PFS G Demetri et al. J Clin Oncol N = 518 PFS improved across all subgroups and posponed subsequent therapies No impact on OS FDA approved in US in L-Sarcomas in December 2015

40 TSAR Randomized phase III trial overview Randomization Advanced STS Unresponsive or intolerable to standard CT regimens 2nd to 4th CT line 1:1 Trabectedin 1.5 mg/m 2 in 24h iv infusion q3wk BSC With cross-over at progression Stratification L-STS vs non L-STS Primary end-point: PFS Number of patients required: 100 pts (90% power to detect a hazard ratio (HR) of 0.50) Centralized review to confirm progression before switch Secondary end-points: RR, safety, QoL, cost effectiveness and OS Trial required by French Health Authorities in 2014 Le Cesne A, et al. ESMO 2016

41 TSAR PFS overall population (central review) Median PFS p-value HR BSC (n=51) 1.51 m 1 T (n=52) 3.12 m < Med PFS p-value HR BSC (n=30) 1.41 m 1 T (n=32) 5.13 m < Median follow-up: 11 months Le Cesne A, et al. ESMO 2016

42 Trabectedin in t(12;16)(q13;p11) Myxoid LPS The first targeted therapy in STS? Soft tissue 16 (43%) Abdominal cavity 14 (38%) Lung/pleura 11 (30%) Heart/pericardium/med 10 (27%) PD SD SD/MR + Choi Delayed R PR, CR 10% 4% 41% 24% 21% N=44 Tissue response = 65% tumour control = 90% OR = 45% 0 +5c Trabectedin acts by inhibiting the oncogenic chimeric protein responsible for the disease, thus reactivating adipocytic differentiation. F. Grosso et al., Lancet Oncology, 2007

43 Eribuline vs dacarbazine in Lipo/leio-STS: A Phase III study (SAR 3007) Benefit on OS only seen in LPS group FDA approval in liposarcoma, January 2016 P. Schoffski et al. Lancet 2016

44 Other chemotherapies in L-STS? GemTax > Gem Maki et al. JCO, % 80% 60% Median follow-up: 20 months (13-30) Meta-analysis: G = GT (ESMO 2010) 84% 55% Gemcitabine Gemcitabine + Docetaxel 40% 20% 0% At risk 63% 53% Months from randomization GemTax = Gem Pautier, The Oncologist 12 GemDTIC > DTIC Garcia Del Muro JCO 11

45 Immunotherapy in STS? 19.5% 42% 59% 100% LMS: 0/11 LPS: 1/9 SS: 1/8 UPS: 4/9 80% 60% 40% 20% 0% PD-L1 1% IDO1 5% KYN 1 Problems with PD-L1 as biomarker May be not required for response IDO1 more expressed in UPS Tawbi et al, ASCO 2016 (abstract 11006) Maud Toulmonde, ASCO 2016 (11008) Breeklin A. Wilky (discutant))

46 Immunotherapy trials in sarcomas

47 Systemic treatment in advanced STS Pre-treated STS: anti-angiogenic agents/targeted therapies

48 Advanced STS «non targeted» oral anti-angiogenic drugs Histology Targets Agents All except lipos VEGFR/PDGFR Pazopanib (ESMO 2014) ASTS t(x-17) target? Cediranib/Sunitinib (ESMO 2014) Solitary Fibrous T target? Sunitinib (ESMO 2014)

49 Palette trial : phase III trial Results PFS and OS CHMP positive, May 2012 and EMA approval, August 2012 Van Der Graaf et al, Lancet Oncol 2012

50 Soft tissue sarcomas and anti-vegfrs STS (four stratas) - Regorafenib vs placebo PFS Placebo Regor HR [95%] p Liposarcoma Leiomyosarcoma Synovial Sarcoma ASTS (T(X;17) (p11;q25) - Cediranib (45mg/d) (VEGFRs, c-kit) 33 pts: RR: 43% PD: 0% - Sunitinib: 3PRs out of 4 evaluable pts - Pazopanib: 30% of OR (28 pts) (Stacchiotti 2016) Other Sarcoma Non-adipous STS ESMO guidelines 2014 Solitary Fibrotic Tumor: Sunitinib (Casali et al, ASCO 09) Sorafenib (Stacchiotti, 2012) These agents are not approved in these diseases O. Mir et al, ASCO 2015 Kummar et al, ASCO 2011 Stacchiotti er al, Cancer therapy 2012 Stacchiotti et al, submitted 2016

