Embed Size (px)
Citation preview
Sarcomas and GISTs
J-Y Blay
Lima, 6 4 2019
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Four ideas on sarcoma(s)
• Altogether rare, <6/100000/year
• >100 subtypes/ complex diagnostic
• Similar local treatment / adjuvant?
• Historically few systemic treatments, nowbecoming more complex
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Diagnosis
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Histological and molecular classification
• Histological diagnosis by expert centers
• Molecular diagnosis
• Histological grading
• Molecular grading
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Sarcoma(s)
Other very rare subtypes (8%)
Endometrial stromal sarcoma (2%)
Synovial sarcoma (2%)
Myxofibrosarcoma (2%)
Angiosarcoma (3%)
Rhabdomyosarcoma (3%)
Leiomyosarcoma (11%)
Unclassified sarcoma (16%)
Dermatofibrosarcoma (5%)
Kaposi sarcoma (3%)
Soft-tissue Ewing sarcoma/pNET (4%)
Liposarcoma (15%)
GIST (18%)
Bone primary (osteosarcoma/
chondrosarcoma) (8%)
8%
18%
15%
4%3%5%
16%
11%
3%
3%2%
2%2% 8%
Ducimetière F et al. PLoS One 2011; 6: e20294.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
27 06 18
GIST
Sarcomas and
aggressive connective
tissue tumors
Kinase
mutations
G5
Ntl
Group
Translocations
DFSP
SyS
Ewing
Mutations
APC/bCat
Desmoids
WD/DDLPSAmplification
12q13-15
MDM2/CDK4
MPNST
PEComas
TSG loss
NF1, TSC1/2
Complex
genomics
LMS, UPS
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
• Specific translocations generating fusion genes (Myx LPS) 15%
• Amplifications chromosome 12 (MDM2+CDK4) 75-80%
• Complex genetic alterations (Pleo LPS, ...) 5-10%
Ducimetière F et al. PLoS One 2011; 6: e20294.
Liposarcomas?
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
0 0.2 0.4 0.6 0.8 1 1.2 1.4
GISTLiposarcomasSarcoma NOS
Leiomyos non ut.Kaposi
DermatofibroSUterine LMS
MFH
MyxofibrosarcomasRhabdomyosarcomas
Synovialosarcomas
Ewing sarcomasAngiosarcomas
LG Fibromyxoid Sarcomas
MPNST
FibrosarcomasSolitary fibrous tumors
OsteoS
Incidence / 100,000 / yr
Others
Each of one with a very low incidence…
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Accuracy of histological diagnosis
For 35% the diagnosis is not totally correct
Rate of concordance by patient subgroup
188
Second opinion requested
53 (28%)
Total
discordance
53 (28%)
Partial
concordance
82 (44%)
Total
concordance
178
Second opinion not requested
17 (10%)
Total
discordance
44 (25%)
Partial
concordance
117 (65%)
Total
concordance
For 56% the diagnosis is not totally correct
Ducimetière F, et al. PLoS One 2011;6:e20294; Cassier PA, et al. Br J Cancer 2010;103:165–70; Lurkin A, et al. BMC Cancer 2010;10:150.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Histological discordances
Healthcare system should ensure that accurate pathology is critical to good care. Histopathologists should be members of a quality assurance scheme which allows second opinions to be routine practice
Histological reviews registered in 2010: 14% of major discordances (341 cases)
Cost of the treatments assessed for the initial diagnosis: €2,186,816 vs. final diagnosis: €1,060,174
Histological reviews/molecular biology result in a cost saving of more than €1,000,000
Lionel Perrier, ISPOR 19th, Canada, June 2014
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Soft tissue sarcomas (n=694)(French Sarcoma Group)
METASTASIS
FREE
SURVIVAL
fb 08-94
YEARS
GRADE 1
GRADE 2
GRADE 3
n=83
n=296
n=315
p=0.0002
p<0.0001
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
Coindre et al Cancer. 2001
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
CINSARC: Complexity INdex in SARComas
Metastasis-Free Survival
Training: 183
sarcomas
Validation: 127
sarcomas
Chibon F, et al. Nat Med 2010;16:781–7.
