1. Trabectedin contribution to the treatment of sarcomas Pr JY Blay Centre Leon Berard, Lyon EORTC

2. Adipocytic tumours Well deifferentiated / dedifferentiated liposarcoma Myxoid / round cell liposarcoma Pleomorphic liposarcoma ….. Fibroblastic / myofibroblastic tumours Fibromatosis (desmoid) Solitary fibrous tumour / haemangiopericytoma Low grade myofibroblastic tumour Infantile fibrosarcoma Adult fibrosarcoma Mixofibrosarcoma ….. So-called fibrohistiocytic tumours Pleomorphic MFH / Undifferentiated pleomorphic sarcoma ….. Smooth muscle tumours Leiomyosarcoma ….. Skeletal muscle tumours Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Vascular tumours Epithelioid haemangioendothelioma Angiosarcoma of soft tissue ….. Chondro-osseous tumours Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumours of uncertain differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing tumour Desmoplastic small round cell tumour Extra-renal rhabdoid tumour Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Intimal sarcoma Many different histotypes And even more molecular subtypes!

3. Connective tissue tumours 5 types of sarcomas Associated with specific translocations generating fusion genes Associated with specific translocations generating fusion genes Ewing t(11;22), … Ewing t(11;22), … Synovialosarcomas t(X;18) Synovialosarcomas t(X;18) Alveolar rhabdomyosarcomas t(1;13), t(2;13) Alveolar rhabdomyosarcomas t(1;13), t(2;13) DSRCT t(11;22) DSRCT t(11;22) etc... etc... Kinase mutations (KIT, PDGFR in GIST) Kinase mutations (KIT, PDGFR in GIST) Gene inactivation (INI1 in rhabdoid tumors) Gene inactivation (INI1 in rhabdoid tumors) Simple genetic alterations: amplifications (mdm2+cdk4 in LPS) Simple genetic alterations: amplifications (mdm2+cdk4 in LPS) Complex genetic alterations (MFH, LMS,...) Complex genetic alterations (MFH, LMS,...)

4. A simple algorithm? LOCAL DISEASE Surgery + Radiotherapy CURE (~50%) METASTASES (~60%) Doxorubicin Ifosfamide Combination Doxorubicin Ifosfamide Combination Surgery ( ~ 10%) Trabectedin Trabectedin Trabectedin Trabectedin Trabectedin Trabectedin Ifosfamide Doxorubicin Ifosfamide Doxorubicin

5. Metastatic phase Doxorubicin- Ifosfamide Doxorubicin- Ifosfamide Trabectedin Trabectedin Gemzar+/-Docetaxel or DTIC Gemzar+/-Docetaxel or DTIC Taxol for angiosarcomas Taxol for angiosarcomas

6. Systemic treatment of sarcomas 2000-2012 2000 All sarcomas Doxorubicin Ifosfamide DTIC Selected subtypes Dactinomycin CDDP Vincaalcaloids Cyclophosphamide 2012 : All subtypes: Same +Trabectedin GIST: Imatinib, sunitinib, nilotinib? Osteosarcomas: MTPPE LPS: Dox, Trabectedin LMS: Dox, Trabectedin, Gem, G/T EWS: A,I,C,V,Ac, TopoI inh., IGF1R A/E RMS: Topo inh ESS: Aromatase inh. All?: mTOR All but LPS: VEGFR TKI Angio: Dox, Paclitaxel, GemTax DFSP: Imatinib PVNS: Imatinib Desmoid Tumors: imatinib

7. Trabectedin (Yondelis®) Marine-derived anticancer agent originally isolated from marine Caribbean tunicate, Ecteinascidia turbinata. Marine-derived anticancer agent originally isolated from marine Caribbean tunicate, Ecteinascidia turbinata. Currently obtained by a synthetic process. Currently obtained by a synthetic process. Approved in more than 70 countries for the treatment of relapsed STS and platinum sensitive ovarian cancer. Approved in more than 70 countries for the treatment of relapsed STS and platinum sensitive ovarian cancer.

