trabectedin contribution to the treatment of sarcomas pr jy blay centre leon berard, lyon eortc
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Trabectedin contribution to the treatment of sarcomas
Pr JY BlayPr JY Blay
Centre Leon Berard, Lyon
EORTC
Centre Leon Berard, Lyon
EORTC
Adipocytic tumoursWell deifferentiated / dedifferentiated liposarcomaMyxoid / round cell liposarcomaPleomorphic liposarcoma…..
Fibroblastic / myofibroblastic tumoursFibromatosis (desmoid)Solitary fibrous tumour / haemangiopericytomaLow grade myofibroblastic tumourInfantile fibrosarcomaAdult fibrosarcomaMixofibrosarcoma…..
So-called fibrohistiocytic tumoursPleomorphic MFH / Undifferentiated pleomorphic sarcoma…..
Smooth muscle tumoursLeiomyosarcoma…..
Skeletal muscle tumoursEmbryonal rhabdomyosarcomaAlveolar rhabdomyosarcomaPleomorphic rhabdomyosarcoma
Vascular tumoursEpithelioid haemangioendotheliomaAngiosarcoma of soft tissue…..
Chondro-osseous tumoursMesenchymal chondrosarcomaExtraskeletal osteosarcoma
Tumours of uncertain differentiationSynovial sarcomaEpithelioid sarcomaAlveolar soft part sarcomaClear cell sarcoma of soft tissueExtraskeletal myxoid chondrosarcomaExtraskeletal Ewing tumourDesmoplastic small round cell tumourExtra-renal rhabdoid tumourMalignant mesenchymomaNeoplasms with perivascular epithelioid cell differentiation (PEComa)Intimal sarcoma
Many different histotypes And even more molecular subtypes!
Connective tissue tumours5 types of sarcomas
Associated with specific translocations generating fusion genesAssociated with specific translocations generating fusion genes Ewing Ewing t(11;22), …t(11;22), … Synovialosarcomas Synovialosarcomas t(X;18)t(X;18) Alveolar rhabdomyosarcomas Alveolar rhabdomyosarcomas t(1;13), t(2;13)t(1;13), t(2;13) DSRCTDSRCT t(11;22)t(11;22) etc...etc...
Kinase mutations (KIT, PDGFR in GIST)Kinase mutations (KIT, PDGFR in GIST) Gene inactivation (INI1 in rhabdoid tumors)Gene inactivation (INI1 in rhabdoid tumors) Simple genetic alterations: amplifications (mdm2+cdk4 in LPS)Simple genetic alterations: amplifications (mdm2+cdk4 in LPS) Complex genetic alterations (MFH, LMS, ...)Complex genetic alterations (MFH, LMS, ...)
A simple algorithm?
LOCAL LOCAL DISEASEDISEASE
Surgery Surgery ++ RadiotherapyRadiotherapy
CURE CURE (~50%)(~50%)
METASTASES METASTASES ((~~60%)60%)
DoxorubicinDoxorubicin IfosfamideIfosfamide Combination Combination
Surgery Surgery ((~~10%)10%)
Trabectedin Trabectedin Trabectedin Trabectedin Trabectedin Trabectedin
IfosfamideIfosfamide DoxorubicinDoxorubicin
Systemic treatment of sarcomas 2000-2012
2000 All sarcomas
Doxorubicin Ifosfamide DTIC
Selected subtypes Dactinomycin CDDP Vincaalcaloids Cyclophosphamide
2012 All subtypes: : Same +Trabectedin GIST: Imatinib, sunitinib,
nilotinib? Osteosarcomas: MTPPE LPS: Dox, Trabectedin LMS: Dox, Trabectedin, Gem,
G/T EWS: A,I,C,V,Ac, TopoI inh.,
IGF1R A/E RMS: Topo inh ESS: Aromatase inh. All?: mTOR All but LPS: VEGFR TKI Angio: Dox, Paclitaxel, GemTax DFSP: Imatinib PVNS: Imatinib Desmoid Tumors: imatinib
Trabectedin (Yondelis®)
Marine-derived anticancer agent originally isolated Marine-derived anticancer agent originally isolated from marine Caribbean tunicate, from marine Caribbean tunicate, Ecteinascidia Ecteinascidia turbinataturbinata..
Currently obtained by a synthetic process. Currently obtained by a synthetic process. Approved in more than 70 countries for the Approved in more than 70 countries for the
treatment of relapsed STS and platinum sensitive treatment of relapsed STS and platinum sensitive ovarian cancer.ovarian cancer.
Yondelis binds covalently Yondelis binds covalently to the DNA minor groove.to the DNA minor groove.11
Interaction with the Interaction with the endonuclease XPG.endonuclease XPG.11
The formation of a large The formation of a large ternary cytotoxic complex ternary cytotoxic complex (DNA-Yondelis-XPG) (DNA-Yondelis-XPG) results in DNA breaks.results in DNA breaks.11
Yondelis: A Unique Mechanism of Action1
Formation of a ternary complex between DNA (blue), Yondelis (Orange) and XPG (Green)
Affecting “the two” cellular processes related to DNA: replication1 and transcription2, and finally inducing an apoptotic cell death.1
1. Herrero AB, et al. Cancer Res. 2006;66(16):8155-62.2. Fayette J, et al. Curr Opin Oncol. 2006;18:347-53.1. Herrero AB, et al. Cancer Res. 2006;66(16):8155-62.2. Fayette J, et al. Curr Opin Oncol. 2006;18:347-53.
