update on sarcomas rare bone sarcomas

UPDATE ON SARCOMAS

Rare bone sarcomas

Silvia Stacchiottisilvia.stacchiotti@istitutotumori.mi.it

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DISCLOSURES

Personal financial interests (honoraria, consultancy or advisory role): Adaptimmune, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Immunedesign, Karyopharm, Maxivax, Pharmamar, Takeda

Institutional financial interests: Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Novartis, Pfizer, Pharmamar

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Cartilage tumours

• Chondrosarcoma

• Dedifferentiated chondrosarcoma

• Mesenchymal chondrosarcoma

• Clear cell chondrosarcoma

Fibrogenic tumours

Fibrohistiocitic tumours

Giant cell tumours

• Giant cell tumor

• Malignancy in giant cell tumours

Notochordal tumours

• Chordoma

Vascular tumours

• Haemangioma and related lesion

• Angiosarcoma

Myogenic, lipogenic, neural and epithelial

tumours

• Leiomyosarcoma of bone

• Liposarcoma of bone

• ...

Congenital snd inherited syndromes

• Enchondromatosis (Ollier/Maffucci

Syndrome)

• ...

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Cartilage tumours

• Chondrosarcoma

Fibrogenic tumours

Giant cell tumours

• Giant cell tumor

• Malignancy in giant cell tumours

Notochordal tumours

• Chordoma

Vascular tumours

• Angiosarcoma

tumours

• ...

Syndrome)

• ...

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Sbaraglia M et al, CTOS 2018

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427 primary vascular tumors diagnosed at IOR (Bologna)

since 1937 (90 yrs!)

289 hemangiomas

183 sarcomas (32%)

52 (12%) angiosarcomas (45 epithelioid)

38 (8.9%) epithelioid hemangiomas

24 (5.6%) pseudomyogenic hemangioendotheliomas

21 (5.2%) epithelioid hemangioendotheliomas

2 retiform hemangioendotheliomas

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Primary tumors

Recurrence free survival

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Primary tumors

Overall survival

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CHEMOSENSITIVITY: THE SAME AS THE

SOFT TISSUE COUNTERPART

?Do not duplicate or d

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Chordoma

bone tumor

mesenchymal/epithelial differentiation

0.8/1.000.000

(benign lesion 20%)

600-750 pts/yr in EU

indolent clinical behaviourDo not duplicate or d

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Age ▪ Median age 60 yrs

A Trama, Sept 2017

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Pathology

▪ Conventional chordoma (>95%)

nuclear staining for brachyury

▪ Dedifferentiated chordoma (<5%)

▪ Poorly differentiated chordoma (<5%)Do not duplica

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INI1 loss and negative nuclear staining of

brachyury

DEDIFFERENTIATEDCHORDOMA

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Images courtesy of Dr. Mrinal Gounder

H&E Brachyury INI1

POORLY DIFFERENTIATED CHORDOMA

CHILDREN (0-21 YRS)Do not duplica

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wide excision +/- HD-RT

- unresected cases -

definitive HD-RT

Primary tumor

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Relapsed chordoma

Ann Oncol 2017

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Ann Oncol 2017

Relapsed chordoma

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Ann Oncol 2017

“Medical therapy is an appropriate palliative option for patients whose disease is actively progressing or who are symptomatic

A brief observation period may be warranted before starting medical therapy to determine whether, and at

what rate, progressing “

Relapsed chordoma

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No active drug formally approved

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No active drug formally approved

the compassionate and off-label use

of new drugs

is widespread in chordoma

a very discordant access

to potentially active treatments

among different European countriesDo not duplica

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Overall <10% RECIST PRreported in literature

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Medical Treatment, chemo

cytotoxic

chemotherapy

“However, anecdotal reports of responses to anthracyclines,

cisplatin, alkylating agents, etoposide

in high-grade dedifferentiated and pediatric cases”

Stacchiotti S et al, Lancet Oncol 2015Ann Oncol 2017

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S David et al, CTOS 2018

Medical Treatment, chemo

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+3 mosbaseline

CDDPDo not duplicate or d

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” At present,

imatinib and sorafenib

are the medical therapies with the greatest evidence of antitumor

activity in chordoma and represent reasonable palliative treatment

options to slow disease progression or alleviate symptoms”

