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
CT lines
Patient
characteristics
Side-effect
management
Dosing
Optimising
efficacy
Maintenance
therapy
Treatment
duration
Sarcoma
histotype
OPTIMAL USE OF TRABECTEDIN
For whom?
For which histotype/genotype of STS ?
When?
How long?
How?
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
5
SAR-3007 Study Design

Population: Locally advanced, metastatic L-sarcoma after previous treatment
with anthracyclines and ifosfamide therapy
Trabectedin 1.5 mg/m²
24h q3wks
Randomization
2:1
DTIC 1000mg/m2
20 min q3wks
Stratification:
•ECOG PS
•Lines of prior therapy
•L-subtypes
• 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
ASCO 2015?
FDA approval in case of positivity ?
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.
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
•
Median PFS:
4.4 months
885 patients
from
centers
6-month
PFS26
rate:
40%
ORR: 135/835 (16%)
CBR: 67%
Median OS:
12.2 months
in France treated with
2-yrs OS rate: 25%
trabectedin between Jan
2008 - Dec 2011.
Prolonged median PFS were observed in nearly all
•
histological sarcoma subtypes including leiomyoS, lipoS,
Most frequent subtypes:
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%)
Liposarcoma (18%)
–
Synovial sarcoma (11%)
–
Leiomyosarcoma (36%)
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
Abdominal cavity
Lung/pleura
Heart/pericardium/med
16 (43%)
14 (38%)
11 (30%)
10 (27%)
Prior CT (Dox/ifo): 98%
Median cycles: 9 (1-43)
N=44
PD
SD
10%
100
4%
80
SD+MR
60
SD/MR
+ Choi
Tissue response = 65%
OR
40
41%
Tumor control = 90%
20
PD
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
months
Delayed R
24%
PR, CR
21%
In myxoid liposarcoma, a high antitumorGrosso
activity
described,
F, et was
al. Lancet
Oncology. with
2007
OR
=
45%
an early phase of tissue changes preceding tumor shrinkage.
A. Gronchi et al, Annals of Oncol 2011
Trabectedin in TRS
Translocation-Related
Sarcomas (TRS)
Unresponsive or intolerable
to standard chemotherapy
regimens
Maximum 4 previous CT
Randomization
Study design
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)
3
( 8.1)
2
( 5.6)
Alveolar rhabdomyosarcoma
2
( 5.4)
3
( 8.3)
Other TRS
11
( 29.7)
10
( 27.8)
Extraskeletal ewing sarcoma / PNET
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
Trabectedin
37
Median
PFS
5.6
BSC
36
0.9
N
90% CI
4.2-7.5
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 37
BSC
36
16
0
9
0
6
0
1
0
0
0
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
Trabectedin 37
BSC
36
Median OS 95% CI
NR
12.8-NR
8.0
7.0-NR
Number at risk
Trabectedin
BSC
37
36
30
28
22
20
17
11
10
7
5
6
1
0
0
0
Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524)
Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)
Advanced STS
Unresponsive or intolerable
to standard chemotherapy
regimens
2 to 4 previous CT
Randomization
TSAR
Phase III® trial of FSG - Study design
Trabectedin
1.5 mg/m2 in 24h
iv infusion q3wk
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)
Trabectedin in elderly patients
Pooled analysis of 5 Phase II
Overall
OSsurvival
1.0
1.0
0.9
0.9
0.8
0.8
0.7
Cumulative probability
Cumulative probability
PFS
Progression-free
survival
p value = 0.4427
HR: 0.9; 95% CI (0.687-1.179)
0.6
0.5
0.4
0.3
0.2
0.7
0.5
0.4
0.3
0.2
0.1
0.1
0.0
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (months)
Median PFS (95% CI): <60: 2.5 (1.9-3.1) vs. ≥60: 3.7 (2.1-5.5)
PFS at 3 mo (95% CI): <60: 45.1% (39.1-51.1) vs. ≥60: 55.1% (44.2-66.0)
PFS at 6 mo (95% CI): <60: 29.5% (23.9-35.0) vs. ≥60: 36.4% (25.6-47.1)
p value = 0.1216
HR: 0.8; 95% CI (0.61-1.06)
0.6
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
Median OS (95% CI): <60: 13.0 (11.3-14.9) vs. ≥60: 14.0 (9.5-23.9)
OS at 12 mo (95% CI): <60: 54.6% (48.6-60.6) vs. ≥60: 55.8% (45.0-66.6)
OS at 24 mo (95% CI): <60: 28.9% (23.4-34.4) vs. ≥60: 38.2% (27.6-48.9)
47% of all STS > 65 years (16%>80 years), Netherlands Cancer Registry (ECCO 2013)
Only
11interval;
% participated
in EORTC
first
clinical
trials with standard drugs (ESMO 14)
CI,
confidence
HR, hazard ratio; mo, months;
OS, overall survival;
PFS,line
progression-free
survival.
•
•
•
•
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 !!