51 Systemic treatment in advanced STS Pre-treated STS: toward a personalized treatment based on pathways/targets? a selected «drug» for a selected «target» for a selected «STS histotype»

52 Rankin et al S0033 Study Proc ASCO 2004, #9005 STS: at least 5 molecular subtypes WDLPS/DDLPS 1p32 2q14 6q23 MDM2 CDK4 Gene amplification: WD/DDLPS Specific translocation EWS FLI1 mrna Ewing Sarcoma New chimeric protein= oncogenic Gene translocation: CONTICANET EGAM March 8th % RB1 CGH of MFH Gene inactivation INI1 loss: Rhabdoid tumors TSG loss, NF1, TSC1-2: MPNST, PEComas GIST: from phenotype to KIT genotype KIT + pacemaker cells of the gut Originally depicted by Cajal C 29 H 31 N 7 O CH 4 SO 3 Molecular weight A A selective TKI of KIT First used in Ph+ CML Druker et al. Nat Med GIST: + C-kit C positive Hirota et al. Science 1998 RB1 is inactivated in 80% of MFH CT scan results Aug 16, 2000 Feb 6, % 80% Imatinib & Overall Survival in metastatic GIST Imatinib 400mg Imatinib 800mg Chemotherapy At Risk Deaths Two-Year Estimate 76% 72% 26% X 60% 40% Survival Improved With Imatinib Complex gene alteration: LMS, UPS Before Glivec Demetri et al, NEJM 2002 After Glivec 20% 0% Pre-Imatinib Years After Registration Gene mutation: GIST/desmoids

53 Proof of concept in mesenchymal tumors Toward selective adjuvant trials? Histology Targets Agents GIST KIT/PDGFR Imatinib DermatoFSP t(17-22) PDFGR Imatinib PECOMAS mtor/tsc1,2 Rapamycin inhibitors Giant Cell Tumor Rank/RankL Denosumab Pigmentitis VNS t(1-2) CSF1 Anti-CSF1 Inflam. Myofi. T. ALK alteration Crizotinib Alveolar STS VEGFR? Anti-VEGFR agents The collection of fresh/frozen tissue and tumour imprints is encouraged because new molecular pathology assessments could be made at a later stage in the patient s interest. Pts had to be included in clinical trials in referral centers.

54 Denosumab in Giant Cell Tumor of Bone (Target: Rank-Rank ligand) Locally aggressive osteolytic neoplasm Composed of osteoclast-like giant cells (expressing RANK) and stromal cells (RANKL) Human RANK Fully human monoclonal antibody - IgG2 isotype High affinity/specificity for human RANK ligand Denosumab Amgen 120 mg SC q4w N = 510 Response = 98% by histology (no giant cells at histology) or by radiology FDA/EMA approval 2014

55 Sarcoma with translocation (20%) Molecular diagnosis with FISH Sarcoma type Chromosomal transl. Fusion gene Ewing s sarcoma t(11;22)(q24;q12) EWS-FLI1 t(21;22)(q22;q12) EWS-ERG Clear cell sarcoma t(12;22)(q13;q12) EWS-ATF1 Desmoplastic small round cell tumor t(11;22)(p13;q12) EWS-WT1 Extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) EWS-CHN Myxoid liposarcoma t(12;16)(q13;p11) TLS-CHOP t(12;22)(q13;q12) EWS-CHOP Angiomatoid fibrous histiocytoma t(12;16)(q13;p11) TLS-ATF1 Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FKHR t(1;13)(p36;q14) PAX7-FKHR Synovial sarcoma t(x;18)(p11;q11) SYT-SSX1,2 Dermatofibrosarcoma protuberans t(17;22)(q22;q13) COL1A1-PDGFB Congenital fibrosarcoma t(12;15)(p13;q25) ETV6-NTRK3 Inflammatory myofibroblastic tumor t(2p23) Various ALK fusions Alveolar soft part sarcoma t(x;17)(p11;q25) ASPL-TFE3 Endometrial stromal sarcoma t(7;17)(p15;q21) JAZF1-JJAZ1 PVNS t(1,2) COL6A3 et CSF1