Ann Oncol 2017

Medical Treatment, TKI

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RECIST

PR = 1 pt (2%)minor response 9 (18%)

SD = 35 pts (70%)

PD = 14 pts (28%)

mPFS = 9 mos

Stacchiotti S et al, JCO 2012

Imatinib

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Baseline

18 mos+

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Bompas E et al, Ann Oncol 2015

RECIST

PR = 1/27

9-mo PFS 73.0%

12-mo OS 86.5%

Sorafenib

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Stacchiotti S et al, Eur J Cancer 2018

Imatinib + everolimus

40 evaluable pts, all progressive

imatinib 400 mg + everolimus 2.5 mg

PR 9/40 (ORR 20.9%)

RECIST

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PR 9/40 (ORR 20.9%)

RECIST

m-PFS (Choi) 11.5 mos

m-PFS (RECIST) 14 mos

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PR 9/40 (ORR 20.9%)

RECIST

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PR 9/40 (ORR 20.9%)

RECIST

30% definitive interruption for toxicity

S6/4EBP1 phosphorylated in a high and

moderate/low proportion of tumor cells in

responsive and nonresponsive patientsDo not duplica

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Sunitinib/ Pazopanib

Lipplaa A et al, Clin Sarc Res 2017

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Launay SG, BMC Cancer 2011

… erlotinibcetuximab

gefitinib

EGFR inhibitors

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Open trials

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Magnaghi P et al, Mol Cancer Ther 2018

IC50 (uM)

Compound UCH-1UCH-2

(Ch. F.)

(ATCC)Chor-IN-1

Chor1JHC7

Biochemical1

Afatinib 0.010 0.208 0.257 0.586 0.260 1.726 2.114 0.001

Neratinib 0.021 1.894 3.756 1.903 2.152 2.944 0.491 0.008

Erlotinib 0.137 6.297 6.885 1.917 2.615 1.712 3.447 0.005

Ibrutinib 0.388 5.600 4.770 9.319 > 10 3.655 3.463 0.021

Lapatinib 0.554 > 10 > 10 > 10 > 10 > 10 3.076 0.030

Gefitinib 0.608 3.418 5.133 8.650 6.787 7.133 4.990 0.004

Vandetanib 1.195 1.948 4.618 4.460 3.654 7.207 1.502 0.039

Rociletinib/CO-1686 2.115 2.650 3.176 0.897 4.615 2.670 0.915 0.535

Open trial, afatinib

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Advanced, progressing

chordoma

Afatinib

40 mg/day

Continue

up to progression

and/or toxicity

Open trials, afatinib

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Images courtesy of Dr. Mrinal Gounder

H&E Brachyury INI1

POORLY DIFFERENTIATED CHORDOMA

CHILDREN (0-21 YRS)

Open trials, tazemetostat

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TAZEMETOSTAT

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CHILDREN (0-23 YRS)

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REGOBONE

Open trials, regorafenib

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Von Witlzleben et al, Cancer Res 2015

Open trials, palbociclib

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Migliorini D et al, Oncoimmunology 2017

Open trials, vaccine

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Chondrosarcoma

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▪ Conventional (85%)

▪ Dedifferentiated

H3K27me3 deficiency

▪Mesenchymal

HEY1-NCOA2

▪ Clear Cell

▪ Extraskeletal Myxoid Chondrosarcoma

Pathology

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wide excision +/- HD-RT

- unresected cases -

definitive HD-RT

Primary tumor

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Relapsed bone chondrosarcoma

limited chemosensitivity

to cytotoxicsDo not duplicate or d

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baseline

+ 4 mos

doxo, conventional/ dediff/ mesenchymal chondro

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- 3 mos

baseline

+ 4 mos

gemcitabine

gemcitabine,

conventional chondro

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trabectedin,mesenchymal chondro

Morioka H et al, BMC Cancer 2016

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antiangiogenics

Jones et al., Mod Oncol 2017

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REGOBONE

Open trial, regorafenib

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Tawbi et al, Lancet Oncol 2017

