Optimizing the use of trabectedin in the daily clinical practice in ASTS Axel Le Cesne, MD

Key factors for successful therapy management in STS with Trabectedin Patient–physician communication Patient characteristics CT lines OPTIMAL USE OF TRABECTEDIN For whom? For which histotype/genotype of STS ? When? How long? How? Side-effect management Dosing Optimising efficacy Sarcoma histotype Maintenance therapy Treatment duration

Key factors for successful therapy management in STS with Trabectedin OPTIMAL USE OF TRABECTEDIN For whom? For which histotype/genotype of STS ? When? How long? How?

Trabectedin in pre-treated patients STS Trabectedin in L-Sarcomas

STS-201 Trial in L-STS PFS and OS within historical context Both trabectedin schedules showed longer PFS than “active” drugs in similar setting (EORTC trials, V Glabbeke. Eur J Cancer. 2002;38:543-9) Acknowledging the limitations of historical comparisons, both trabectedin schedules showed substantially longer OS than other drugs in a similar setting Le Cesne A, et al. Drugs Today (Barc). 2009;45:403-21

Trabectedin 1.5 mg/m² 24h q3wks SAR-3007 Study Design Population: Locally advanced, metastatic L-sarcoma after previous treatment with anthracyclines and ifosfamide therapy Primary endpoint: OS Statistical Assumptions DTIC, OS = 10.0 mo Trabectedin, OS = 13.5 mo 35% improvement in median OS (HR=0.74), 80% power Two-sided significance level of 0.05 Need ~570 patients to observe 376 deaths Interim analysis for futility or superiority for potential early stopping ~188 death events Randomization DTIC 1000mg/m2 20 min q3wks 2:1 Trabectedin 1.5 mg/m² 24h q3wks Stratification: ECOG PS Lines of prior therapy L-subtypes ASCO 2015? FDA approval in case of positivity ? 6

Trabectedin in other sarcomas

Trabectedin has shown activity and Clinical Benefit in all subtypes of STS Liposarcoma and leiomyosarcoma Uterine leiomyosarcoma Malignant fibrous histiocytoma/Pleomorphic sarcoma Fibrosarcoma Hemangiopericytoma Solitary fibrous tumor Translocation Related Sarcomas (TRS) Myxoid liposarcoma Synovial sarcoma Alveolar sarcoma Desmoplastic small round cell tumor Endometrial stromal sarcoma Le Cesne A, et al. Eur J Cancer. 2012;48:3036-44; Demetri G, et al. J Clin Oncol. 2009;27:4188-96; Sanfilippo R, et al. Gynecol Oncol. 2011;123:553-6; Grosso F, et al. Lancet Oncol. 2007;8:595-602; López-González A, et al. Med Oncol. 2011;28 Suppl 1:S644-6; Martinez-Trufero J, et al. Anticancer Drugs. 2010;21:795-8; Chaigneau L, et al. Rare Tumors. 2011;3:e29. 8

Retrospectyon – a Large Retrospective Analysis of Trabectedin in 885 Patients with Advanced STS: Patient Characteristics 885 patients from 26 centers in France treated with T between Jan 2008 - Dec 2011 Most frequent subtypes: Leiomyosarcoma (36%) Liposarcoma (18%) Synovial sarcoma (11%) Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563

Retrospectyon – Retrospective Analysis of Trabectedin in 885 Patients with ASTS ORR: 135/835 (16%) CBR: 67% Median PFS: 4.4 months 6-month PFS rate: 40% 885 patients from 26 centers in France treated with trabectedin between Jan 2008 - Dec 2011. Most frequent subtypes: Leiomyosarcoma (36%) Liposarcoma (18%) Synovial sarcoma (11%) Median OS: 12.2 months 2-yrs OS rate: 25% Prolonged median PFS were observed in nearly all histological sarcoma subtypes including leiomyoS, lipoS, SFT, chondrosarcoma, fibrosarcoma, epithelioid sarcoma, synovial sarcoma, and largely surpassed the thresholds criteria to define drug activity in pretreated STS (i.e.: 3-months PFS rate of 40%) Trabectedin has proved effective in liposarcoma and in leiomyosarcoma. Clinical benefit with trabectedin was also obtained in other histologic types of STS Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted)