Blue /red: low/high cinsarc
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Establishing prognosis
• Size• Age• Grade (histological & molecular grading)• Gender• Depth• Location• Histological subtypes
• Composite tools (e.g., Sarculator app.)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Diagnosis of genomic alterations
Dufresne A, et al. Nat Rev Clin Oncol 2018;15:443–58.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Management in localized phase
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
• Biopsy first
– Assessment by an experienced team
• Appropriate imaging of the tumor: MRI andd/or CT scan
• Staging : CT scan (adapted to histology)
• En bloc surgical resection by a trained surgeon
– Planning R0; If R1, consider re resection
• Post operative radiotherapy (or preoperative)
– (G2-3 and/or deep seated, and/or >5cm)
• (Neoaduvant/adjuvant chemotherapy)5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
Surgery is the mainstay of sarcoma
treatment
• R0
• Programmed R1 by an expert team
• High risk of relapse with R2 or fragmentation
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Overa
ll surv
ival
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
• At a median follow-up of 7.3 years:
– 5 year disease-free survival is 52% for the no chemotherapy and 56% for the chemotherapy arm (P=0.3548).
– 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P=0.2204).
Neoadjuvant?
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
ESMO Guidelines 2018
• There is no consensus on the current role of adjuvant ChT.
• Study results are conflicting, in the presence of negative results from the largest studies, though data are available from smaller studies suggesting that adjuvant ChT might improve, or at least delay, distant and local recurrence in high-risk patients [18, 19]. … Given the conflicting results of trials included in the meta-analyses, adjuvant ChT is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient (high-grade, deep, > 5 cm tumour) for a shared decision making with the patient [II, C].
• ChT was used as neoadjuvant treatment, aiming at a local benefit facilitating surgery, in addition to the systemic one. A randomised trial showed no differences between three (preoperative) and five (pre- and postoperative) courses of full-dose ChT in high-risk STS patients [21]. A subsequent trial compared preoperative ChT with full-dose epirubicin plus ifosfamide versus a histology-driven ChT. This trial was closed slightly in advance because three interim analyses showed a statistically significant benefit in terms of both RFS and OS in favour of neoadjuvant therapy with epirubicin and ifosfamide. ….While awaiting these results, neoadjuvant ChT with anthracyclines plus ifosfamide for at least 3 cycles can be viewed as an option in the high-risk individual patient, for shared decision making [II, C ].
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Bone
Soft tissue
Visceral
NetSARC: a network of 26 sarcoma referencecenters in France
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Question 1 : does presentation of the patient to a MDT prior to treatment impact on management and prognosis?
Suspecteddiagnosis
DiagnosisNETSARC
MDTBNETSARC
MDTBNETSARC
MDTBTreatment
NETSARCCenters
NETSARCCenters
NETSARCCenters
Non NETSARCCenters
Non NETSARCCenters
Non NETSARCCenters
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Worse clinical presentation when MDT before treatment
• Metastases at diagnosis 16% vs 10% p<0.0001
• Larger tumors: median size 104 vs 91mm p<0.0001
• More deep seated: 85,7% vs 76,3% p<0.0001
• Higher grade: G1 15,8% vs 12,0%, p<0.0001
Also: younger age, more male patients, less visceral sarcomas
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Better management when MDT beforetreatment
• A higher number of pts presented in NetsarcMDTB had
– Adequate imaging of the tumor before treatment/ surgery (87,9% vs 67,8%, p<0.0001)
– Biopsy prior the first resection (87,% vs 55,0%, p<0.0001).
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Better adhesion to CPGs when MDT beforetreatment
• Primary surgery performed before vs after presentation to a Netsarc MDT: R0, R1, R2, and R (unk or NE) surgery in:
– 53.0%, 26.8%, 9.1%, 11.0% (MDT before) vs
– 34,2%, 32.7%, 17,6%, 15.5% (MDT after)(p<0.0001).
• 1125 (15.3%) pts had secondary resection after primary surgery performed without previous NetSarc MDT vs 99 (5.5%) in NetSARC centers (p<0.0001).
• Final surgery:R0, R1, R2, and R (unk or NE) surgery in:
– 57.9%, 25.8%, 6.5%, 9.8% (MDT before) vs
– 48,8%, 26,9%, 10,6%, 13.7% (MDT after) (p<0.0001).
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Question 2 : Does primary surgery the patient within a NetSARC center impacts survival?
