1. 13 years of trabectedin and 5 years of Yondelis® in STS: what have we learnt? Le Cesne Axel, CTOS 2012, Prague

2. ET-743 Trabectedin Yondelis® Marine derived anticancer compound EMA approval on 20 th of September 2007 « Yondelis® is indicated for the treatment of patients with advanced STS after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients » Ecteinascidia turbinata

3. STS-201 trial q3wk 24-h median TTP 4.2 m qwk 3-h median TTP 2.5 m p=0.0028 HR=0.658 223 events Trabectedin: 1.5 mg/m 2 24 h CI q3w Trabectedin: 0.58 mg/m 2 3h wkly 3wks/4 ® AdvancedLipoS/LeioS George D. Demetri et al, JCO 09

4. STS-201 trial Consistency of benefit with trabectedin q3wk 24-h Trabectedin q3wk 24h induced significantly induced significantly greater tumour shrinkage than qwk-3h (p= 0.0008) q3wk 24-h qwk 3-h 32.4% 50.5% Tumour shrinkage

5. 1 2 3 4 1. Trabectedin q3wk 24-h 2. Trabectedin qwk 3-h 3. Active agents (EORTC STBSG) 4. Inactive agents (EORTC STBSG) STS-201-Historical Context (EORTC) PFS in Sarcomas 14% 6 months PFS 36% 6 months PFS Trabectedin q3w 24h Trabectedin weekly Both trabectedin schedules showed longer PFS than “active” drugs in similar setting (EORTC trials, Le Cesne et al. Drugs of today 2009;45(6):403-21)

6. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

7. Trabectedin, phase II (N = 189) Survival outcome 29.3% of pts alive >2 years > 6 cycles28% …Despite an ORR < 10% according to RECIST Clinical Benefit / tumour Control: PR+MR+SD 51.5% Pooled Data A.Le Cesne et al JCO 05, A.Yovine et al JCO 04, R.G.Carbonero et al JCO 04, J.Jimeno et al Current.Op.Orthop 2003

8. Progression free / Tumour control 2nd line treatment DrugsN (>40) PAR 2nd cycle Trabectedin123 54% Ifosfamide141 52% Docetaxel7447% Gemcitabine9539% Dacarbazine4436% Inactive agents< 20% Jaap Verweij, Educational book, ASCO 2003 Median: 5.3 months Time to response Pooled Data A.Le Cesne et al JCO 05, A.Yovine et al JCO 04, R.G.Carbonero et al JCO 04, J.Jimeno et al Current.Op.Orthop 2003

9. Trabectedin in elderly patients Pooled analysis of 5 phase II studies Le Cesne et al, EJC 2012, submitted PFS rates at 6 months: 29.5% (younger) vs. 36.4% (older); p=0.2638 A slightly higher incidence of some grade 3/4 AEs was observed in older patients. No major differences were found in the efficacy and safety profile of patients aged ≥70 years. Median OS: 13.0 m vs 14.0 m

10. Trabectedin: the first « RECIST problem » with conventional CT in the radiological evaluation of efficacy in STS The intriguing pattern of tumour response of trabectedin! Impact on survival Size ? …vs Hounsfield Unit? “Sometimes, tumour cells do not understand what we are doing!” GISTPlaceboSunitinibRegorafenibPR0%7%5% SD48%58%71% PD37%29%21% …..Paolo Casali

11. GMI: clinical benefit assessment among ASTS pts receiving trabectedin as salvage therapy GMI in patients treated with Yondelis ® (N = 279)GMI in patients treated with Yondelis ® (N = 279) –177 patients (63.4%) experienced a GMI < 1 –21 patients (7.5%) a GMI=[1-1.33] –81 patients (29.0%) a GMI>1.33 GMI < 1: median OS was 9.1m GMI > 1.33: median OS was 23.8m p=0.0005 N. Penel et al, Annals of Oncol 2012 Prognostic factors for GMI>1.33: PS only GMI as an indicator of drug activity! Same results in 227 pts treated in FSG Even for drugs considered as inactive According to EORTC rules Cousin et al, ASCO 2012 (abstract 10014)

12. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

13. NCI-CTC grade Total (n=1,132) 1/234 ALT increased (91%) 4737.16.9 AST increased (85%) 5626.52.8 AP increased (56%) 532.70.3 Common transient transaminase increases: Peak elevation at d 5-7, return to grade <1 at d15 Trend towards reduction in subsequent cy No clinical consequences NCI-CTC grade Total (n=1,132) 1/234 Neutropenia (69%) 3319.316.9 Thrombocyt (69%) 26.28.21.9 Neutropenia rarely associated with fever (1.9%) Discontinuations due to neutropenia: 4.2% of pts G-CSF support: 9.8% of patients Alopecia (3.7%), Renal toxicity (2.4%), Cardiac disorders (1.5%) Drug-related deaths: 15/1132 patients (1.3%) Trabectedin Safety profile

15. Drug Delivery qwk 3-h n=130 q3wk 24-h n=130 Median treatment duration (wks) 11.515.4 Median No. cycles (range)2 (1 – 21) 5 (1 – 37) Patients with 7 or more cycles 19%38% Median relative dose intensity 86%81% STS-201

16. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

17. Trabectedin active in STS subtypes other than lipo-leiomyoS ? Hemangiopericytoma Martínez Trufero Zaragoza, Spain Synovial sarcoma P. Schöffski UZ/KU Leuven

18. Liposarcoma and leiomyosarcomaLiposarcoma and leiomyosarcoma Uterine leiomyosarcomaUterine leiomyosarcoma Malignant fibrous histiocytoma / Pleomorphic sarcomaMalignant fibrous histiocytoma / Pleomorphic sarcoma FibrosarcomaFibrosarcoma Meningeal hemangiopericytomaMeningeal hemangiopericytoma Solitary fibrous tumourSolitary fibrous tumour Translocation Related Sarcomas (TRS)Translocation Related Sarcomas (TRS) - Myxoid liposarcoma - Myxoid liposarcoma - Synovial sarcoma - Synovial sarcoma - Alveolar sarcoma - Alveolar sarcoma - Desmoplastic small round cell tumour - Desmoplastic small round cell tumour - Endometrial stromal sarcoma - Endometrial stromal sarcoma Trabectedin has shown antitumour activity and clinical benefit in multiple histological subtypes of STS Le Cesne A, et al. Eur J Cancer 2012 Demetri GD, et al. J Clin Oncol. 2009, Sanfilippo R, et al. Gynecol Oncol. 2011, Grosso F, et al. Lancet Oncol. 2007, Blay JY. Eur J Clin Med Oncol. 2009, López-González A, et al. Med Oncol. 2011, Martinez-Trufero J, et al. Anticancer drugs. 2010, Chaigneau L, et al. Rare tumours. 2011

19. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

20. OR = 45% PD SD SD/MR + Choi Delayed R PR, CR 24% 41% 10% 21% 4% tumour control = 90% t(12;16)(q13;p11) MLPS /Yondelis The first targeted therapy in STS? Tissue response = 65% N=44 F. Grosso et al., Lancet Oncology, 2007  Soft tissue 16 (43%)  Abdominal cavity 14 (38%)  Lung/pleura 11 (30%)  Heart/pericardium/med 10 (27%) Prior CT (Dox/ifo): 98% Median courses: 9 (1-43) PD SD+MR OR A. Gronchi et al, ASCO 09, ECCO 09

21. Courtesy of Dr F Grosso Translocation Related Approach Trabectedin in TRS Alveolar soft part S t(X;17)(p11;q25)ASPL-TFE3 Ewing’s sarcoma t(11;22)(q24;q12)EWS-FLI1 Endometrial stromal sarcoma t(7;17)(p15;q21)JAZF1-JJAZ1

