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Controversies and State-of-the Art Systemic Treatment in Soft Tissue
Sarcoma
Farid Associate Consultant Medical Oncology National Cancer Centre Singapore 2 March 2013
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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Cancer treatment must be founded upon :
–Clear definition of therapeutic objectives
– Sound biological principles (pertaining to both disease and therapy)
– Scientifically and clinically meaningful metric of failure and success
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Chmielowski et al Expert Rev Anticancer Ther 2012
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Chmielowski et al Expert Rev Anticancer Ther 2012
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Van Glabbeke et al EJC 2002
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Van Glabbeke et al EJC 2002
… for first-line therapy, a 6-month PFR of ≥ 30-56% (depending on
histology) can be considered as a reference value to suggest drug
activity; for second-line therapy, a 3-month PFR of ≥ 40% would
suggest a drug activity, and ≤ 20% would suggest inactivity.
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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GIST 23%
UPS/MFH 14%
Leiomyo sarcoma
11%
Lipo sarcoma
11% Angiosarcoma
6%
Osteosarcoma 5%
Synovial sarcoma
4%
Ewings / PNET 3%
Myxofibrosarcoma 3%
Chondrosarcoma 2%
Rhabdomyo sarcoma 2%
Hemangiopericytoma /SFT 1%
NCCS Sarcomas 2002 - 2012 Dermatofibrosarcoma Protruberans
MPNST
Endometrial stromal sarcoma
Hemangiopericytoma/SFT
Desmoid/Fibromatosis
Epitheloid sarcoma
Fibrosarcoma
Sarcoma, nos
Chordoma
Alveolar soft part sarcoma
Fibromyxoid Sarcoma
Giant Cell Tumour of Bone
Others
N = 1245
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GIST 23%
UPS/MFH 14%
Leiomyo sarcoma
11%
Lipo sarcoma
11% Angiosarcoma
6%
Osteosarcoma 5%
Synovial sarcoma
4%
Ewings / PNET 3%
Myxofibrosarcoma 3%
Chondrosarcoma 2%
Rhabdomyo sarcoma 2%
Hemangiopericytoma /SFT 1%
NCCS Sarcomas 2002 - 2012 Dermatofibrosarcoma Protruberans
MPNST
Endometrial stromal sarcoma
Hemangiopericytoma/SFT
Desmoid/Fibromatosis
Epitheloid sarcoma
Fibrosarcoma
Sarcoma, nos
Chordoma
Alveolar soft part sarcoma
Fibromyxoid Sarcoma
Giant Cell Tumour of Bone
Others
N = 1245
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UPS/MFH 22%
Leiomyosarcoma 17%
Liposarcoma 16%
Angio -sarcoma
8%
Synovial sarcoma
6%
Myxofibrosarcoma 4%
Rhabdomyosarcoma 3%
DFSP 3%
MPNST 3%
Endometrial stromal sarcoma3%
Hemangiopericytoma /SFT 2%
Desmoid/Fibromatosis 2%
Epitheloid sarcoma 2%
4%
NCCS STS 2002-2012
Fibrosarcoma
Sarcoma, nos
Alveolar soft part sarcoma
Fibromyxoid Sarcoma
Others
N = 816
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“Cancer biology trumps clinical empiricism”
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ESMO 2012 plenary session from EORTC STBSG 62012
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EORTC 62012 ESMO 2012
n = 455
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EORTC 62012 ESMO 2012
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EORTC 62012 ESMO 2012
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EORTC 62012 ESMO 2012
12.8 m 14.3 m
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1st line • Anthracycline +/- Ifosfamide
2nd Line
• Gemcitabine - Docetaxel
• Trabectedin
• Pazopanib
• Gemcitabine-Navelbine, Dacarbazine, Temozolamide
Nth line
• Off label vs Trials if available
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Targeting the VEGF Pathway with Tyrosine Kinase Inhibitors
Rini et al Exp Opinion Pharmacother 2011
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Pazopanib
Van der Graaf et al Lancet 2012
- Non- adipocytic, non GIST
- ≥ 1 regimen containing anthracycline, ≤ 4 lines of systemic therapy for metastatic disease (≤ 2 lines of combination regimens).
