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Le Cesne Axel, CTOS 2012, Prague
13 years of trabectedin and 5 years of Yondelis
in STS what have we learnt?
2
ET-743TrabectedinYondelis
Marine derived anticancer compound
Ecteinascidia turbinata
EMA approval on 20th of September
2007  Yondelis is indicated for the treatment
of patients with advanced STS after failure of
anthracyclines and ifosfamide, or who are
unsuited to receive these agents. Efficacy data
are based mainly on liposarcoma and
leiomyosarcoma patients 
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STS-201 trial
George D. Demetri et al, JCO 09
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STS-201 trial
q3wk 24-h
qwk 3-h
Trabectedin q3wk 24h induced significantly
greater tumour shrinkage than qwk-3h (p
0.0008)
32.4
50.5
Tumour shrinkage
Tumour shrinkage
Consistency of benefit with trabectedin q3wk 24-h
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STS-201-Historical Context (EORTC) PFS in Sarcomas
Trabectedin q3w 24h
36 6 months PFS
Trabectedin weekly
14 6 months PFS
Both trabectedin schedules showed longer PFS than
active drugs in similar setting (EORTC trials,
Le Cesne et al. Drugs of today 200945(6)403-21)
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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Trabectedin, phase II (N 189)Survival outcome
Despite an ORR lt 10 according to RECIST
gt 6 cycles 28
Clinical Benefit / tumour Control PRMRSD
51.5
Pooled Data A.Le Cesne et al JCO 05, A.Yovine et
al JCO 04, R.G.Carbonero et al JCO 04, J.Jimeno
et al Current.Op.Orthop 2003
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Progression free / Tumour control
2nd line treatment
Time to response
Drugs N (gt40) PAR 2nd cycle Trabectedin 12
3 54 Ifosfamide 141
52 Docetaxel 74 47 Gemcitabine 95 39 Dacarba
zine 44 36 Inactive agents lt 20
Median 5.3 months
Jaap Verweij, Educational book, ASCO 2003
Pooled Data A.Le Cesne et al JCO 05, A.Yovine et
al JCO 04, R.G.Carbonero et al JCO 04, J.Jimeno
et al Current.Op.Orthop 2003
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Trabectedin in elderly patients Pooled analysis
of 5 phase II studies
PFS rates at 6 months 29.5 (younger) vs. 36.4
(older) p0.2638 A slightly higher incidence
of some grade 3/4 AEs was observed in older
patients. No major differences were found in the
efficacy and safety profile of patients aged 70
years. Median OS 13.0 m vs 14.0 m
Le Cesne et al, EJC 2012, submitted
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Trabectedin the first  RECIST problem  with
conventional CT in the radiological evaluation of
efficacy in STS
The intriguing pattern of tumour response of
trabectedin! Impact on survival
..Paolo Casali
GIST Placebo Sunitinib Regorafenib
PR 0 7 5
SD 48 58 71
PD 37 29 21
Sometimes, tumour cells do not understand what
we are doing!
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GMI clinical benefit assessment among ASTS pts
receiving trabectedin as salvage therapy

• GMI in patients treated with Yondelis (N 279)
  
• 177 patients (63.4) experienced a GMI lt 1
• 21 patients (7.5) a GMI1-1.33
• 81 patients (29.0) a GMIgt1.33

N. Penel et al, Annals of Oncol 2012
GMI gt 1.33 median OS was 23.8m
Prognostic factors for GMIgt1.33 PS only GMI as
an indicator of drug activity!
p0.0005
Same results in 227 pts treated in FSG Even for
drugs considered as inactive According to EORTC
rules Cousin et al, ASCO 2012 (abstract 10014)
GMI lt 1 median OS was 9.1m
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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Trabectedin Safety profile
NCI-CTC grade Total (n1,132) Total (n1,132) Total (n1,132)
NCI-CTC grade 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 lt1 at d15
Trend towards reduction in subsequent cy No
clinical consequences
NCI-CTC grade Total (n1,132) Total (n1,132) Total (n1,132)
NCI-CTC grade 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)
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Drug Delivery
STS-201
qwk 3-h n130 q3wk 24-h n130
Median treatment duration (wks) 11.5 15.4
Median No. cycles (range) 2 (1 21) 5 (1 37)
Patients with 7 or more cycles 19 38
Median relative dose intensity 86 81
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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Trabectedin active in STS subtypes other than
lipo-leiomyoS ?
Hemangiopericytoma Martínez Trufero Zaragoza,
Spain
Synovial sarcoma P. Schöffski UZ/KU Leuven
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Trabectedin has shown antitumour activity and
clinical benefit in multiple histological
subtypes of STS
Le Cesne A, et al. Eur J Cancer 2012