22. PFS by translocation-related STS and patient N = 81 Tumour control: SS: PR+SD: 54% MLPS: PR+SD: 67% Total: 59% Recently confirmed SS (N=61): 50% of control rate Sanfilippo et al, CTOS 2012 Trabectedin in TRS SS=45 MLPS=27 Le Cesne et al, EJC 2012

23. 24h q3w vs weekly Median PFS: 11.9 vs 5.6 Median OS: 34.4 vs 10.5 Trabectedin in TRS Median OS: 17.4 months SS: 13.9 months MLPS: 18.3 months Le Cesne et al, EJC 2012 George D. Demetri et al, JCO 09 TRS STS

24. Translocation-Related Approach Trabectedin in TRS Sarcoma typeChromosomal transl. Fusion gene Clear cell sarcoma t(12;22)(q13;q12) EWS-ATF1 Extraskeletal myxoid chondroSt(9;22)(q22;q12) EWS-CHN Myxoid liposarcoma t(12;16)(q13;p11) TLS/EWS-CHOP Angiomatoid fibrous histiocytoma t(12;16)(q13;p11) TLS-ATF1 Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3/7-FKHR Desmoplastic small round cell tumourt(11;22)(p13;q12) EWS-WT1 Synovial sarcoma t(X;18)(p11;q11) SYT-SSX1,2 Inflammatory myofibroblastic T 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 Trabectedin: 1.5 mg/m2 24h q3w ® Doxorubicin-based CT q3w 55% reduction in the relative risk of PD or death N = 80 Front-line ET-C-002-07

25. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

26. Trabectedin as first-line therapy in patients with unresectable STS Thirty-six patients with STS were treated with 1.5 mg/m2 of trabectedin:Thirty-six patients with STS were treated with 1.5 mg/m2 of trabectedin: ORR 17.1%ORR 17.1% 1-year progression-free survival rate: 21% 1-year progression-free survival rate: 21% Overall survival rate at 1 year:72%Overall survival rate at 1 year:72% Results in the range of single-agent up-front therapy with doxorubicin and ifosfamide.Results in the range of single-agent up-front therapy with doxorubicin and ifosfamide. Garc í a-Carbonero R, et al. J Clin Oncol. 2005 EMA approval on 20 th of September 2007 « Yondelis® is indicated for the treatment of patients with advanced STS after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. »

27. SARC020 – EORTC 62091 TRUST A phase IIb/III study comparing the efficacy of trabectedin (3h or 24h) to doxorubicin in patients with advanced STS Study PI: James Butrynski, Dana Farber Cancer Institute/SARC Binh Bui, MD Institut Bergonie/EORTC Binh Bui, MD Institut Bergonie/EORTC Excluded: WD liposarcoma End-point: PFS

28. Before After 6 cycles Before After 6 cycles The MTD and recommended dose is D60 mg/m² + T1.1 mg/m² ORR + SD (tumour control) = 95% 6-months PFS: 59% (> baseline reference EORTC first line) JY Blay et al CCR 2008 Trabectedin + Doxorubicin (N=41) Trabectedin + Doxorubicin (N=41) Phase II ® study of Trabectedin + Dox vs Dox in untreated STS patients (GEIS-20) Phase II study of Doxorubicin + Trabectedin in metastatic CT-naïve LMS (IGR) SAR-1001

29. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

30. Trabectedin Importance of maintenance treatment? p=0,001 p=0,009 N = 181, median follow-up 6 years continuation interruption continuation interruption N=56, interruption vs continuation after 6 courses Blay et al, poster CTOS 2012

31. Phase II randomised evaluating two strategies: Interruption vs continuation in responding patients after 6 courses of Yondelis ® Main end-point PFS at 24 weeks after randomization Rechallenge of trabectedin in case of PD in the interruption arm T-DIS-1001 PI: Dr Nicolas Penel October 2012 N=122

32. Patient with metastatic leiomyosarcoma after 6 cycles randomised in the interruption arm Phase II randomised evaluating two strategies: Interruption vs continuation in responding patients after 6 courses of Yondelis ® T-DIS-1001

33. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable safety profileFavourable safety profile Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin

34. Rechallenge with trabectedin in STS Esma Saâda-Bouzid et al, ASCO 2012 Median OS since TS1: 5 years! TSeq1: 49median T cycles: 7 TSeq2: 49median T cycles: 6 TSeq3: 8median T cycles: 6 TSeq4: 16 courses Due to the lack of cumulative toxicities over time with T, rechallenge in responding patients to T can be considered as a useful option in advanced STS.