Yondelis is a multitarget agent
TF
FP
DNA bindingand distortion
Displacement ofTF and FP
Transcription inhibition
ARN pol II
Tumour microenvironment
Pre-treatment Cycle 3
Pre-treatment Cycle 2
N
N
OH
O
O
AcO
OCH3
HO
S
O
NH
HO
O
H
MeO
Adapted from M D’Incalci et al, 2010Adapted from M D’Incalci et al, 2010
DNA repair
XPF
XPG
Major impact (tumor control, 6-PFS) in:• Leiomyosarcoma (LMS) 56%
• Liposarcoma (LPS) 40%
• 270 patients randomized (260 treated)
• Baseline characteristics well balanced between both arms
• 66% leiomyosarcomas / 34% liposarcomas
• Prior chemotherapy: PD after anthracyclines and ifosfamide
• 2/3 of pts received additional agents (Gem, 32%; docetaxel, 24%....)
STS-201
Trabectedin: 1.5 mg/m2 24-h CI q3wk
Trabectedin: 0.58 mg/m2 3-h wkly 3wks/4 ®Advanced
LPS/LMS
STS-201 Historical Context (EORTC): PFS in Sarcomas
Both trabectedin schedules showed longer PFS than “active” drugs in similar setting Le Cesne et al. Drugs of today 2009;45(6):403-21Le Cesne et al. Drugs of today 2009;45(6):403-21
1
2
3
4
1. Trabectedin q3wk 24-h2. Trabectedin qwk 3-h3. Active agents (EORTC STBSG)4. Inactive agents (EORTC STBSG)
14% 6 months PFS
36% 6 months PFS
LPSLPS
MRMR(SD)(SD)15 cy15 cy
Alive at 11+ yrs
Objective response vs Survival
Linking with clinical use of trabectedin
HistologyHistology
CombinationsCombinations
Maintenance treatmentMaintenance treatment
RechallengeRechallenge
0 +4 c
Trabectedin in MLPS: Induction CT in Localized MLPS?
N = 23: 4 to 6 cycles of trabectedin/Surgery/ RT End-point: complete histological rate
Analysis of fusionTranscripts/Response
Multicenter Phase II (IGR/Milan/CLB/US)
A. Gronchi et al, Ann Oncol 2011A. Gronchi et al, Ann Oncol 2011
Before After 6 cycles• 41 pts
• MTD and recommended dose: D60 mg/m² + T1.1 mg/m²
• ORR + SD (tumor control) = 95%
• 6-months PFS: 59% (> baseline reference EORTC first line)
• Currently several studies are ongoing with combination therapy:
• Phase II randomised multicenter study of Trabectedin
plus Doxorubicin vs. Doxorubicin in untreated STS patients (GEIS) Blay JY et al CCR 2008Blay JY et al CCR 2008
Trabectedin + Doxorubicin
Trials ongoing in first line
Translocation related sarcomasTranslocation related sarcomas TRUSTsTRUSTs GEIS-20 (Trabectedin + Doxorubicin)GEIS-20 (Trabectedin + Doxorubicin) LMS-02 (Doxorubicin + Trabectedin)LMS-02 (Doxorubicin + Trabectedin)
Future of Trabectedin in STS
• Molecular targeted therapy with trabectedin in TRS
• Combination with others drugs
• Personalised treatment with surrogate biological markers. Adjuvant approaches?
Marker +
Marker -
TrabectedinImportance of maintenance treatment?
N=56, interruption vs continuation after 6 coursesExplored in the randomized T-DIS trial
p=0,001
p=0,009
Blay JY et al, BMC 2012 (Submitted)Blay JY et al, BMC 2012 (Submitted)
ITALIAN SARCOMA GROUP GRUPO ESPAŇOL de INVESTIGACIÓN de SARCOMAS
GROUPE SARCOMES FRANÇAIS
Cooperative groups for clinical and translational research into sarcomas
LOCALIZED HIGH-RISK SOFT TISSUE SARCOMAS OF THE EXTREMITIES AND TRUNK WALL IN ADULTS: AN INTEGRATING APPROACH COMPRISING
STANDARD VS HISTOTYPE-TAILORED NEOADJUVANT CHEMOTHERAPY (ISG-STS 10-01)
Prospective controlled randomized trial
November 2011 Study Chairman: Alessandro Gronchi Fondazione IRCCS Istituto Nazionale Tumori, Milano Methodological coordination and data management
D.F. Merlo, M. Mannucci Istituto Nazionale per la Ricerca sul Cancro, Genova
Design and statistical analysis:
Paolo Bruzzi Istituto Nazionale per la Ricerca sul Cancro, Genova
European Clinical trials in Rare Sarcomas within an
integrated translationalGrant agreement no.:
278742