• Liposarcoma and leiomyosarcoma
• Uterine leiomyosarcoma
• Malignant fibrous histiocytoma / Pleomorphic
  sarcoma
• Fibrosarcoma
• Meningeal hemangiopericytoma
• Solitary fibrous tumour
• Translocation Related Sarcomas (TRS)
• - Myxoid liposarcoma
• - Synovial sarcoma
• - Alveolar sarcoma
• - Desmoplastic small round cell
  tumour
• - Endometrial stromal sarcoma

Demetri GD, et al. J Clin Oncol. 2009, Sanfilippo
R, et al. Gynecol Oncol. 2011, Grosso F, et al.
Lancet Oncol. 2007, Blay JY. Eur J Clin Med
Oncol. 2009, López-González A, et al. Med Oncol.
2011, Martinez-Trufero J, et al. Anticancer
drugs. 2010, Chaigneau L, et al. Rare tumours.
2011
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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t(1216)(q13p11) MLPS /YondelisThe 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 courses 9 (1-43)
N44
PD
10
SD
4
Tissue response 65
SD/MR Choi
41
tumour control 90
Delayed R
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F. Grosso et al., Lancet Oncology, 2007
OR 45
PR, CR
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A. Gronchi et al, ASCO 09, ECCO 09
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Translocation Related Approach Trabectedin in TRS
Ewings sarcoma t(1122)(q24q12) EWS-FLI1
Alveolar soft part S t(X17)(p11q25) ASPL-TFE3
Endometrial stromal sarcoma t(717)(p15q21)
JAZF1-JJAZ1
Courtesy of Dr F Grosso
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Trabectedin in TRS
N 81
Tumour control SS PRSD 54 MLPS PRSD
67 Total 59
SS45
Le Cesne et al, EJC 2012
MLPS27
Recently confirmed SS (N61) 50 of control
rate Sanfilippo et al, CTOS 2012
PFS by translocation-related STS and patient
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Trabectedin in TRS
24h q3w vs weekly Median PFS 11.9 vs 5.6 Median
OS 34.4 vs 10.5
Median OS 17.4 months SS 13.9 months MLPS 18.3
months
TRS
STS
Le Cesne et al, EJC 2012
George D. Demetri et al, JCO 09
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ET-C-002-07
Translocation-Related Approach Trabectedin in TRS
Sarcoma type Chromosomal transl. Fusion gene
Clear cell sarcoma t(1222)(q13q12)
EWS-ATF1 Extraskeletal myxoid
chondroS t(922)(q22q12) EWS-CHN Myxoid
liposarcoma t(1216)(q13p11)
TLS/EWS-CHOP Angiomatoid fibrous histiocytoma
t(1216)(q13p11) TLS-ATF1 Alveolar
rhabdomyosarcoma t(213)(q35q14)
PAX3/7-FKHR Desmoplastic small round cell
tumour t(1122)(p13q12) EWS-WT1 Synovial
sarcoma t(X18)(p11q11) SYT-SSX1,2 Inflammat
ory myofibroblastic T t(2p23) Various ALK
fusions Alveolar soft part sarcoma
t(X17)(p11q25) ASPL-TFE3 Endometrial
stromal sarcoma t(717)(p15q21) JAZF1-JJAZ1
Trabectedin 1.5 mg/m2 24h q3w Doxorubicin-bas
ed CT q3w
55 reduction in the relative risk of PD or
death
N 80 Front-line
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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Trabectedin as first-line therapy in patients
with unresectable STS

• Thirty-six patients with STS were treated with
  1.5 mg/m2 of trabectedin
• ORR 17.1
• 1-year progression-free survival rate 21
• Overall survival rate at 1 year72

EMA approval on 20th of September
2007  Yondelis is indicated for the treatment
of patients with advanced STS after failure of
anthracyclines and ifosfamide, or who are
unsuited to receive these agents. Efficacy data
are based mainly on liposarcoma and
leiomyosarcoma patients. 
García-Carbonero R, et al. J Clin Oncol. 2005
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SARC020 EORTC 62091 TRUST

• A phase IIb/III study comparing the efficacy of
  trabectedin (3h or 24h) to doxorubicin in
  patients with advanced STS
• Study PI James Butrynski, Dana Farber Cancer
  Institute/SARC
• Binh Bui, MD Institut Bergonie/EORTC