35. Rechallenge with trabectedin in STS Advanced loco-regional relapse WD and DD LPS………… R1 resection followed with adjuvant AI and RT in 1998 1st sequence: 2002: 15 courses of T, SD (48% of tumour reduction) 2 nd sequence: 2009: 12 courses of T, SD Alive in October 2012 D115 cy

36. Tumour evolution during treatment 0 5 10 15 20 25 30 01234 time (AU) tumour size CT Dox +/- Ifo (30% of pts) Trabectedin (50% of patients)

37. General treatment algorithm in STS outside clinical trials 1 st -line chemotherapy Surgery ± RT+/- CT CURE METASTASES 2 nd -line chemotherapy Trabectedin (Europe) Pazopanib Non approved options Anthracyclines Trabectedin (Europe)* 3 rd -line and beyond Ifosfamide Trabectedin (Europe)* Trabectedin (Europe) Pazopanib Non approved options LOCAL RELAPSE LOCAL RELAPSE AND METASTASES LOCAL DISEASE Anthracycline-based multi-agent chemotherapy Trabectedin (Europe)* Surgery ± RT+/- CT Surgery +/- CT Paliative“Curative”? 50-60% 10%90% *If patients unsuited to doxo/ifo

38. Trabectedin in STS: Conclusions 1)Induces long lasting OR and tumour control in a relevant proportion of sarcoma patients resistant/relapsed to conventional CT. 2)No cumulative toxicity and is suitable for chronic and repetitive administration. 3)It has shown clinical benefit in all STS subtypes. 4)May suggest a targeted therapeutic approach in MLPS and in other translocation-related mesenchymal tumours. 5)Currently tested in front-line CT regimen. Trabectedin:

39. 13 years of trabectedin: from the abyss to the summit……

40. Trabectedin: 13 years of experience Yondelis®: 5 years of experience The first « prolonged tumour control TT » in STSThe first « prolonged tumour control TT » in STS Favourable pattern of toxicitiesFavourable pattern of toxicities Trabectedin active in all STS histological subtypesTrabectedin active in all STS histological subtypes Trabectedin in translocation-related STSTrabectedin in translocation-related STS Trabectedin in front line therapyTrabectedin in front line therapy Maintenance of responseMaintenance of response Rechallenge with trabectedinRechallenge with trabectedin Further steps with trabectedin….Further steps with trabectedin…. …..Peter Reichardt

41. Thank’s to PharmaMar, all patients… Demetri, G.D. Chawla, S. Schuetze, S. Von Mehren, M. Le Cesne, A. Budd, G. Casali, P. Garin, A. Hamm, J. Manikhas, G. Ritch, P. Rushing, D. Blay, J. Y. Samuels, B. Blackstein, M. Kaiser, P. Keohan, M. L. Turner, R. Verma, S. Baker, L. Hande, K. Morris, D. Ryan, C. Elias, A. Okuno, S. Albritton, K. Biakhov, M. Butrynsk, J. Mardynsky, Y. Patterson, K. Van Oosterom, A. Gershanovich, M. Judson, I. Lopez, A. Makhson, A. Patel, S. Pavlick, A. Pliner, L. Schutte, H.J. Staddon, A. Taub, R. Buys, S. Byrne, M. Kopp, M. Poveda, A. Skubitz, K. Ushakov, I. Younus, J. Reichardt, P. …….. …and all participating investigators and collaborating teams