- No previous anti-VEGF treatment
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PFS OS
Van der Graaf et al Lancet 2012
Pazopanib in STS : The PALETTE Study
ORR (Pazopanib) : 6% ORR (Placebo) : 0%
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Karavasilis et al Cancer 2008 Minchom et al Sarcoma 2010
OS in metastatic STS
1st line chemo n = 488 (1991 – 2005) 2nd line chemo
n = 379 (1991 – 2005)
mOS 12m
mOS 8m
5y OS 10%
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Improving OS with time?
n = 1024 (1987 – 2006)
mOS 12m
mOS 18m
Italiano et al Cancer 2011
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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Different Behaviour of Different Histological Subsets of STS Treated Similarly
n = 2185 All treated with anthracyclines in 1st line
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Antman et al J Clin Oncol. 1993;11:1276-85
Different Behaviour of Different Histological Subsets of STS Treated Similarly
A MAP AI
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Histo / Regimen
LMS Gem + Tax
LPS (myxoid)
Trabectedin
AS Pacli taxel
Initially exciting results from small / retrospective series ….
In a single-arm phase II study (n=34) comprised primarily of pts with uterine LMS, ORR of 53% was achieved (Hensley JCO 2002). Subsequent evaluation of the regimen in uterine LMS in both the first and second line continued to demonstrate promising activity.
A retrospective review (n=51) of international pts with myxoid LPS ORR of 51%, and a 6- mth PFR of 88% (Grosso et al, Lancet Oncol 2007). Longer term follow up of a single institution series corroborated these findings with median PFS of 17 m (Grosso et al Annals of Oncology 2009)
A small retrospective study demonstrated major responses in 8 out of 9 patients with scalp or face AS treated with Paclitaxel (Fata et al, Cancer 1999). A subsequent larger retrospective study demonstrated ORR of 75% in scalp AS and 58% in other primary sites (Schlemmer et al, EJC 2008).
More sobering data from prospective studies ….
In a randomised phase II study (n =90), of gemcitabine vs gemcitabine plus docetaxel in 2nd line, there were no significant efficacy differences between the 2 arms. ORR was 19% and 24% respectively for uterine, and 14 % and 5% respectively for non uterine. Median PFS was 5.5 m and 4.7 m respectively for uterine, and 6.3 m and 3.8 m respectively for non-uterine (Pautier et al, Oncologist 2012).
In a single arm phase II study (n = 23) of neoadjuvant chemotherapy in locally advanced previously untreated myxoid LPS, the ORR was 24%, with 3 patients (13%) achieving pathological CR (Gronchi et al, Annals of Oncology 2011).
In a single arm Phase II study ( n= 30) for all- comers, ORR was 18%, with a 2, 4, ad 6 month PFR of 74%, 45% and 24% respectively (Penel et al, JCO 2008).
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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Adjuvant Chemotherapy in Sarcoma
• Adjuvant chemotherapy aims to eradicate micro-metastatic disease to improve survival.
• What of STS?
• In GIST, Imatinib remains the first and only tyrosine kinase inhibitor to improve survival in adjuvant setting.
• In osteosarcoma and Ewing’s, cure rates improve from 20% to 60% with the addition of chemotherapy.
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EORTC I : 62771
1994 1997 2000s
SMAC I:
2008 2012
EORTC II : 62931
SMAC II :
Small Prospective
Studies
Adjuvant Chemotherapy in STS in last 2 decades
2000s
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EORTC I : 62771
1994 1997 2000s
SMAC I:
2008 2012
Adjuvant Chemotherapy in STS in last 2 decades
n = 1568, m f/up : 9 y
10 y L-RFI D-RFI RFS OS OS extremity STS
HR 0.73 0.70 0.75 0.89 0.80
Absolute benefit 6% 10% 10% 4% 10%
Interpretation : Positive study
Bramwell et al JCO 1994
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EORTC I : 62771
1994 1997 2000s
SMAC I:
2008 2012
EORTC II : 62931
SMAC II :
Small Prospective
Studies
Adjuvant Chemotherapy in STS in last 2 decades
2000s
N = 351 (1995 – 2003) m f/up 8 y
Resected intermediate / high grade sarcoma
5 cycles (Doxo 75 mg/m2 + Ifos 5g/m2 )
+/-RT
Woll et al Lancet Oncology 2012
+/-RT
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EORTC I : 62771
1994 1997 2000s
SMAC I:
2008 2012
EORTC II : 62931
SMAC II :
Small Prospective
Studies
Adjuvant Chemotherapy in STS in last 2 decades
LR- recurrence
OS RFS
D- recurrence
HR 0.94; 5y m OS 66% vs 67% mOS 11y vs 12y
HR 0.91; 5y RFS 55% vs 53% mRFS 7.5y vs 6.5y
Possible Limitations
Suboptimal Surgery ? - > 50% patients with unknown or close surgical margins (<5 mm)
Suboptimal Chemo ? - > Low ifosfamide dose (5g /m2)
Patient Heterogeneity ? - > (25% < 5 cm, central path grade High 46%, Intermediate 48%, Low 6%)
Woll et al Lancet Oncology 2012
5y LRR 19% vs 24% 5y DRR 35% vs 35%
NO DIFFERENCE in largest prospective study
in the modern era
Interpretation : Negative study
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Even if decision made for adj. chemotherapy, questions remain ….