Suspecteddiagnosis
DiagnosisNETSARC
MDTBNETSARC
MDTBNETSARC
MDTBTreatment
NETSARCCenters
NETSARCCenters
NETSARCCenters
Non NETSARCCenters
Non NETSARCCenters
Non NETSARCCenters
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Median follow-up 30 months
LRFS but not MFS nor OS is betterin Netsarc centers
Logrank, p=0.43
LRFS
Logrank, p<0.0001
OSRFS OS
Logrank, p<0.0001 Logrank, p=0.49
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Multivariate analysis for RFS
Parameter HR p value
Grade 3 2,336 0,000
Grade 2 1,426 0,000
Size 1,002 0,000
Internal trunk 1,125 0,006
Grade 1 0,751 0,000
Surgery in NetSARC center 0,622 ,000
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Multivariate analysis for OS
Parameter HR p value
Grade 3 1,768 0,000
Depth 1,605 0,000
Size 1,003 0,000
Surgery in NetSARC center 0,622 0,000
Internal trunk 1,246 0,01
Gender 0,863 0,06
Grade 1 0,329 0,000
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Retroperitoneal sarcomas
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Intermediate conclusionDiagnosis and management in localized phase
• Rare and multiple heterogenous subtypes and molecularsubtypes
• Quality of primary management and multidisciplinarity
• Histological review by reference center
• Management in a reference center from the initial diagnosis
• Training of primary care physician for recognition
• Neo/Adjuvant CT: indications to be refined
• Neo/Adjuvant RT: >5cm, or deep seated, Grade 2-35th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Management in advanced phase
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Systemic treatment of sarcomas 2000-2018
2000
– All sarcomas• Doxorubicin• Ifosfamide• DTIC
– Subtypes• Dactinomycin• CDDP• Vinca-alcaloids• Cyclophosphamide• HDMTX
2018
– Trabectedin
– Other than LPS : Pazopanib
– GIST : Imatinib, sunitinib
– Osteosarcomas : MTPPE
– LPS : Dox, ET743 (MRCL++)
– LMS : Dox, ET743, Gem, GemTax
– EWS : A,I,C,V,Ac, TopoI inh.
– A/E RMS : Topo inh
– ESS : Aromatase inh.
– PEComa : mTOR
– Angio : Paclitaxel, GemTax
– DFSP : Imatinib
– PVNS : Imatinib, MCSFR Ab or TKI
– TD/FA : HT, imatinib, sorafenib
This slide includes the information about the drug that not approved in Japan.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
High doses when response or PFS is the most important enpoint (eg presurgery)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
After failure of anthracyclins
Ifosfamide
Trabectedine
Pazopanib
Eribuline
Gemcitabine and Docetaxel
Dacarbazine and Gem5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
HR (95% CI) = 0.55 (0.436,0.696)
p<0.0001
PFS events: 329 (63.5% of 518 patients)
mPFS Trabectedin: 4.2 months
mPFS Dacarbazine: 1.5 months
Unstratified analysis
A Randomized Phase 3 Study of Trabectedin or Dacarbazinefor the Treatment of Patients With Advanced Liposarcoma (LPS)
or Leiomyosarcoma (LMS)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
CI, confidence interval
• The primary endpoint of OS was met, indicating a 30% improvement (based on HR)
Eribulin 228 197 162 138 120 97 88 64 45 34 25 14 7 1
1 0
Dacarbazine 224 190 158 130 103 81 64 45 32 24 16 8 3 0
0 0
Patients at Risk:
1.0
0.8
0.6
0.4
0.2
Surv
ival P
robabili
ty
0 3 6 9 12 15 21 24 27 30 33 36 39 42 4518
Survival Time (months)
Eribulin
Dacarbazine
Eribulin Dacarbazine
Median(months)
13.5 11.5