56 Future of sarcoma? Which tumor, which target, which agent, which trial? Anaplastic large cell lymphoma (ALCL), Inflammatory myofibroblastic tumor (IMFT) Papillary renal cell carcinoma type (PRCC) Alveolar soft part sarcoma (ASPS) Clear cell sarcoma (CSC) alveolar rhabdomyosarcoma (ARMS))

57 MOSCATO 01 trial: High through-put analysis in a high volume phase I center Monocentric Target accrual > 1000 patients FRESH TUMOR BIOPSY PATHOLOGICAL CONTROL MOLECULAR SCREENING CGH Array & NGS & WES by RNAseq CLINICAL DECISION TREATMEN T Max 21 calendar days Antoine Hollebecque et al., ASCO 2013; Charles Ferte et al, AACR 2014

58 Axel Le Cesne Institut Gustave Roussy, Villejuif Discussion

59 STS- Increase of OS? Control arm SMAC. Lancet 1997; 350: 1647 EORTC Woll, LO ) Surgical techniques improvement 2) Optimization of the «beginning» 3) Referral centers Overall survival Overall Logrank test: p=0.891 (years) Observation Adjuvant 5-yr OS 59% 69% 10% absolute increase of OS in 20 yrs Trials on adjuvant CT improved.. Surgeons/surgery!

60 Adjuvant chemotherapy according to gender Progression free survival Males N = Progression free survival Females CT No CT (years) Cnt-Male Adj-Male 0 (years) Cnt-Female Adj-Female Females Males trials only in males? Le Cesne et al, Annals of Oncol 2014

61 Adjuvant chemotherapy according to age Progression free survival N = 819 < 40 yrs 100 > 40 yrs Progression free survival 0 (years) Cnt < 40 y Adj < 40 y 0 (years) Cnt > 40 y Adj > 40 y trials in > 40 yrs? < 40 yrs > 40 yrs Le Cesne et al, Annals of Oncol 2014

62 Effect of adjuvant CT on OS in FNCLCC grade 3 STS A multivariate analysis of the FSG database Period : 1513 patients Median follow-up: 9 years Impact of Adjuvant Chemotherapy: Overall survival Adjusted hazard ratio for Grade 2 patients Adjusted hazard ratio for Grade 3 patients 0.79 [ ], p= [ ], p= A. Italiano et al, ASCO 09

63 STS Adjuvant CT - Meta-Analysis (1568 patients, 14 trials, no impact of CT on OS) Pts who benefit the most of CT: Male yrs Extremity 5-10 cm High grade OS advantage (0.029) for high grade extremity STS Tierney et al, Lancet (1997); 350:

64 Probability of survival OS and surgical conformity for STS patients 1,0 0,9 Surgery conformed to CPG s 0,8 0,7 0,6 0,5 Surgery not conformed to CPG s p = ,4 0,3 0,2 0,1 Survival at 5 yrs : Conformed surgery: 86% (majority of R0) Non conformed surgery: 68% (majority of R1) 0, Months Derbel et al, PloS ONE 2016

65 French Sarcoma Group (N = 694) 1 M E T A S T A S I S F R E E S U R V I V A L P =.0002 P <.0001 GRADE 1 N = 83 GRADE 2 N = 296 GRADE 3 N = fb YEARS Metastases at 5 yrs : 45-50% Mortality for sarcoma: - 10% in 5 yrs (Jemal A et al. CA Cancer J Clin. 2005; 55:10)

66 Meta-analysis of adjuvant CT for soft tissue sarcoma Overall survival 1568 patients in 14 randomised trials comparing chemo with no chemo Overall Survival: HR: 0.91 (NS) Local relapse: HR: 0.74 (p = 0.024) On source data meta-analysis 14 trials, 1568 patients ( ) CT No CT If adjuvant CT improves local control..better before surgery than postoperatively! Tierney et al, Lancet (1997); 350:

