I sarcomi

(1)

I Sarcomi

- Dei tessuti molli - Dell’osso

- I GIST Bruno Vincenzi

Università Campus Bio-Medico di Roma

b.vincenzi@unicampus.it

(2)

Bias:

• Lungo periodo di arruolamento

• Elevato numero di pazienti inelegibili

• Dosaggio ifosfamide inadeguato

• Inclusi pazienti con leiomiosarcomi

La Chemioterapia adiuvante può essere proposta al paziente con STM ad alto rischio informandolo

dell’incertezza del risultato sulla base degli studi sinora disponibili.

(3)

Jean-Yves Blay, Eberhard Stoeckle, Antoine Italiano , R Rochwerger, Florence Duffaud,

Sylvie Bonvalot, Charles Honoré, Guy Decanter, Carlos Maynou, Philippe Anract, Gwenael Ferron, Francois Guillemin, Francois Gouin, Maria Rios, Antonio Di Marco1, D. Cupissol, Pierre Meeus,

Jean-Michel Coindre, Isabelle Ray-Coquard1, Nicolas Penel, Axel Le Cesne

BETTER OVERALL AND PROGRESSION FREE SURVIVAL AFTER SURGERY IN EXPERT SITES FOR SARCOMA PATIENTS: A NATIONWIDE STUDY OF FSG-GETO/NETSARC

Abstr 14740

(4)

THE DATA SET 2010-14

• Almost 10.000 adult (>15 yrs) patients with a first sarcoma

• F: M equal

• One third within and two thirds treated outside a NETSARC center

• Median age almost 60 yrs (15-103!); 30% older than 70 years

• 9% GIST; 9% intermediate, rest sarcoma

(5)

MULTIVARIATE ANALYSIS BECAUSE OF CASEMIX

Parameter HR p value

in NetSARC center LRFS 0.67 0.000

RFS 0.62 0.000

OS 0.62 0.000

(6)

WHO ARE THE PATIENTS OPERATED IN NETSARC CENTERS?

Significantly:

• Larger tumors

• More deep seated

• Higher grade: G2/3

• Casemix: younger, more male, less visceral sarcomas

(7)

ISG-STS 1001

(8)

R

ht-CT x 3  Surg + RT EI x 3  Surg + RT

Grade III, adult type STS Extremities and trunk wall Size > 5 cm

Hypothesis: HT CT reduces by 30% the risk of relapse (40 to 27%, HR: 0.66) N random = 350, 500 registered

Analysis: 150 events (relapses or deaths) with interim analysis for futility (IDMC)

Standard versus histotype-tailored CT

MRC LipoS  Trabectedin Synovial S  HD-IFX

LeiomioS  GEM - DTIC UPS  GEM – TAX MPNST  IFX + Etoposide

ISG-STS 1001

Homogeneous group of STS

(9)

ISG-STS 1001 - Results

P=0.004

62%

38%

N = 287 ® pts

P=0.033

89 % 64

%

RFS OS

(10)

RFS by histology subtype Histological response

A. Gronchi et al, Annals of Oncol 2011

A. Gronchi et al, Lancet Oncology 2017

4 pCR, 10 pPR, no clinical PD Phase II trial - trabectedin in

resectable MLPS N = 23

HT-regimen EI

Phase II trial - AI regimen - GR

(11)

>90% TUMOR NECROSIS MIGHT BE RELATED TO PFS AND OS

11

(12)

1st line therapy….variables: mets, size

vs

(13)

R A N D O M

I Z E

Olaratumab monotherapy until

progression

Olaratumab

15 mg/kg D1,8 +

Dox

75

mg/m²D1 for 8 cycles*

Optional olaratumab monotherapy after

progression

Dox

75 mg/m²D1 for 8 cycles

• Same entry criteria as Phase 1b

ECOG PS

• Stratification:

• PDGFRα (IHC)

• Lines of prior treatment

•

• Histology (leiomyosarcoma, synovial, other)

Phase 2

Primary endpoint: Progression-free survival (PFS) : 2-sided alpha = 0.2) Secondary end points: Overall survival (OS), RR, PFS at 3 months

Biomarkers: PDGFRα (IHC) and its ligands

*During Cycles 5-8, patients receiving Dox could receive dexrazoxane at the investigator’s discretion.