Excluded WD liposarcoma
End-point PFS
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SAR-1001
Trabectedin Doxorubicin (N41)
Before After 6 cycles
The MTD and recommended dose is D60 mg/m² T1.1
mg/m² ORR SD (tumour control) 95 6-months
PFS 59 (gt baseline reference EORTC first line)
JY Blay et al CCR 2008
Phase II study of Trabectedin Dox vs Dox in
untreated STS patients (GEIS-20) Phase II study
of Doxorubicin Trabectedin in metastatic
CT-naïve LMS (IGR)
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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TrabectedinImportance of maintenance treatment?
p0,009
p0,001
continuation
continuation
interruption
interruption
N 181, median follow-up 6 years
N56, interruption vs continuation after 6 courses
Blay et al, poster CTOS 2012
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T-DIS-1001
Phase II randomised evaluating two
strategies Interruption vs continuation in
responding patients after 6 courses of Yondelis
PI Dr Nicolas Penel
Main end-point PFS at 24 weeks after
randomization Rechallenge of trabectedin in
case of PD in the interruption arm
October 2012 N122
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T-DIS-1001
Phase II randomised evaluating two
strategies Interruption vs continuation in
responding patients after 6 courses of Yondelis
Patient with metastatic leiomyosarcoma after 6
cycles randomised in the interruption arm
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable safety profile
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin

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Rechallenge with trabectedin in STS
TSeq1 49 median T cycles 7 TSeq2 49 median T
cycles 6 TSeq3 8 median T cycles 6 TSeq4
1 6 courses
Due to the lack of cumulative toxicities over
time with T, rechallenge in responding patients
to T can be considered as a useful option in
advanced STS.
Median OS since TS1 5 years!
Esma Saâda-Bouzid et al, ASCO 2012
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Rechallenge with trabectedin in STS
Advanced loco-regional relapse WD and DD LPS
D1 15 cy
R1 resection followed with adjuvant AI and RT in
1998 1st sequence 2002 15 courses of T, SD
(48 of tumour reduction) 2nd sequence 2009 12
courses of T, SD Alive in October 2012
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Tumour evolution during treatment
30
25
Trabectedin (50 of patients)
20
15
tumour size
Dox /- Ifo (30 of pts)
10
CT
5
0
-1
0
1
2
3
4
time (AU)
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General treatment algorithm in STSoutside
clinical trials
LOCAL DISEASE
Surgery RT/- CT
50-60
CURE
LOCAL RELAPSE
LOCAL RELAPSE AND METASTASES
METASTASES
Surgery RT/- CT
10
90
Paliative
Curative?
Surgery /- CT
1st-line chemotherapy
Anthracyclines Trabectedin (Europe)
Anthracycline-based multi-agent
chemotherapy Trabectedin (Europe)
2nd-line chemotherapy
Ifosfamide Trabectedin (Europe)
Trabectedin (Europe) Pazopanib Non approved
options
Trabectedin (Europe) Pazopanib Non approved
options
3rd-line and beyond
If patients unsuited to doxo/ifo
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Trabectedin in STS Conclusions
Trabectedin

1. Induces long lasting OR and tumour control in a
   relevant proportion of sarcoma patients
   resistant/relapsed to conventional CT.
2. No cumulative toxicity and is suitable for
   chronic and repetitive administration.
3. It has shown clinical benefit in all STS
   subtypes.
4. May suggest a targeted therapeutic approach in
   MLPS and in other translocation-related
   mesenchymal tumours.
5. Currently tested in front-line CT regimen.

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13 years of trabectedin from the abyss to the
summit
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Trabectedin 13 years of experience Yondelis 5
years of experience

• The first  prolonged tumour control  TT in STS
• Favourable pattern of toxicities
• Trabectedin active in all STS histological
  subtypes
• Trabectedin in translocation-related STS
• Trabectedin in front line therapy
• Maintenance of response
• Rechallenge with trabectedin
• Further steps with trabectedin.

..Peter Reichardt
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Keohan, M. L. Turner, R. Verma, S. Baker,
L. Hande, K. Morris, D. Ryan, C. Elias, A. Okuno,
S. Albritton, K. Biakhov, M. Butrynsk,
J. Mardynsky, Y. Patterson, K. Van Oosterom,
A. Gershanovich, M. Judson, I.
Lopez, A. Makhson, A. Patel, S. Pavlick,
A. Pliner, L. Schutte, H.J. Staddon, A. Taub,
R. Buys, S. Byrne, M. Kopp, M. Poveda,
A. Skubitz, K. Ushakov, I. Younus, J. Reichardt,
P. ..
Demetri, G.D. Chawla, S. Schuetze, S. Von Mehren,
M. Le Cesne, A. Budd, G. Casali, P. Garin,
A. Hamm, J. Manikhas, G. Ritch, P. Rushing,
D. Blay, J. Y. Samuels, B. Blackstein, M. Kaiser,
P.
Thanks to PharmaMar, all patients
and all participating investigators and
collaborating teams
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