Trabectedin in translocation-related sarcoma (TRS)

t(12;16)(q13;p11) MLPS/Trabectedin The First Targeted Therapy in STS? Soft tissue 16 (43%) Abdominal cavity 14 (38%) Lung/pleura 11 (30%) Heart/pericardium/med 10 (27%) Prior CT (Dox/ifo): 98% Median cycles: 9 (1-43) N=44 PD 10% PD SD+MR OR SD 4% Tissue response = 65% SD/MR + Choi 41% Tumor control = 90% In myxoid liposarcoma, a high antitumor activity was described, with an early phase of tissue changes preceding tumor shrinkage. Delayed R 24% OR = 45% Grosso F, et al. Lancet Oncology. 2007 PR, CR 21% A. Gronchi et al, Annals of Oncol 2011

Trabectedin in TRS Study design Translocation-Related Sarcomas (TRS) Unresponsive or intolerable to standard chemotherapy regimens Maximum 4 previous CT Randomization Trabectedin BSC 　Trabectedin (N=37) 　　BSC(N=36) 　Myxoid / round cell liposarcoma 14 ( 37.8) 10 ( 27.8) 　Synovial sarcoma 7 ( 18.9) 11 ( 30.6) Extraskeletal ewing sarcoma / PNET 3 ( 8.1) 2 ( 5.6) 　Alveolar rhabdomyosarcoma ( 5.4) 3 ( 8.3) 　Other TRS ( 29.7) Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524) Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)

Progression free survival Median PFS 90% CI Trabectedin 37 5.6 4.2-7.5 BSC 36 0.9 0.9-1.0 HR= 0.07 (90% CI [0.03 , 0.14] ) P value < 0.0001 RR: 8.1% Disease control rate (CR+PR+SD): 65% Number at risk Trabectedin BSC 37 36 16 9 6 1 Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524) Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)

Overall Survival HR= 0.38 (95% CI [0.16 , 0.91] ) P= 0.025 N Median OS Trabectedin 37 NR 12.8-NR BSC 36 8.0 7.0-NR Number at risk Trabectedin BSC 37 36 30 28 22 20 17 11 10 7 5 6 1 Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524) Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)

Unresponsive or intolerable to standard chemotherapy regimens TSAR Phase III® trial of FSG - Study design Advanced STS Unresponsive or intolerable to standard chemotherapy regimens 2 to 4 previous CT Trabectedin 1.5 mg/m2 in 24h iv infusion q3wk Randomization BSC With cross-over at progression Stratification L-STS vs non L-STS (including TRS....) N= 46 pts per arm End-point: PFS

Trabectedin in elderly patients with STS

Retrospectyon – a Large Retrospective Analysis of Trabectedin in 885 Patients with Advanced STS: Patient Characteristics 885 patients from 26 centers in France treated with T between Jan 2008 - Dec 2011 Most frequent subtypes: Leiomyosarcoma (36%) Liposarcoma (18%) Synovial sarcoma (11%) Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted) 18

Trabectedin in elderly patients Pooled analysis of 5 Phase II PFS rates at 6 months: 29.5% (younger) vs. 36.4% (older); p=0.2638 No major differences were found in the efficacy/safety profile of pts aged ≥70 years Median OS: 13.0 m vs 14.0 m One of the very few reference data in elderly in STS !! 47% of all STS > 65 years (16%>80 years), Netherlands Cancer Registry (ECCO 2013) Only 11 % participated in EORTC first line clinical trials with standard drugs (ESMO 14) Le Cesne A, et al. Br J Cancer (2013); 109: 1717-1724 Van der Graaf W, et al. Ann Oncol 2014; 25 (Suppl.4, Abs 1415O)

