optimizing the use of trabectedin in the daily clinical practice in asts axel le cesne, md
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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
Optimising efficacy
Side-effect management
Dosing
Maintenance therapy
Treatment duration
CT linesPatient
characteristics
Sarcomahistotype
OPTIMAL USE OF TRABECTEDIN
For whom?
For which histotype/genotype of STS ?
When?
How long?
How?
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
Trabectedin in pre-treated patients STS Trabectedin in L-Sarcomas
Both trabectedin schedules showed longer PFS than “active” drugs in
similar setting (EORTC trials, V Glabbeke. Eur J Cancer. 2002;38:543-9)
STS-201 Trial in L-STSPFS and OS within historical context
Le Cesne A, et al. Drugs Today (Barc). 2009;45:403-21 5
Acknowledging the limitations of historical comparisons, both trabectedin schedules showed
substantially longer OS than other drugs in a similar setting
SAR-3007 Study Design
Population: Locally advanced, metastatic L-sarcoma after previous treatment with anthracyclines and ifosfamide therapy
Random
ization
DTIC 1000mg/m2
20 min q3wksDTIC 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 ?
• 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
Trabectedin in other sarcomas
• 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
Trabectedin has shown activity and Clinical Benefit in all subtypes of STS
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.
• 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%)
Retrospectyon – a Large Retrospective Analysis of Trabectedin in 885 Patients with Advanced STS: Patient Characteristics
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563
• 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 PFS:4.4 months6-month PFS rate: 40% Median OS: 12.2 months
2-yrs OS rate: 25%
ORR: 135/835 (16%)CBR: 67%
Retrospectyon – Retrospective Analysis of Trabectedin in 885 Patients with ASTS
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted)
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
Trabectedin in translocation-related sarcoma (TRS)
OR = 45%
PDSD
SD/MR + Choi
Delayed R
PR, CR
24%
41%
10%
21%
4%
Tumor control = 90%
Tissue response = 65%
N=44
Grosso F, et al. Lancet Oncology. 2007
• Soft tissue16 (43%)
• Abdominal cavity 14 (38%)• Lung/pleura
11 (30%)• Heart/pericardium/med 10 (27%)
Prior CT (Dox/ifo): 98%Median cycles: 9 (1-43)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
100
80
60
40
20
0
months
PD
SD+MR
OR
A. Gronchi et al, Annals of Oncol 2011
t(12;16)(q13;p11) MLPS/Trabectedin
The First Targeted Therapy in STS?
In myxoid liposarcoma, a high antitumor activity was described, with an early phase of tissue changes preceding tumor shrinkage.
Trabectedin
Rand
omiz
ation
BSC
Translocation-Related Sarcomas (TRS)
Unresponsive or intolerableto standard chemotherapy
regimens Maximum 4 previous CT
Trabectedin in TRSStudy design
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 2 ( 5.4) 3 ( 8.3)
Other TRS 11 ( 29.7) 10 ( 27.8)
Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524)Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)
NMedian
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
Number at risk Trabectedin
BSC
16 0
90
60
10
00
3736
Progression free survival
RR: 8.1%Disease control rate (CR+PR+SD): 65%
Takahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524)Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)
3028
2220
1711
10
00
3736
10 7
56
N Median OS 95% CITrabectedin 37 NR 12.8-NRBSC 36 8.0 7.0-NR
Overall Survival
HR= 0.38 (95% CI [0.16 , 0.91] ) P= 0.025
Number at risk Trabectedin
BSCTakahashi et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 10524)Yonemoto et al. Ann Oncol 2014; 25 (Suppl. Abs 1422PD)
Trabectedin1.5 mg/m2 in 24h iv infusion q3wk
Rand
omiz
ation
BSC
Advanced STSUnresponsive or intolerableto standard chemotherapy
regimens 2 to 4 previous CT
TSARPhase III® trial of FSG - Study design
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
• 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%)
Retrospectyon – a Large Retrospective Analysis of Trabectedin in 885 Patients with Advanced STS: Patient Characteristics
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted)
Progression-free survival Overall survival
PFS
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24
Cu
mu
lati
ve p
rob
abil
ity
1.0
0.9
0.8
0.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
p value = 0.4427
HR: 0.9; 95% CI (0.687-1.179)
PFS
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 240 2 4 6 8 10 12 14 16 18 20 22 24
Cu
mu
lati
ve p
rob
abil
ity
1.0
0.9
0.8
0.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
p value = 0.4427
HR: 0.9; 95% CI (0.687-1.179)
OS
Cu
mu
lati
ve p
rob
abil
ity
1.0
0.9
0.8
0.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Time (months)
p value = 0.1216
HR: 0.8; 95% CI (0.61-1.06)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
OS
Cu
mu
lati
ve p
rob
abil
ity
1.0
0.9
0.8
0.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Time (months)
p value = 0.1216
HR: 0.8; 95% CI (0.61-1.06)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
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)
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)
CI, confidence interval; HR, hazard ratio; mo, months; OS, overall survival; PFS, progression-free survival.