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)
N (%)
≥ 65 yrs
(N=274)
N (%)
Total
(N=2636)
N (%)
Histology
Leiomyosarcoma
Synovial sarcoma
Liposarcoma
Other
711 (30.1)
246 (10.4)
218 (9.2)
1058 (44.8)
107 (39.1)
8 (2.9)
14 (5.1)
123 (44.9)
818 (31.0)
254 (9.6)
232 (8.8)
1181 (44.8)
Extent of disease*
Primary site involved
Bone metastases
Liver metastases
Lung metastases
Other metastases
1034 (43.8)
232 (9.8)
399 (16.9)
1351 (57.2)
953 (40.3)
131 (47.8)
22 (8.0)
52 (19.0)
130 (47.4)
98 (35.8)
1165 (44.2)
254 (9.6)
451 (17.1)
1481 (56.2)
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
4.4
12.2
Number of trabectedin line
2nd 4.8
3rd 4.5
4 or more 3.4
12.9
12.2
9.5
All population
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014Trabectedin
(submitted)
is “the” second line option
General treatment algorithm in
STS
LOCAL DISEASE
Surgery ± RT+/- CT
*Yondelis is indicated for the treatment of 50-60%
adults patients with advanced
CURE
RELAPSE
LOCAL
RELAPSE
AND METASTASES
METASTASES
STS, afterLOCAL
failure
of anthracyclines
and ifosfamide,
or who
are unsuited
to
receive these agents
Surgery ± RT+/- CT
Paliative
1st-line
chemotherapy
2nd-line
chemotherapy
3rd-line
and beyond
80-90%
Anthracyclines*
Anthracycline-based
multi-agent chemotherapy*
Ifosfamide*
Trabectedin
Pazopanib
gemcitabine + docetaxel (US)
Clinical trials
10-20%
“Curative”?
Surgery
Trabectedin
Pazopanib
gemcitabine + docetaxel (US)
Clinical trials
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
Surgery
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.
26
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
Trabectedin
6 Cycles Trab
PD
Responders
N=50
No Chemotherapy
PD
Trabectedin
Primary endpoint:
 6-month PFS 24 weeks post Randomization
Secondary endpoints:
 ORR
 PFR at 12 & 54 weeks
 Survival at 12 & 24 months
PI: Dr Nicolas Penel. www.clinicaltrials.gov #NCT01303094
N=178 at inclusion
® = 53
ASCO, ESMO 2014
PD
T-DIS Initial cohort (all patients)
Overall survival
Progression-Free survival
1.00
0.90
0.90
0.80
0.80
0.70
0.70
Probability
1.00
0.60
0.50
0.40
0.60
0.50
0.40
0.30
0.30
Median PFS: 4.6 months.
0.20
Median OS: not reached.
0.20
0.10
0.10
0.00
0.00
0
3
6
9
12
Months
Number at risk (number of events)
173
(59)
96
(31)
46
0
3
6
9
12
15
18
Months
(17)
29
(10)
19
Number at risk (number of events)
174 (8) 96 (0) 53 (1) 51
(2)
47
(4)
42
(5)
32
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.
Probability
T-DIS – Results
Progression-free survival (intent to treat analysis)
Arm A (cont)
Arm (discont)
3-m PFS
81.5% (61.1-91.8)
Progression-Free survival
6-m PFS
51.9% (31.9-68.6)
1.00
9-m PFS
0.90
33.3% (16.8-50.9)
53.9% (33.3-70.6)
23.1% (9.4-40.3)
19.2% (7.0-36.0)
Median f.u: 21 m from ®
0.80
0.70
0.60
Logrank test: p=0.02
0.50
0.40
0.30
0.20
ARM A
ARM B
0.10
0.00
0
3
median PFS: 7.2 months
median PFS: 4.0 months
6
9
12
15
Months
ARM A
ARM B
Number at risk (number of events)
27
(5)
22
(8)
14
(5)
26
(12)
14
(8)
6
(1)
9
5
(0)
(1)
8
4
(1)
(0)
6
4
Le Cesne et al. Ann Oncol 2014; 25 (suppl 4; abs 1414O)
T-DIS – Result
Overall survival (intent to treat analysis)
Overall survival
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
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)
ARM A
ARM B
0.10
0.00
0
3
6
Logrank test: p=0.12
9
12
15
18
21
24
Months
ARM A
ARM B
Number at risk (number of events)
27 (0) 27 (2) 25 (2) 23 (0) 21 (0) 18 (2) 11 (1)
26 (0) 25 (1) 24 (1) 20 (4) 16 (3) 13 (4) 7 (0)
8
6
(2)
(1)
1
3
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)
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
28.4% of patients received  6 cycles and
8.8% of patients received  10 cycles
NCI-CTC grade
Overall discontinuation rate
due to toxicity: 10.2%
Total (n=1,132)
1/2
3
4
ALT increased
(91%)
47
37.1
6.9
AST increased
(85%)
56
26.5
2.8
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
AP
increased
NCI-CTC
grade
(56%)
Total
53 (n=1,132)
2.7
1/2
3
0.3
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.
Key factors for successful therapy
management in STS with Trabectedin
Retrospectyon study (N = 885)
Side-effect
management
Dosing
Optimising
efficacy
Initial dose 1.5 mg/m2:
Dose reduction:
Hospitalisation due to T:
Death
81%
47%
9.2%
0.4%
Flexibility of treatment +++++
Treatment
duration
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
YON1014-738