Avances en el Tratamiento de los

Sarcomas de Partes Blandas:

De la Quimioterapia a los fármacos antidiana

Xavier García del Muro Solans

Institut Català d’Oncologia. Barcelona

SOFT TISSUE SARCOMA: TREATMENT RESULTS

• Primary treatment of extremity STS with wide excision and

radiotherapy achieves more than 90% control success

• However, 5-year overall survival in the group of patients of

high-risk is 50%, because of development of metastases

• Some selected patients with

isolated pulmonary metastases could

benefit from surgery, achieving up to

20% of long-term survivors. For the

rest of pts, chemotherapy is the only available treatment

Van Glabbeke M. J Clin Oncol 1999

RESULTS OF CURRENT CHEMOTHERAPY IN ADVANCED STS:

Prognostic factors for the outcome of chemotherapy in 2185 pts

with STS treated with anthracycline-containing first-line regimens

• Retrospective analysis of 2185

pts with STS included in 7

EORTC clinical trials

• 1st-line Chemo including

anthracyclines: Doxorubicine,

Epirubicine, Doxo-IFX, Cyvadic

• RR (CR + PR): 26%

• Overall Survival: 51 weeks

Combination Chemotherapy in Soft Tissue Sarcoma

Study Drug N RR Survival

ECOG Doxorubicin 93 19% 8 mo

Doxorubicin + DTIC 95 13% 8 mo

SWOG Doxorubicin + DTIC 79 32% 9 mo

Doxo + DTIC + cytoxan 95 35% 10.5 mo

ECOG Doxorubicin 90 20% 9 mo

Doxorubicin + Ifosfamide 88 34% 12 mo

ISSG Doxorubicin + DTIC 170 17% 13 mo

MAID 166 32% 12 mo

EORTC Doxorubicin 212 24% 12 mo

Doxorubicin + Ifosfamide 202 27% 12 mo

Doxorubicin alone remains the standard treatment altough a combination

regimen seems justified when obtainig a response is important

Doxo continues being standard 1st-line treatment and HD regimens should only be used in clinical trials

132 pts from 23 centers from Spain and Portugal

Treatment Schedule:

ARM A: Doxorubicin 75 mg/m2

ARM B: DOX 90 mg/m2 + G-CSF q 2 wk x 3 cycles plus IFOS 12.5 gr/m2 + G-CSF q 3wk x 3 cycles

Study Design:Randomized phase II study. Endpoint: PFS. Premature closure if less than 25% RR differences

PICASSO 3: A phase 3 international, randomized, double-blind, placebo-

controlled study of doxorubicin plus palifosfamide vs. dox plus placebo for

patients in first-line for metastatic soft tissue sarcoma

C.W. Ryan, P. Schoffski, O. Merimsky, M. Agulnik, J.Y. Blay, S.M. Schuetze, J.Y. Buck,

X. Garcia del Muro, I.R. Judson, R.G. Maki

ESMO 2013 • 447 pts with mSTS randomized to

receive pali+dox (n=226) or

placebo+dox (n=221)

• Median PFS was 5.98 months for

pali+dox compared with 5.23

months for placebo+dox (HR=0.87,

95%CI 0.70–1.07; p=0.18)

• At interim analysis, median overall

survival was 15.91 months for

pali+dox vs 16.89 months for

placebo+dox (HR=1.05, 95%CI

0.79–1.39; p=0.74)

Incorporating new drugs in

the treatment of soft

tissue sarcoma:

- Chemotherapy

- Targeting agents

Stacchiotti S. Radiology 2009

RECIST RESPONSE CRITERIA ARE NOT ALWAYS USEFUL TO

IDENTIFY ACTIVITY

Correlation between Radiologic and Pathologic Response

by Using RECIST and Choi Criteria

New method for identifying active drugs in STS in clinical trials, based on the PFR at 3 m. found

in EORTC database. They establish a PFR at 3 m in pretreated pts for active and inactive agents

q3wk 24-h

n=136

qwk 3-h

n=134

Stats

n=270

206 events 104 102

Median, mo. 3.7 2.3 HR: 0.734 p=0.0302

Predictive impact of DNA repair functionality on clinical

outcome of advanced sarcoma treated with Trabectedin

Schöffski P. EJC 2011

16.8 m vs 8.2 m (HR, 0.56; 95% CI, 0.36 to 0.90; P .014) 4.2 m vs 2 m (HR, 0.58; 95% CI, 0.39 to 0.86; P .005)

Randomized phase II trial of Gemcitabine +/-

Docetaxel in advanced STS

Maki R. JCO 2007

Ensayo Fase I/II de Doxorubicina seguida

de Gemcitabina en SPB. Estudio GEIS

• Ptes con SPB avanzado sin Tto previo

• Esquema Tto:

Doxorubicina 60 mg/m2, d 1

Gemcitabina 800 mg/m2 en 80 m. d 1 y 8

• Fase II, 47 pts eval.:

Actividad: RR 19.5 % (CI 95%; 8-31)