HR (95% CI) 0.768 (0.618, 0.954)
Stratified P-value
0.0169
Randomized, open-label, multicenter, phase 3 study of eribulin versus dacarbazine in patients (pts) with
leiomyosarcoma (LMS) and adipocytic sarcoma (ADI)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Randomized Phase II Study Comparing Gemcitabine Plus Dacarbazine Versus Dacarbazine Alone in Patients With Previously Treated Soft Tissue Sarcoma: A Spanish
Group for Research on Sarcomas Study
• 113 pts with STS (2 previous lines of CT; adria & ifosfamide)
• Gem 1800mg/m² fixed + DTIC 500 mg/m² q2 weeks or DTIC 1200 mg/m² q3 weeks
• Primary endpoint, PFR @ 3 months (40% to 60%)
García-del-Muro et al. J Clin Oncol 29:2528-2533
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
REGOBONE: study design <br /> Regorafenib for Advanced/Metastatic Bone Sarcomas
Presented By Florence Duffaud at 2018 ASCO Annual Meeting
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Osteosarcoma in REGOBONE: Progression-Free Survival <br /> Primary end-point per blinded central review
Presented By Florence Duffaud at 2018 ASCO Annual Meeting
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
GIST
Sarcomas and
aggressive connective
tissue tumors
Kinase
mutations
G5
Ntl
Group
Translocations
DFSP
SyS
Ewing
Mutations
APC/bCat
Desmoids
WD/DDLPSAmplification
12q13-15
MDM2/CDK4
MPNST
PEComas
TSG loss
NF1, TSC1/2
Complex
genomics
LMS, UPS
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Imatinib mesylate in advanced dermatofibrosarcoma protuberans (DFSP) -pooled analysis of two phase II clinical trials
P. Rutkowski, S. Schuetze, M. M. Van Glabbeke, C. Rankin, W. Ruka, B. P. Rubin, M. Debiec-Rychter, A. Lazar, H. Gelderblom, J-Y Blay, R. Sciot, P. Hohenberger, A. T. van Oosterom; for the EORTC Soft Tissue/Bone Sarcoma Group and South-West Oncology Group
Study
EORTC
(N=16)
SWOG
(N=8)
Total
(N=24)
N (%) N (%) N (%)
Response at 14 weeks
PR 5 (31.3)
SD 6 (37.5)
PD 3 (18.8)
Not evaluable 2 (12.5)
Best overall response
PR (confirmed) 3 (18.8) 4 (50.0) 7 (29.2)
PR (resected) 4 (25.0) 0 (0.0) 4 (16.7)
SD 4 (25.0) 2 (25.0) 6 (25.0)
PD 3 (18.8) 1 (12.5)* 4 (16.7)
Not evaluable 2 (12.5) 1 (12.5) 3 (12.5)
(years)
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : all
6 24 20 15 4 1
Overall survival(ITT)
(years)
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Group
8 16 9 6 3
4 8 3 2 0
EORTC
SWOG
Time to progression(ITT)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Hyman DM et al., abstr. LBA2501
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
Var
iati
on
max
imal
e d
e la
tai
lle t
um
ora
le (
%)
Thyroïd
Colo-rectal
Melanoma
Sarcoma
Lung
GIST
Appendix
Infantile fibrosarcoma
Breast
Salivary glands
Cholangiocarcinome
Pancreas
Sarcomas
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
60 year old woman with widely metastatic, refractory MPNST
TPM4-NTRK3 fusion
Enrolled in Phase II trial of larotrectinib – ASCO 2017 Oral Developmental Therapeutics
RC Doebele et al. Cancer Discovery 2015;5:1049-1057M Gounder ASCO 2017
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
GIST
Sarcomas and
aggressive connective
tissue tumors
Mutations
kinases
G5
Ntl
Group
Translocations
DFSP
SyS
Ewing
Mutations
APC/bCat
Desmoids
WD/DDLPSAmplification
12q13-15
MDM2/CDK4
MPNST
PEComas
TSG loss
NF1, TSC1/2
Genomique
complexe
LMS, UPS
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