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PFS OS

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Doxorubicin ± olaratumab: Phase 1b-2 trial

Vincenzi et al, CROH 2017

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(17)

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[TITLE]

Chawla, ASCO2016 abs # 163

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o Molecular techniques in clinical practice o New definition of categories

o Inclusion and reshape of known entities o New subtypes reported

o Abolishment of obsolete entities

HISTOLOGY-DRIVEN THERAPY

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B. Vincenzi, BJC 2017

(21)

SARC 028 Pembrolizumab

• 11/37 with tumor regressions, UPS,

dedifferentiated LPS and synovial sarcoma

• Overall 19% ORR rate by RECIST, additional 40% of patients with stable disease as best response

•Melanoma 33%

•NSCLC 19%

•>20% ORR gastric, bladder, head and neck

11 pts

• Median F/U – 7,5 months

• 4-months PFR 44% [C.I., 22%-66%] statistically

significant improvement relative to historical control

PFR rate (20%)

(22)

Phase II Nivolumab for uLMS

• 12 patients – small numbers

• All with progressive disease at 3 month scans

• Consistent with lack of response for LMS in SARC 028

• However one exeptional responder reported separately

Response in 20 patients who recieved at least 4 doses of Nivolumab

Presented By Breelyn Wilky at 2016 ASCO Annual Meeting

(23)

CMB305: ACTIVE IMMUNOTHERAPY TARGETING NY-ESO-1

Despite more advanced patients higer disease control rate, too early for OS Immunological response observed

Phase III trial planned

23

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LONG-TERM EFFICACY OF DENOSUMAB IN GIANT CELL TUMOR OF BONE: RESULTS OF AN OPEN-

LABEL PHASE 2 STUDY

Emanuela Palmerini MD,

¹

Jean-Yves Blay MD, PhD,

²

Axel Le Cesne MD,

³

Peter Reichardt MD, PhD,

⁴

Piotr Rutkowski MD, PhD,

⁵

Hans Gelderblom MD, PhD,

⁶

Robert J. Grimer MB BS, DSc, FRCS,

⁷

Amy Feng PhD,

⁸

Danielle D. Jandial MD,

⁸

Sant Chawla MD, FRACP

⁹

1Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy; ²Department of Medicine, Centre Léon Bérard Cancer Center, Lyon, France;

3Medical Oncology, Institut Gustave Roussy, Villejuif, France; ⁴Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Germany ⁵Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland;

6Leiden University Medical Center, Leiden, Netherlands; ; ⁷Royal Orthopaedic Hospital, NHS Foundation, Birmingham, UK; ⁸Amgen Inc., Thousand Oaks, CA, USA; ⁹Sarcoma Oncology Center, Santa Monica, CA, USA

LBA56

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Q4W=every 4 weeks; SC=subcutaneous C S

R E N E N I G

N E R O L L M E N T

Cohort 1 Unsalvageable Denosumab 120 mg SC Q4W

with loading doses (n=267)

Cohort 3

20040215 Rollover Subjects Denosumab 120 mg SC Q4W

(n=12) Cohort 2 Salvageable

Denosumab 120 mg SC Q4W with loading doses

(n=253)

F O L L O W U P N E

D O F S T U D Y Continue denosumab

120 mg SC Q4W if clinical benefit

Continue denosumab 120 mg SC Q4W if clinical benefit If complete resection denosumab 120 mg SC

Q4W for 6 doses Surgery

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ADVERSE EVENTS OF INTEREST

*Positively adjudicated

†Suspected diagnosis based on multidisciplinary expert review

‡Occurred 4 years following radiation therapy for GCTB treatment

AEs of Interest

N=526 n (%)

Osteonecrosis of the jaw* 28 (5.3)

Atypical femur fracture* 4 (0.8)

New malignancy in GCTB 10 (1.9)

Primary Malignant GCTB^† 5 (1.0)

Secondary Malignant GCTB^‡ 1 (0.2)

Sarcomatous transformation 4 (0.8)

≥Grade 3 Hypercalcemia following denosumab discontinuation 4 (0.8)

(27)

ADVERSE EVENT OF INTEREST: OSTEONECROSIS OF THE JAW

*Positively adjudicated

Cohort 1 (N=264)

Cohort 2 (N=250)

Cohort 3 (N=12)

All (N=526)

Osteonecrosis of the jaw,* n (%) 21 (8.0) 7 (2.8) 0 28 (5.3)

Median doses of denosumab (Q1, Q3) 43 (23, 67) 20 (15, 43) 66 (40, 79) 32 (17, 59)

(28)

esmo.org

TIME TO DEFINITIVE FAILURE

TO THE FIRST TYROSINE KINASE INHIBITOR

• IN LOCALIZED GASTROINTESTINAL STROMAL TUMORS (GIST) TREATED WITH IMATINIB AS AN ADJUVANT

• Final results of the EORTC STBSG, AGITG, UNICANCER, FSG, ISG, and GEIS

• randomized clinical trial

P. G. Casali (Milan, Italy) A. Le Cesne (Villejuif, France) A. Poveda (Valencia, Spain) D. Kotasek (Adelaide, Australia) P. Rutkowski (Warsaw, Poland) P. Hohenberger (Mannheim, Germany) E. Fumagalli (Milan, Italy) I. Judson (London, United Kingdom) A. Italiano (Bordeaux, France) H.