67 Is neoadjuvant chemotherapy in resectable STS a new standard of care? Evidence for neoadjuvant CT: «Facilitate» surgery: «planed» surgery vs «unplaned» one High level of R0 resection, pre-requisite for a better outcome in STS Very few PD during CT (3%) : no lost of chance for the vast majority of patients Validation of routine practice in referral center using neoadjuvant full dose since a few decades in «marginally» operable STS patients Rigorous selection of patients (50-70% risk of relapse, use of a «sarcomator algorythm»?) Translational studies for precision medecine programs in large/referral centers with techniques used to identify new actionable targets (Moscato, MOST, MultiSarc.) Impact of MTB in the decision making in referral centers dedidated to STS (NetSarc, ESMO 2016)

68 Is neoadjuvant chemotherapy in resectable STS a new standard of care? Evidence against neoadjuvant CT/ Limits Not indicated in all extremity high grade STS (<50% risk of relapse?) where a R0 resection is a «easy» achievement with free tumor margins. Discussion in MTB!! Optimal management of pts with early PD under CT at first tumor evaluation (after 2 cycles)? : RT, ILPs, local hyperthermia, salvage CT, amputation? Selection of histotype based on early predictive factors of sensitivity/resistance to anthracyclins/alkylating agents has to be defined! Quality of induction CT no equivalent to quality of surgery!! Induction CT has to be performed in referral centers qualified for surgery of these diseases +++ Optimal duration of induction CT in «responding» patients? How many cycles of EI?

69 No adjuvant chemotherapy Chart Title Soft tissue sarcoma (Histologically proven) Definitive surgery Randomization DOXORUBICIN 75 mg/m2 d1 IFOSFAMIDE 5 g/m2 d1 G-CSF 3 ug/kg d3 to 13 q 3 wks STS Adjuvant CT EORTC RFS Radiotherapy if indicated Radiotherapy if indicated 100 Pattern of relapse Grade 2 and some grade 1 STS Grade (years) Observation Adjuvant P. Woll, Lancet Oncol 2012

70 Preplanned OS subgroups analysis FDA approval in liposarcoma, January 2016

71 Isolated lung metastases of STS in 2016 «Take home messages» The first step: no emergency (metachronous mets = synchronous infra-clinical mets!) The second step: pluridisplinary discussion in a «sarcoma» tumor board The third step: strategy depending of mets evolution after two consecutive CT scan at two-three months (size and number) Increase in size, not in number Planned Surgery «Adjuvant» CT if naive pts? Increase in both size and number Systemic treatments Planned surgery in responders? When surgery of lung metastases is selected, an abdominal CT scan and a bone scan or a fluorodeoxyglucose (FDG)-PET are mandatory to confirm that lung metastases are isolated.

72 Palette trial : phase III trial pazopanib vs placebo (EORTC 62072) Pazopanib: 800 mg/d Metastatic STS failing doxo/ifo (no more than 2 comb or 4 mono CT) N = 246 No cross-over PFS Best supportive care N = 123 Van Der Graaf et al, ASCO 11 Lancet Oncol 2012

73 What is a good target in STS? Alteration Possible target Alteration Activation Promising target Alteration Activation Mécanisme A major target Alteration Activation Mécanisme Drogue Clinical trial J Fletcher. Sarcoma State of the Science Meeting, 17 June 2002, Bethesda, MD, USA

74 PFS Improved Across All Subgroups

75 R2/R1 resection: prerequisite for relapse/death?

76 Therapeutic options in locally advanced STS (ESMO 2014) In case of mutilating surgery, options have to be discussed with the patient, including - Induction chemotherapy and/or radiotherapy - Extremity: ILP with tumour necrosis factor alpha + melphalan - Extremity: Regional hyperthermia combined with chemotherapy Median OS of locally advanced inoperable STS pts:15 months (as metastatic) O Sullivan B et al, Lancet 2002; 359: Issels RD et al, Lancet Oncol 2010; 11: Deroose JP et al. J Clin Oncol 2011; 29:

77 Randomized Phase 3 Study of Trabectedin vs Dacarbazine (ET743-SAR-3007): Study Design and Status at Interim Analysis

78 TSAR PFS overall population (central review) Median PFS (95% IC) p-value log rank HR [95% IC] BSC (n=51) 1.51 m ( ) 1 T (n=52) 3.12 m ( ) < ( ) ORR T BSC PR 6 (11.8%) 0 SD 35 (68.6%) 31 (63.3%) PD 10 (19.6%) 18 (36.7%) Median follow-up: 11 months Le Cesne A, et al. ESMO 2016