59
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Phamacokinetic and pharmacodynamic data
60
Genes whose knockdown is anti-proliferative in dedifferentiated liposarcoma, and the consequences of CDK4, MDM2
and YEATS4 knockdown in dedifferentiated liposarcoma
Nat Gen 2010
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Phase I combinations of MDM2/CDK4 ongoing
First example of the need for a dual oncogene blockade (from a single amplicon) ?5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
Soft tissue sarcomas: intermediate conclusions
• Rare and multiple heterogeneous subtypes and molecular subtypes
• Quality of primary management and multidisciplinarity
• Histological review by reference centre
• Management in a reference centre from the initial diagnosis
• Molecular characterization (early)
• Systemic treatment : adapted
• Curable in advanced phase
• Development of novel agents/strategies in rare cancers5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Heinrich et al. Hum Pathol. 2002;33:484; Science 2003,
Corless et al. Proc AACR. 2003
KIT & PDGFRa are mutated in GIST
Membrane
Cytoplasm
Exon 11 (67.5%)
Exon 9 (11%)
Exon 13,14 (1%)
Exon 17 (0.5%)
Exon 12 (0.9%)
Exon 18 (6.3%)
KIT PDGFRa
•KIT & PDGFRA : 85%
•Other genes:
•NF1, Raf, SDH,
IGF1R
Exon 14 (0.3%)
Imatinib sensitive
+ Sunitinib sensitive
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
3 years of imatinib remains
the standard of care
SSG-AIO: 1 vs 3 years adjuvant imatinibFollow-up 7,5 years Joensuu et al, JCO, 2016
RFS
HR = 0.60
HR = 0.60
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Risk stratification
(2006 AFIP criteria)
Tumor Parameters% Patients with
Disease Recurrence or Metastases
SizeMitotic
CountStomach Duodenum
Jejunum /
IleumRectum
≤ 2 cm
≤ 5 per 50
HPFs
0 0 0 0
> 2, ≤ 5 cm 1.9 8.3 4.3 8.5
> 5, ≤ 10 cm 3.6
} 34
24
} 57> 10 cm 12 52
≤ 2 cm
> 5 per 50
HPF
* * * 54
> 2, ≤ 5 cm 16 50 73 52
> 5, ≤ 10 cm 55
} 86
85
} 71> 10 cm 86 90
* Too few cases
Miettinen & Lasota. Semin Diagn Pathol., 2006; 23:70-83.5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
Risk of recurrence of GIST after surgery: An
analysis of pooled population-based cohorts
Joensuu et al. Lancet Oncol. 2012; 13:265-74.5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
STOP Imatinib
An open-label phase III study in high risk patient in
CR after 3 years of adjuvant imatinib
Imatinib for 36 / 24 months
Follow-up
Follow-up
Ongoing trials: ImadGIST & SSG XXII
Random
Assignment
1:1
Stratification:
1) Tumour rupture
2) Risk <80%
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Imatinib interruption
in advanced GIST - PFS
Blay et al. J Clin Oncol. 2007; 25:1107-13; Le Cesne et al. Lancet Oncol. 2010; 11: 942-49; Bertucci et al. J Clin Oncol. 2012: 30
[abstract 10095]5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Median PFS
(months)6 / 19
3-year
estimate (%)5 / 17
P value
(logrank test)0.017
KIT exon 9 mutants (10% of patients)
KIT exon 9 mutants: 400 mg / 800 mg
Other patients: 400 mg / 800 mg
0 1 2 3 4 50
10
20
30
40
50
60
70
80
90
100
Years
GIST Are at Least 10 Diseases
Blay JY, et al. Discov Med. 2012;13:357-367.
Dose Adjuvant
KIT
KIT exon 11 Im 400 +
KIT exon 9 Im 800 +
KIT ex 13,14,17 Im 400 ?
PDGFRA
Non-D842V Im 400 +
D842V: 0 0
KIT/PDGFR WT Im 400 +/-
NF1 ?/Im 400 +/?
SDHB ?/Im 400 +/?
Raf ? ?
others ? ?
