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