Toxicidad: Neutropenia G4:49%, Mucositis G3:46%

Reducción dosis >40% pts

Lopez Pousa. Br J Cancer 2006

RANDOMIZED PHASE II TRIAL OF

TRABECTEDIN PLUS DOXORUBICIN VS

DOXORUBICIN IN ADVANCED STS

Study Design

Arms

Random

Assigment

1:1

Doxorubicin75mg/m23wx6cycles Followup

Trabectedin1.1mg/m2+Doxorubicin/3w60mg/m23wx6cycles FollowUp

CONTROL ARM

EXPERIMENTAL ARM

Clinical and Radiological every 6

weeks

ASSOCIATED STUDIES Pathologic Independent Review (done)

Radiological Independent Review (in process) Translational Research (in process)

Stratification Factor:

M1 ≤12m vs >12m

Control Arm

Experim Arm

P= 0.20

Months

Efficacy Data Progression Free Survival

Efficacy Data Survival

ControlArm(59)

ExperimentalArm(55)

p

MedianPFS(months)PFSat6mPFSat12m

5.80(3.5-8)49%26%

5.7(2.9-8.5)48%15%

0.20

MedianOS(months)OSat6mOSat12m

15.1(7.2-23)81%53%

13.3(10.1-16.5)77%54%

0.51

HR(IC95%) P

PFS 1.31(0.86-1.98) 0.20

OS 1.18(0.72-1.96) 0.51

Risk Reduction in Experimental Arm Martín Broto et al. ESMO 2013

SOFT TISSUE

SARCOMA: 60 subtypes

Updated WHO 2012

classification reflecting

relationship among

lineages and

prognosis:

- Malignant

- Locally aggressive

- Rarely metastasizing

Are there differences in chemosensitivity between

histopathologic STS subtypes

Subtype Chemotherapy Uterine Leiomyosarcoma GEM+DOC Temozolomide Synovial Sarcoma HD-IFOS Scalp Angiosarcoma Paclitaxel Caelyx Mixoid Liposarcoma Trabectedin Doxorubicin

Should clinical trials be performed on specific subtypes instead of all STS?

Pathways for Targeted Therapy in Sarcoma

VEGFR inhibitors in Specific Sarcoma Types

• Cediranib for metastatic alveolar soft part sarcoma

Phase II study with 43 evaluable pts

RR 35% PR+SD at 24 wk: 84%

Kummar et al. J Clin Oncol 2013

• Sunintib in solitary fibrous tumor

Observational study with 35 pts

2 PR 16 SD 14 Choi R mPFS 6 months

Stacchiotti et al. Ann Oncol 2012

• Temozolomide plus bevacizumab in hemangioperic.-SFT

Observational study with 14 pts

79% Choi R mPFS 9.7 months

Park et al. Cancer 2011

• Sorafenib in advanced angiosarcoma

Phase II study in superficial (26) and visceral (15) angiosarc.

mPFS 1.8 and 3.8 m, respectively

Ray-Coquard et al. Oncologist 2012

La inactivación del gen supresor PTEN en líneas musculares en ratones se

asocia al desarrollo de leiomiosarcomas con activación constitutiva de mTOR

Hernando E. Nat Med 2007

Wagner A. JCO 2010

Dermatofibrosarcoma protuberans

• 10 pts con DFSP fueron tratados con Imatinib 400 mg/12h

• 8 pts con DFSP localmente avanzado t(17;22): 4 RC / 4 RP

• 2 pts con DFSP metastásico con APª de fibrosarcoma, cariotipos más complejos: 1 pts t(17;22): RP y 1 pte no: PRO

• Imatinib es activo frente a DFSP con t(17;22), y parece no serlo en las variantes fibrosarcomatosas que carecen de ella

McArtur. JCO 2005

IMATINIB in Aggressive Fibromatosis (Desmoid Tm)

• Clinical and molecular studies of imatinib on advanced aggressive

fibromatosis

19 pts included, 3 RP (15%) and 4 SD >1y; PFR at 1y: 37%

16 pts WNT pathway mutations (APC or CTNNB1).

High plasma levels of PDGF-A and PDGF-B

Heinrich MC et al J Clin Oncol 2006

• Efficacy of Imatinib in Aggressive Fibromatosis:Phase II SARCtrial

51 pts included; PR 6%; PFR at 1y: 66%

Chugh R et al. Clin Cancer Res 2010

• Imatinib for progressive and recurrent aggressive fibromatosis:

FNCLCC/FSG Phase II trial

40 pts included; PR 12%; PFR at 1y: 66%; at 2y: 55%

Penel N et al. Ann Oncol 2011

Barretina J. Nat Genet 2010

• The efficacy of the current available treatments for

advanced sarcomas is limited and research is needed in

this field

• Participation in cooperative groups and Intergroup

collaboration should be encouraged to investigate

several of the important questions concerning sarcomas

• Close collaboration between clinicians and basic

researchers is necessary to design studies that will

provide answers to outstanding questions

Final Comments