8. Yondelis binds covalently to the DNA minor groove. 1 Yondelis binds covalently to the DNA minor groove. 1 Interaction with the endonuclease XPG. 1 Interaction with the endonuclease XPG. 1 The formation of a large ternary cytotoxic complex (DNA-Yondelis-XPG) results in DNA breaks. 1 The formation of a large ternary cytotoxic complex (DNA-Yondelis-XPG) results in DNA breaks. 1 Yondelis: A Unique Mechanism of Action 1 Formation of a ternary complex between DNA (blue), Yondelis (Orange) and XPG (Green) Affecting “the two” cellular processes related to DNA: replication 1 and transcription 2, and finally inducing an apoptotic cell death. 1 1. Herrero AB, et al. Cancer Res. 2006;66(16):8155-62. 2. Fayette J, et al. Curr Opin Oncol. 2006;18:347-53.

9. Yondelis is a multitarget agent TF FP DNA binding and distortion Displacement of TF and FP Transcription inhibition ARN pol II Tumour microenvironment Pre-treatmentCycle 3 Pre-treatmentCycle 2 Adapted from M D’Incalci et al, 2010 DNA repair XPF XPG

10. Major impact (tumor control, 6-PFS) in: Leiomyosarcoma (LMS) 56% Liposarcoma (LPS) 40% 270 patients randomized (260 treated) Baseline characteristics well balanced between both arms 66% leiomyosarcomas / 34% liposarcomas Prior chemotherapy: PD after anthracyclines and ifosfamide 2/3 of pts received additional agents (Gem, 32%; docetaxel, 24%....) STS-201 Trabectedin: 1.5 mg/m 2 24-h CI q3wk Trabectedin: 0.58 mg/m 2 3-h wkly 3wks/4 ® Advanced LPS/LMS

11. STS-201 Historical Context (EORTC): PFS in Sarcomas Both trabectedin schedules showed longer PFS than “active” drugs in similar setting Le Cesne et al. Drugs of today 2009;45(6):403-21 1 2 3 4 1. Trabectedin q3wk 24-h 2. Trabectedin qwk 3-h 3. Active agents (EORTC STBSG) 4. Inactive agents (EORTC STBSG) 14% 6 months PFS 36% 6 months PFS

12. LPSMR(SD) 15 cy Alive at 11+ yrs Objective response vs Survival

13. Linking with clinical use of trabectedin Histology Histology Combinations Combinations Maintenance treatment Maintenance treatment Rechallenge Rechallenge

14. 0 +4 c Trabectedin in MLPS: Induction CT in Localized MLPS? N = 23: 4 to 6 cycles of trabectedin/Surgery/ RT End-point: complete histological rate Analysis of fusion Transcripts/ Response Multicenter Phase II (IGR/Milan/CLB/US) A. Gronchi et al, Ann Oncol 2011

15. Before After 6 cycles 41 pts MTD and recommended dose: D60 mg/m² + T1.1 mg/m² ORR + SD (tumor control) = 95% 6-months PFS: 59% (> baseline reference EORTC first line) Currently several studies are ongoing with combination therapy: Phase II randomised multicenter study of Trabectedin plus Doxorubicin vs. Doxorubicin in untreated STS patients (GEIS) Blay JY et al CCR 2008 Trabectedin + Doxorubicin

16. Trials ongoing in first line Translocation related sarcomas Translocation related sarcomas TRUSTs TRUSTs GEIS-20 (Trabectedin + Doxorubicin) GEIS-20 (Trabectedin + Doxorubicin) LMS-02 (Doxorubicin + Trabectedin) LMS-02 (Doxorubicin + Trabectedin)

17. Future of Trabectedin in STS Molecular targeted therapy with trabectedin in TRS Combination with others drugs Personalised treatment with surrogate biological markers. Adjuvant approaches? Marker + Marker -

18. Trabectedin Importance of maintenance treatment? N=56, interruption vs continuation after 6 courses Explored in the randomized T-DIS trial p=0,001 p=0,009 Blay JY et al, BMC 2012 (Submitted)

19. European Clinical trials in Rare Sarcomas within an integrated translational Grant agreement no.: 278742