Gelderblom (Leiden, Netherlands) N. Penel (Lille, France) H. Kopp (Tübingen, Germany) D. Goldstein (Sydney, Australia) J. Martin Broto (Sevilla, Spain) A. Gronchi (Milan, Italy) E. Wardelmann (Münster, Germany) S. Marreaud (Brussels, Belgium) J. Zalcberg (Melbourne, Australia) S. Litière (Brussels, Belgium) J. Blay (Lyon, France)

LBA55

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STUDY DESIGN

R

29

Imatinib x 2 yrs

no further therapy

Eligible following surgery (2-12 wks):

- GIST (CD117+)

- High & Intermediate risk (NIH Consensus) - R0 & R1

(incl. tumour rupture & contaminated surgery) Stratification:

- High vs Intermediate risk (NIH Consensus) - R0 vs R1

- Stomach vs others

- Institution

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30 20 10 0 80 70 60 50 40 100 90

0 O N

(years)

2 4 6 8 10 12 14

Number of patients at risk : Treatment a r m

R F S H i g h risk

0 30 20 10 50 40 80 70 60 100 90

0 O N

(years)

2 4 6 8 10 12 14

Number of patients at risk : Treatment arm

51 193 183 164 138 118 32 0 Observation

44 195 187 176 153 121 41 1 Imatinib adjuv

Survival time High risk

(years)

2 4 6 8 10 12

30 20 10 0 40 80 70 60 50 100 90

Number of patients at risk : 0

O N

66 193 56 195

173 182

142 160

121 135

102 109

31 37

0 1

14

Treatment arm Observation Imatinib adjuv

30

HIGH-RISK

Imatinib Failure free Survival (IFS)

High risk

(95.7% CI) % at 10 years

Observation 62.4 (54.1, 69.6)

Imatinib 69.3 (61.6, 75.7)

(31)

LOW/INTERMEDIATE-RISK

(years)

8 10 12

0 60 50 40 30 20 10 70 80 100 90

0 O N

2 4 6

Number of patients at risk :

14 Treat ment arm 1

2

11 213 202 195 175 155 66 Observation

12 210 203 193 168 135 57 Imatinib adjuv

Survival time

Low/intermediate risk

(years) 10

0 20 30 100 90 80 70 60 50 40

0 O N

2 4 6 8 10 12

14

Treatment arm

27 213 187 173 152 133 61 1 Observation

25 210 197 181 154 116 47 1 Imatinib adjuv

R F S Low/intermediate risk

(years)

2 4 6 8 10 12

10 0 40 30 20 60 50 70 100 90 80

Number of patients at risk : 0

O N

15 213 16 210

202 202

193 192

171 168

151 135

65 55

1 2

14

Treatment arm Observation Imatinib adjuv

Imatinib Failure free Survival (IFS)

Low/intermediate grade

(32)

PTS WITH TUMOUR RUPTURE

(years)

8 10

20 10 0 40 30 60 50 90 80 70 100

0 O N

2 4 6

12

Treatment arm

RFS

Tumor ruptures

(years)

8 10

20 10 0 40 30 60 50 90 80 70 100

0 O N

2 4 6

12 Treatment arm

37 48 17 13 9 7 3 Observation 21 48 41 38 29 21 10 Observation

35 49 40 19 10 7 2 Imatinib adjuvan 19 49 46 39 30 28 12 Imatinib adjuvan

Survival time

Tumor ruptures

(33)

Abstr 14730

33

(34)

DURATION OF TREATMENT ON DCC-2618 – ALL GIST PATIENTS (N=57)

57% disease control rate at 6M for doses >100mg day

Phase III planned!

34

(35)

Key factors for successful therapy management in STS with any agent

Optimising efficacy Side-effect

management

Dosing

Maintenance therapy

Treatment duration CT lines Patient

characteristics

Sarcoma histotype