Elderly in the STBSG/EORTC data base Front-line trials   < 65 yrs (N=2362) ≥ 65 yrs (N=274) Total (N=2636) N (%) Histology Leiomyosarcoma 711 (30.1) 107 (39.1) 818 (31.0) Synovial sarcoma 246 (10.4) 8 (2.9) 254 (9.6) Liposarcoma 218 (9.2) 14 (5.1) 232 (8.8) Other 1058 (44.8) 123 (44.9) 1181 (44.8) Extent of disease* Primary site involved 1034 (43.8) 131 (47.8) 1165 (44.2) Bone metastases 232 (9.8) 22 (8.0) Liver metastases 399 (16.9) 52 (19.0) 451 (17.1) Lung metastases 1351 (57.2) 130 (47.4) 1481 (56.2) Other metastases 953 (40.3) 98 (35.8) 1051 (39.9) * non-cumulative Van der Graaf W, et al. Ann Oncol 2014; 25 (Suppl.4, Abs 1415O)

Key factors for successful therapy management in STS with Trabectedin OPTIMAL USE OF TRABECTEDIN For whom? For which histotype/genotype of STS ? When? How long? How?

STS-201: Efficacy of trabectedin as an early treatment for advanced L-STS The efficacy outcomes were better in the subset of patient receiving trabectedin after failure of first line anthracyclines + ifosfamide relative to patients with more extensive prior therapy, with similar safety profile. Blay JY, et al. Futur Oncol. 2013. 2014 Jan;10 (1): 59-68.

RETROSPECTYON – Treatment Description 885 patients, 26 centers in France treated with trabectedin (2008 – 2011) Most frequent subtypes: LMS (36%), LPS (18%), Synovial sarcoma (11%) Objective response rate: 135/835 (16.1%), median PFS 4.4 months, median OS 12.2 months Median follow-up: 22.6 months Median PFS Median OS All population 4.4 12.2 Number of trabectedin line 2nd 3rd 4 or more 4.8 4.5 3.4 12.9 9.5 Trabectedin is “the” second line option Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted)

General treatment algorithm in STS LOCAL DISEASE Surgery ± RT+/- CT 50-60% *Yondelis is indicated for the treatment of adults patients with advanced STS, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents CURE LOCAL RELAPSE METASTASES LOCAL RELAPSE AND METASTASES Surgery ± RT+/- CT 80-90% 10-20% Paliative “Curative”? 1st-line chemotherapy Anthracyclines* Anthracycline-based multi-agent chemotherapy* 2nd-line chemotherapy Ifosfamide* Surgery Trabectedin Pazopanib gemcitabine + docetaxel (US) Clinical trials Trabectedin Pazopanib gemcitabine + docetaxel (US) Clinical trials 3rd-line and beyond Surgery Le Cesne A. Expert Rev Anticancer Ther. 13 (6 Suppl 1)11-19 (2013); The ESMO / European Sarcoma Network Working Group. Ann Oncol 2014; 25: 102-112 24 24

Key factors for successful therapy management in STS with Trabectedin OPTIMAL USE OF TRABECTEDIN For whom? For which histotype/genotype of STS ? When? How long? How?

Real Life Data Trabectedin Worldwide Expanded Access N=1,803 patients Trabectedin treatment: Median number of cycles: 3 30% of patients ≥ 6 cycles on Trabectedin 13% of patients ≥ 9 m on Trabectedin 7% of patients ≥ 1 year on Trabectedin Safety Safety profile consistent with clinical trials No cumulative toxicities detected Samuels B, et al. Ann Oncol. 2013;24:1703-9.