• Optimal regimen? • Choice of drugs • Number of cycles
• Optimal patient selection?
• Impact of histology • Clinicopathologic risk factors
• Neoadjuvant approach?
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• Principles of Systemic Therapy
• Systemic Treatment in Unselected Patients
• Systemic Treatment in Enriched Populations
• Adjuvant Therapy
• Genomics, Novel Therapeutics and the Way Ahead
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Cancer is a genomic disease, driven by pathological alterations – mutations – to our genes that regulate cellular survival.
Cancer bears certain molecular pathogenetic hallmarks
Treating established cancer involves redressing these deviant cellular processes (e.g. abrogating aberrant proliferation or restoring pathologically shut-off apoptosis) Hanahan and Weinberg, Cell 2011
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A Genomic Approach to Sarcomas
Genetically / Karyotypically Simple
• Near diploid karyotypes
• Simple genetic alterations
• Usually arise denovo
• Single defining cytogenetic abnormality present at initiation, retained throughout clonal evolution
Genetically / Karyotypically Complex
• Genomically unstable
• Multiple genomic and chromosomal (numerical and structural) aberrations in single tumour; heterogeneity of aberrations across tumours of given type.
• Can arise from less aggressive form and pass through discrete stages of increasing complexity (though most high grade ones arise de novo without antecedent lower grade lesions).
• Reminiscent of most solid tumours
0 5 10 20 > 100 > 1000 mutations
GIST, DFSP EWING’s, RMS, DD LPS
LMS, OSTEOSARC, PLEOMORPHIC LPS
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Genomically Simple
Driven by pathognomonic translocations or point
mutations
Genomically Intermediate
Non translocation –associated sarcomas
characterized by few, but highly recurrent
amplifications (e.g DD LPS)
Genomically Comples Karyotypically complex arcomas that are heterogeneous, unstable and profoundly altered in genomic copy number.
0 5 10 20 > 100 > 1000 mutations
GIST, DFSP EWING’s, RMS, DD LPS
LMS, OSTEOSARC, PLEOMORPHIC LPS
A Genomic Approach to Sarcomas
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Genomic Copy Number Alterations
Transcriptional Target Dysregulation
Aberrant transcriptional proteins resulting from gene fusions secondary to recurrent
tumour specific translocations
Mutations in Key Genes and Signalling Pathways
Highly recurrent driver genes
Molecular Mechanisms of Sarcomagenesis
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Barretina et al Nat Genetics 2010
Some Key Findings : Mutations : - Tp53 (17% pl LPS) - NF1 (10.5% mxyF,
8% pl LPS) - PiK3CA (18% MRC)
Pathway Validation : - CDK4 in dD LPS
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Pathway Driven Therapeutics in Sarcoma
• ALK in inflammatory myofibroblastic tumour
• MDM2 in liposarcoma
• Hedgehog in chondrosarcoma
• mTOR in PEComa
• IGF1-R in Ewing’s / Solitary fibrous tumour
• ……
• ……
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G1
G2
G0
M
S
MDM2
CDK4
RB
p53
APOPTOSIS
PROLIFERATION
12q14
12q15
MDM2 / CDK4 Pathway
Amplicon 12q14-15 Cell survival proliferation
Cancer cell
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MDM2 / CDK4 Amplification in STS (LPS)
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Ray-Coquard Lancet Oncol 2012
Phase I MDM2 inhibitor in MDM2 amp. WD/DD LPS (n = 20)
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Taylor et al Nat Rv Cancer 2011
A Proposed Modern Phylogeny of Sarcoma Lineage Prognosis Driver alterations
Additional parameters.
Distal
Proximal
B R A N C H I N G
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Taylor et al Nature
Rv Cancer 2011
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Conclusions
• Improved apprehension of the genomic underpinnings of sarcomagenesis (leading to appropriate pathway driven therapeutics) has led to notable success, and holds much promise for the future.
• In unselected populations, traditional cytotoxics (anthracyclines +/- ifosfamide) remain the systemic therapy of choice in first line, with any of several agents (including novel cytotoxics and pathway inhibitors) showing meaningful benefit.
• In histologically selected populations, certain cytotoxic agents may have particular efficacy.
• The utility of adjuvant chemotherapy remains unproven.
• The median survival of advanced STS is 12-18 m.