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PDGFRA GIST
in the advanced phase
MonthsC
um
ula
tiv
e s
urv
ival p
rob
ab
ilit
y
Months
Pro
bab
ilit
y o
f P
rog
ressio
n-f
ree s
urv
ival
Cassier et al. Clin Cancer Res. 2012; 18: 4458-64.5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Tumor regression across all dose levels in PDGFRa
D842-mutant GIST (central radiology review)
78
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
A randomized trial of surgery in metastatic GIST
Shi et al Eur J Cancer 2014
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Sunitinib and regorafenib
Second and Third line agents
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Secondary GIST Mutations in Patients Progressing on Imatinib or Sunitinib
Distribution of secondary mutations (n = 27) DHPLC
65
4
67
0
82
9
82
3
82
2
82
2
82
0
82
0
81
6V T AD YNNDD
Exon 13 Exon 14 Exon 17 Exon 18
A I PH DKYYG
Drug/ATP binding pocket 42.9%
Kinase activation loop 57.1%
-
-Exon 11
Exon 9
Exon 13
Primary KITMutation
544 550 580 589 976937
KIT Kinase Domain
V654 T670K623 810 830
Exon 11 deletions
P-loopActivation
loopCatalytic
loop
DHPLC, denaturing high-pressure liquid chromatography.Liegl B, et al. J Pathol. 2008;216(1):64-74; Wilhelm S. 2006; Patent #WO2007059154 A2, C’KIT Cytoplasmic Domain figure.5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
BLU-285 Phase 1 study
Advanced GIST MTD
Part 2
Dose expansion enrolling
Unresectable GIST after imatinib
and ≥1 other TKI (n=50)
PDGFRa D842V-mutant GIST (n=50)
Part 1
Dose escalation completed
Key objectives
• Part 1: MTD, safety, pharmacokinetics, ctDNA analyses, anti-tumor activity
• Part 2: response rate, duration of response, safety
• 3+3 design with enrichment
• Dose levels: 30, 60, 90, 135,
200, 300, 400 and 600 mg QD
• MTD determined to be 400 mg PO QD
84
Important clinical activity in heavily pre-treated
KIT-mutant GIST
Central radiographic review
* 1 confirmed, 1 pending confirmation
↑ PFS with BLU-285 ≥300 mgBest
response
(N=25)
Choi Criteria
n (%)
RECIST 1.1
n (%)
PR 8 (32) 2* (8)
SD 6 (24) 12 (48)
DCR (PR + SD) 14 (56) 14 (56)
PD 11 (44) 11 (44)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
2017 ESMO – Proffered Paper
Encouraging activity of novel pan-KIT and
PDGFRa inhibitor DCC-2618 in patients (pts)
with Gastrointestinal Stromal Tumor (GIST)
F Janku, A Razak, M Gordon, D Flynn, M Kaufman, J Pitman,
B Smith, N Somaiah, J Jennings, S Salah, D Westwood, D
Greensmith, J Jacobson, O Rosen, S George
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
86
Despite small sample size results suggest that doses of 40 or 60 mg/d are insufficient
Supported by outcome in patient at 30 mg BID following dose escalation (not shown)
mPFS cannot be determined
mPFS is 15.2 weeks (CI 4.4 to 24)
Encouraging activity of novel pan-KIT and PDGFRa
inhibitor DCC-2618 in patients (pts) with Gastrointestinal
Stromal Tumor (GIST)
F Janku, A Razak, M Gordon, D Flynn, M Kaufman, J Pitman,
B Smith, N Somaiah, J Jennings, S Salah, D Westwood, D
Greensmith, J Jacobson, O Rosen, S George
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Accessed at https://clinicaltrials.gov/ct2/show/NCT02365441.
Study Schema: ALT-GISTA randomized phase II trial of imatinib ALTernating with regorafenib
compared with imatinib alone for the first-line treatment of
advanced gastrointestinal stromal tumor (GIST)
Stratify by:• Prior
adjuvant therapy (Y/N)
• Site• Commenced
imatinib for metastatic disease <21 days prior (Y/N)
RANDOMI ZATI ON
Cycle 1
Imatinib
for
between
21 and 25
days*
3-
7
da
y
ga
p
7
da
y
ga
p
Regorafenib
for 21 days
Continuous Imatinib Continuous Imatinib
Cycle 1Cycle 2 and
ongoing
Cycle 2 and ongoing
Imatinib
for
between
21 and 25
days
3-
7
da
y
ga
p
7
d
a
y
g
a
p
Regorafenib
for 21 days
28 days in total 28 days in total
ARM A
ARM B
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Intermediate conclusions : GISTs
• Molecular characterization routine• Different diseases
• Localized phase: SURGERY and adjuvant medical treatment
• Advanced phase: MEDICAL TREATMENT (Im, Su, Re) and surgery
• Reference centers
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Summary and close
• >100 subtypes/ complex diagnostic, value of molecularbiology
• Biopathology
• Local treatment in expert centers
• Systemic treatments : cytotoxics and targetedtreatments
• New paradigms for cancer treatments
• National networks
• International collaboration5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
RARE SOLID ADULT CANCERS
Melanoma Patient Network Europe
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