RETROSPECTYON: Maintenance Therapy in Responders (Stop vs Continuation after 6 cycles?) PFS OS Le Cesne A, et al. J Clin Oncol. 2013;31(suppl; abstr 10563), Eur J Cancer 2014 (submitted)

T-DIS study Interruption vs Continuation in Responding Patients After 6 Cycles of Trabectedin 6 Cycles Trab Trabectedin PD No Chemotherapy Responders PD N=50 PD Primary endpoint: 6-month PFS 24 weeks post Randomization Secondary endpoints: ORR PFR at 12 & 54 weeks Survival at 12 & 24 months N=178 at inclusion ® = 53 ASCO, ESMO 2014 PI: Dr Nicolas Penel. www.clinicaltrials.gov #NCT01303094

T-DIS Initial cohort (all patients) Median PFS: 4.6 months. Median OS: not reached. 6-months PFS: 39% 12-months PFS 16%. The rate of patients achieving a tumor control after 6 cycles of trabectedin is higher (30% vs 25%) and the 6-months PFS is also higher (39% vs 30%) than previous studies highlighting a better selection of ASTS pts taking in charge in referral centers and a better management of trabectedin.

T-DIS – Results Progression-free survival (intent to treat analysis) Arm A (cont) Arm (discont) 3-m PFS 81.5% (61.1-91.8) 53.9% (33.3-70.6) 6-m PFS 51.9% (31.9-68.6) 23.1% (9.4-40.3) 9-m PFS 33.3% (16.8-50.9) 19.2% (7.0-36.0) Median f.u: 21 m from ® Logrank test: p=0.02 median PFS: 7.2 months median PFS: 4.0 months Le Cesne et al. Ann Oncol 2014; 25 (suppl 4; abs 1414O) 30

T-DIS – Result Overall survival (intent to treat analysis) Arm A Arm B 12-m OS 85.2% (65.2-94.2) 73.3% (49.9-87.1) 18-m OS 73.2% (48.3-87.5) 39.1% (18.8-59.4) Logrank test: p=0.12 LMS04: DOX vs DOX+Trab with a ® after 6 cy, maintenance vs interruption Le Cesne et al. Ann Oncol 2014; 25 (suppl 4; abs 1414O) 31

Key factors for successful therapy management in STS with Trabectedin OPTIMAL USE OF TRABECTEDIN For whom? For which histotype/genotype of STS ? When? How long? How?

Trabectedin Safety No cumulative toxicity with trabectedin 28.4% of patients received  6 cycles and 8.8% of patients received  10 cycles Overall discontinuation rate due to toxicity: 10.2% NCI-CTC grade Total (n=1,132) 1/2 3 4 ALT increased (91%) 47 37.1 6.9 AST increased (85%) 56 26.5 2.8 AP increased (56%) 53 2.7 0.3 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 No cumulative toxicity with trabectedin NCI-CTC grade Total (n=1,132) 1/2 3 4 Neutropenia (69%) 33 19.3 16.9 Thrombocyt (69%) 26.2 8.2 1.9 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%) Le Cesne A, et al. Invest New Drugs. 2012;30:1193-202. 33

Key factors for successful therapy management in STS with Trabectedin Patient–physician communication Optimising efficacy Side-effect management Dosing Treatment duration Retrospectyon study (N = 885) Initial dose 1.5 mg/m2: 81% Dose reduction: 47% Hospitalisation due to T: 9.2% Death 0.4% Flexibility of treatment +++++ Le Cesne A, et al. J Clin Oncol. 2013;31(suppl; abstr 10563), Eur J Cancer 2014 (submitted)

CONCLUSIONS Trabectedin has shown activity and Clinical Benefit in all subtypes of STS (ESMO recommendations 2014 in pretreated STS) A survival advantage (PFS and OS) has been observed in patients with TRS treated with trabectedin (compared with BSC) Trabectedin could be an option in elderly patients where alternatives lacked The efficacy outcomes were better in the subset of patient receiving trabectedin in second line therapy in advanced setting As maintenance therapy beyond the 6th cycle, trabectedin is associated with a statistically significant improvement of median PFS (7.2 versus 4.0 months) “Flexibility” of trabectedin treatment (dose, interval, duration) allows for patient tailored optimization

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