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

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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

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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