Trabectedin in elderly patientsPooled 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 !! 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)
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)
ELDERLY IN THE STBSG/EORTC DATA BASE FRONT-LINE TRIALS
< 65 yrs
(N=2362)≥ 65 yrs(N=274)
Total(N=2636)
N (%) N (%) 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)
254 (9.6)
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)
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
STS-201: Efficacy of trabectedin as an early treatment for advanced L-STS
Blay JY, et al. Futur Oncol. 2013. 2014 Jan;10 (1): 59-68.
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.
RETROSPECTYON – Treatment Description
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl):abstr 10563, Eur J Cancer 2014 (submitted)
Median PFS Median OS
All population 4.4 12.2
Number of trabectedin line2nd3rd
4 or more
4.84.53.4
12.912.29.5
• 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
Trabectedin is “the” second line option
General treatment algorithm in STS
1st-line chemotherapy
Surgery ± RT+/- CT
CURE METASTASES
2nd-linechemotherapy
Trabectedin Pazopanib
gemcitabine + docetaxel (US)Clinical trials
Anthracyclines*
3rd-line and beyond
Ifosfamide*
TrabectedinPazopanib
gemcitabine + docetaxel (US) Clinical trials
LOCAL RELAPSE LOCAL RELAPSE AND METASTASES
LOCAL DISEASE
Anthracycline-based multi-agent chemotherapy*
Surgery ± RT+/- CT
Surgery
Paliative “Curative”?
50-60%
10-20%80-90%
Surgery
*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
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
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
Samuels B, et al. Ann Oncol. 2013;24:1703-9. 26
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
Real Life Data TrabectedinWorldwide Expanded Access
RETROSPECTYON: Maintenance Therapy in Responders (Stop vs Continuation after 6 cycles?)
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl; abstr 10563), Eur J Cancer 2014 (submitted)
PFS OS
T-DIS studyInterruption vs Continuation in Responding Patients After 6 Cycles of Trabectedin
PI: Dr Nicolas Penel. www.clinicaltrials.gov #NCT01303094
6 Cycles Trab
Trabectedin
PDNo Chemotherapy
Trabectedin
Responders
Primary endpoint: 6-month PFS 24 weeks post
Randomization
Secondary endpoints: ORR PFR at 12 & 54 weeks Survival at 12 & 24 months
PD
PD
N=50
N=178 at inclusion® = 53
ASCO, ESMO 2014
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
173 96(59) 46(31) 29(17) 19(10) Number at risk (number of events)
0 3 6 9 12Months
Progression-Free survival
T-DIS Initial cohort (all patients)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
174 96(8) 53(0) 51(1) 47(2) 42(4) 32(5) Number at risk (number of events)
0 3 6 9 12 15 18Months
Overall survival
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)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
26 14(12) 6(8) 5(1) 4(1) 4(0)ARM B27 22(5) 14(8) 9(5) 8(0) 6(1)ARM ANumber at risk (number of events)
0 3 6 9 12 15Months
ARM AARM B
Progression-Free survival
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)
Logrank test: p=0.02
median PFS: 4.0 months median PFS: 7.2 months
Median f.u: 21 m from ®
Le Cesne et al. Ann Oncol 2014; 25 (suppl 4; abs 1414O)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
26 25(0) 24(1) 20(1) 16(4) 13(3) 7(4) 6(0) 3(1)ARM B27 27(0) 25(2) 23(2) 21(0) 18(0) 11(2) 8(1) 1(2)ARM ANumber at risk (number of events)
0 3 6 9 12 15 18 21 24Months
ARM AARM B
Overall survival
Logrank test: p=0.12
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)
T-DIS – ResultOverall survival (intent to treat analysis)
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)
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
Le Cesne A, et al. Invest New Drugs. 2012;30:1193-202.
Overall discontinuation rate due to toxicity:
10.2%
Trabectedin Safety
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
28.4% of patients received 6 cycles and
8.8% of patients received 10 cycles
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%)
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 0.3NCI-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
No cumulative toxicity with trabectedin
Key factors for successful therapy management in STS with Trabectedin
Optimising efficacy
Side-effect management
Dosing
Treatment duration
Le Cesne A, et al. J Clin Oncol. 2013;31(suppl; abstr 10563), Eur J Cancer 2014 (submitted)
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 +++++
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 TRStreated 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