79 TSAR PFS L-Sarcomas (central review) Median PFS (95% IC) p-value log rank HR [95% IC] BSC (n=30) 1.41 m ( ) 1 T (n=32) 5.13 m ( ) < ( ) 60% of patients included Le Cesne A, et al. ESMO 2016

80 Distant metastases impact of «sarcoma» tumor boards Investigation Rhône Alpes Distant metastasis and multidisciplinary assessment («good clinical practice») Lurkin A et al, BMC 2010 Advanced disease in STS: The decision-making is complex, depending on diverse presentations and histologies, and should always be multidisciplinary

81 Probability (%) Randomized phase II study comparing trabectedin and BSC in pretreated TRS PFS HR=0.07 P< Time (Months) N OS Median OS 95% CI Trabectedin 37 NR ** 12.8-NR BSC NR HR= 0.38 P= Significant difference in PFS: 5.8 vs 0.9 months N: 74 Kawai et al. Lancet Oncol 2015 Trabectedin was approved in this setting of STS in 2015 in Japan

82 Eribuline vs dacarbazine in Lipo/leio-STS: A Phase III study (SAR 3007) Study design and objectives

83 Imatinib in dermatofibrosarcoma t(17,22) :17q22 and 22q13 COL1A1 and PDGFRB Autocrine loop with PDGFb Imatinib approval in DFSP after two phase II Maki et al IJC, Rubin et al JCO Mc Arthur et al JCO

84 M. Toulmonde et al, ASCO 2016 (abstract 11008) Breeklin A. Wilky (discutant)

85 GIST- changing paradigms C 29 H 31 N 7 O CH 4 SO 3 Molecular weight KIT + pacemaker cells of the gut Originally depicted by Cajal GIST: + C-kit positive Hirota et al. Science 1998 A selective TKI of KIT First used in Ph+ CML Druker et al. Nat Med % 80% 60% 40% Imatinib & Overall Survival in metastatic GIST Imatinib 400mg Imatinib 800mg Chemotherapy At Risk Deaths Survival Improved With Imatinib Two-Year Estimate 76% 72% 26% KIT PDGFR Clinical proof of concept 20% Rankin et al S0033 Study Proc ASCO 2004, #9005 Pre-Imatinib 0% Years After Registration

86 Localized resectable STS (R0-R1) Adjuvant vs neo-adjuvant? Gronchi,et al, ESMO 2016 EORTC Woll Lancet Oncol neoadjuvant HTCT cycles 3 neoadjuvant EI cycles (years) Observation Overall survival Overall Logrank test: p=0.891 Adjuvant Positive impact on metastases (OS) New standard in high risk grade 3 STS of extremity/trunk wall? (10-15% of our patients) Impact on metastases unknown 10-15% in France (5-6 AI cycles)

87 No adjuvant chemotherapy Radiotherapy if indicated Chart Title Soft tissue sarcoma (Histologically proven) Definitive surgery Randomization DOXORUBICIN 75 mg/m2 d1 IFOSFAMIDE 5 g/m2 d1 G-CSF 3 ug/kg d3 to 13 q 3 wks Radiotherapy if indicated STS Adjuvant CT EORTC N: 351 in 9 years (2/95-12/03) Relapse free survival Overall survival Overall Logrank test: p= Overall Logrank test: p= Observation Adjuvant (years) 0 (years) Observation Adjuvant P. Woll, Lancet Oncol 2012

88 T-Dis protocol PFS in continuation and interruption groups 178 pts included, 53 pts (30% of initial pts achieving 6 courses) Le Cesne A. et al., Lancet Oncol. 2015

89 Anti-tyrosine kinases and antibodies against CSF1 in Pigmented Villonodular Synovitis (PVNS) Incidence ~ 600 new cases per year in US, often young adults Clonal neoplastic process: over-expression of CSF1 in synovium: Due to a genetic translocation t(1;2) CSF1:COL6A3 Proliferation of CSF1R-expressing cells (macrophages, giant cells, osteoclasts) Standard of care, joint replacement, amputation PLX3397 (Plexicon) N = 18 RG7155 (Roche) n= 20 evaluable by RECIST: N = 20 60% PR (12/20) 35% SD (7/20) 5% PD (1/20) W.D. Tap et al, ASCO 2014 P. Cassier et al, ASCO 2014