Pembrolizumab

RECIST

PR = 1/5 ptminor response (<30%) 0

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Martin Broto J et al, ASCO 2018

Sunitinib + nivolumab

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bone tumor

mesenchymal/epithelial differentiation

synonym: osteoclastoma

4-5% of all primary bone tumor

Paget-related cases

>20-45 yrs

benign, locally aggressive

malignant transformation

Giant Cell Tumor of Bone

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Behjati S et al, Nature Genetics 2013

point mutations of

H3F3A gene

- coding for a histone H3.3

protein -

Pathology

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Behjati S et al, Nature Genetics 2013Righi A, Human Path 2017

Pathology

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Cartilage tumours

• Chondrosarcoma

Fibrogenic tumours

Giant cell tumours

• Giant cell tumour

• Malignancy in giant cell tumour

Notochordal tumours

• Chordoma

Vascular tumours

• Angiosarcoma

tumours

• ...

Syndrome)

Fletcher C et al, WHO 2013

Pathology

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“benign but locally aggressive primary bone neoplasm”

Pathology

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mononuclear stromal spindle cells

macrophage osteoclast-like giant round multinuclear cell

RANKL is expressed by stromal tumor cell

RANK is expressed by giant osteoclast-like cells

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Metastases can have

benign path aspects

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“A high-grade malignant neoplasm arising in GCT may be

identified at initial diagnosis (ie primary malignancy in

GCT) or at relapse (secondary malignancy in GCT)”

Pathology

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“Primary malignancy in GCT refers to cases where an area or nodule of

highly pleomorphic mononuclear cells is present in an otherwise

conventional GCT. The transition between the two components varies.

The high-grade sarcoma has no specific morphology; it may or may not

produce osteoid. In secondary malignancy in GTC, the pre-existing GCT

may or may not be evident”

Pathology

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Folpe AL et al. Mod Pathol 1999

Pathology

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surgery

recurrence rate:complete resection: 10-20%

curretage: > 60%

2-5% metastases (>lung)

Primary tumor

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Malignancy in GTC incidence

▪ 1-3% high-grade sarcoma dedifferentiation

Saada et al, JCO 2011

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Critical sites requiring demolitive surgery

(benign GCT)

Medical therapy, when?

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Critical sites requiring demolitive surgery

(benign GCT)

Metastatic cases

«Benign»

Malignant GCT

Medical therapy, when?

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Denosumab

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Bransletter et al, Clin Cancer Res 2012

Denosumab, path response

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282 pts

9/2008-3/2011

Chawla et al, Lancet Oncol 2013

PD: 8/282 pts (3%)

RECIST ORR: 41%

Denosumab

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ADVERSE EVENTS OF INTEREST N=526 (%)

Osteonecrosis of the jaw 28 (5%)

Palmerini E et al, ESMO 2017, 2740067

Denosumab

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Atypical femur fracture 4 (1%)

New malignancy in GCTB

•Primary malignant

•Secondary malignant

•Sarcomatous transformation

10 (2%)

5 (1%)

Denosumab

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Atypical femur fracture 4 (1%)

New malignancy in GCTB

•Primary malignant

•Secondary malignant

•Sarcomatous transformation

10 (2%)

5 (1%)

≥ Grade 3 hypercalcemia (following

discontinuation)

4 (1%)

Denosumab

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+ 6 months

+ 24 months

Denosumab

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0 + 6 months

Denosumab

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+ 1 month

+ 6 months

Denosumab

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0 + 3 months

Denosumab

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Treatment duration?

Which is the best surgical approach after d’mab?

Relapse-free survival after d’mab + surgery?

Denosumab, open issues

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Which medical therapy in

sarcoma in GCTB?

+ 5 cycles

Epi-Ifx

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Silvia Stacchiotti

silvia.stacchiotti@istitutotumori.mi.it

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Bone SFT

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COHORT 1 – unresectable GCTB

COHORT 2 – resectable GCTB

• 5-yr PFS 88%

• 67% surgery

• 5-yr EFS 88%

• 44% less extensive surgery

• 27% relapses

CURRETTAGE vs RESECTION

34% vs 12%

Denosumab

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CTOS 2013, ChicagoDo not duplica

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update on sarcomas rare bone sarcomas

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