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

2. 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

3. 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?

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

5. 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

6. 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

7. Trabectedin in other sarcomas

8. 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: ; Demetri G, et al. J Clin Oncol. 2009;27: ;
Sanfilippo R, et al. Gynecol Oncol. 2011;123:553-6; Grosso F, et al. Lancet Oncol. 2007;8: ;
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

9. 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 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

10. 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 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)

11. Trabectedin in translocation-related sarcoma (TRS)

12. t(12;16)(q13;p11) MLPS/Trabectedin The First Targeted Therapy in STS?
Soft tissue (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

13. 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
( 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)

14. Progression free survival
Median
PFS
90% CI
Trabectedin 37
5.6
BSC 36
0.9
HR= 0.07 (90% CI [0.03 , 0.14] )
P value <
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)

15. 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)

16. 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

17. Trabectedin in elderly patients with STS

18. 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 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

19. 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:
Van der Graaf W, et al. Ann Oncol 2014; 25 (Suppl.4, Abs 1415O)

20. 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)

21. 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?

22. 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 Jan;10 (1):

23. 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)

24. 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: 24 24

25. 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?

26. 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:

27. 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)

28. 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. #NCT

29. 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.

30. T-DIS – Results Progression-free survival (intent to treat analysis)
Arm A (cont)
Arm (discont)
3-m PFS
81.5% ( )
53.9% ( )
6-m PFS
51.9% ( )
23.1% ( )
9-m PFS
33.3% ( )
19.2% ( )
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

31. T-DIS – Result Overall survival (intent to treat analysis)
Arm A
Arm B
12-m OS
85.2% ( )
73.3% ( )
18-m OS
73.2% ( )
39.1% ( )
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

32. 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?

33. 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: 33

34. 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)

35. 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

36. YON