Soft Tissue Sarcoma: Can We Refine The Approach? 1) Soft tissue sarcomas are a heterogeneous group of cancers accounting for 1% of malignancies with over 50 histological subtypes and poor outcomes for metastatic disease. 2) The PALETTE trial found that treatment with pazopanib resulted in a median progression-free survival of 20 weeks compared to 7 weeks for placebo, representing a 65% reduction in risk of disease progression or death. 3) Subgroup analyses showed benefit of pazopanib across patient characteristics including number of prior therapies. Pazopanib was generally well-tolerated with mainly grade 1-2 adverse events.

1. Soft Tissue Sarcoma:
Can We Refine The Approach?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University ACOD 2015 – Novartis Symposium
Helnan Palestine – 22/10/2015

2. Member of Advisory Board, Consultant, and Speaker for:
● Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer
Speaker Disclosures:

3. Fast Statistics & Challenges:
• 1% of all malignancies.
• More than 50 histopathological subtypes.
• Local Control is 75 – 80% after definitive surgery.
• 5 Year OAS  50% (Death From Metastases).
• 5 Year OAS (Isolated Operable Lung Deposits)  25%.
• Median survival = 12 months for metastatic disease.
• Grouped as 1 disease for many decades.

4. Improvement of Disease Specific
Survival: “DSS”
Proper
Surgery
Radiation
Therapy
Systemic
Therapy
Improvement in Local Control Eradication of Micrometastases

5. Sensitivity of STS to Systemic Agents:
● Very Sensitive:
Ewing/PNET, RMS, Desmoblastic Small Round Cell Tumor, GIST,
DFSP, Angiosarcoma, Myxoid/Round Cell Sarcoma, Synovial,
Leiomyosarcoma.
● Intermediately Sensitive:
MFH, Fibrosarcoma, MPNT, Hemangiopericytoma, Solitary Fibrous
Tumor, Heamgioendothelioma.
● Minimally Sensitive:
Extraskeletal Myxoid Chondrosarcoma, Epithelioid Sarcoma,
Dedifferentiated Liposarcoma, Perivascular Epithelioid Cell
Sarcoma.
● Resistant Histologies:
Alveolar Soft Part Sarcoma, Clear Cell Sarcoma, Melanoma of Soft
Parts, Conventional Chondrosarcoma, GI Leiomyosarcoma

6. High Risk Patients:
• High Grade Lesions.
• Large Tumors > 5 cm.
• Deep Lesions.
• Recurrent Tumors at Presentations.
• Leiomyosarcoma & PNST.
• Positive Margins.??
Van Glabbeke M, et al. J Clin Oncol. 1999;17:150

7. Histopathological Grading:

8. Classical Management for Non
Metastatic Disease:
• R0 Resection is the only curative management.
• Adjuvant Radiation Therapy:
1. High Grade Lesions.
2. Intermediate Grade with Positive Margins.
3. Low Grade Lesions with Positive Margins.
4. Recurrent Tumors.
5. Retroperitoneal Disease.
Local
Recurrence
10%
Amputation
Rate 5%
75% of All Patients with Localized Extremity STS will not Relapse
After Effective Local Treatment.
No Need For Further Therapy

9. • Neo-adjuvant + Surgery vs Surgery:
No Survival Advantage.
(Gortzak et al, Eur J Cancer; 2001)
• Neo-adjuvant vs Adjuvant:
No Superiority
(DeLaney et al, Int J Oncol Biol Phys; 2003).
Neo-Adjuvant Chemotherapy:

10. Results with Adjuvant Chemotherapy:
Endpoint HR Absolute Benefit P Value
Local RFI .73 6% .016
Distant RFI .70 10% .0003
Overall RFS .75 10% .0001
OAS (All Sites) .89 4% .12
OAS (Extremities) .80 7% .029
Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350:1647

11. Updated Results with Adjuvant
Chemotherapy:
Therapy Local
Recurrence
ARR (95%CI)
Distant
Recurrence
ARR (95%CI)
Any
Recurrence
ARR (95%CI)
Survival
ARR (95%CI)
A 3% 9% 9% 5%
AI 5% 10% 12% 11%
A or AI 4% 9% 10% 6%
Peraviz et al. Cancer. 2008;13:573
Treatment Related Toxicity

12. Primary Treatment of Non Metastatic STS:
Guidelines

13. Trials of Doxorubicin + Ifosfamide in
Metastatic Disease:
Dose (AI) Number RR %
50/5000/m2(a) 258 25
60/7500/m2(b) 88 34
75/5000/m2(c) 104 45
75-90/10000/m2(d) 79 65
(a) Santoro et al. JCO. 1995;13:1537.
(b) Edmonson et al. JCO. 1993;11:1269.
(c) Steward et al. 1993. JCO.11.15.
(d) Patel et al. Expert Opin Investig Drugs. 2000;9:1545.
• Growth Factor Support
• Treatment Related Toxicity

14. Metastatic STS: Other Regimens:
Soft Tissue Sarcoma Regimen
General Doxorubicin Single Agent.
Doxorubicin, Ifosfamide, Mesna (AIM)
Doxorubicin, Dacarbazine (AD)
Mesna, Doxorubicin, Ifosfamide, Mesna (MAID)
Gemcitabine, Docetaxel.
Gemcitabine, Vinoralbine.
Leiomyosarcoma Doxorubicin, Gemcitabine, Dacarbazine
Gemcitabine, Docetaxel
Myxoid Liposarcoma Anthracyclines
Trabectedin
Ifosfamide
G III Liposarcoma Ifosfamide
Angiosarcoma Paclitaxel or Docetaxel or Liposomal Doxorubicin
Desmoid Tumor Doxorubicin based or Methotrexate or Vinblastine or
Tamoxifen.

15. Soft Tissue Sarcoma:
Biological Key Players & Possible Targets
Characteristic Chromosomal
Translocation
Complex
Karyotypes
• Overexpression of Growth Factors
• Upregulation of Biological Cascades
++ Angiogenesis
Mahaling et al. Targeting sar- comas: novel biological agents and future perspectives. Curr Drug
Targets. 2009;10:937–49.
Soft Tissue Sarcoma
• High Grade
• Advanced Disease
• Metastases

16. Tyrosine Kinase Receptors
VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2
VEGFs
VEGF - A VEGF - B VEGF - C VEGF - D PlGF
Soft Tissue Sarcoma:
Biological Key Players & Possible Targets

17. VEGF
R
AKT
Grb SOS
mTOR
Protein Synthesis
HIF-1@
Metabolism
Growth
Angiogenesis
RAS
RAF
Mek
Erk
Cell Cycle Progression &
Proliferation
1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J
Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer
Healthcare Pharmaceuticals; 2007.
Bevacizumab
Everolimus
Soft Tissue Sarcoma:
Biological Key Players & Possible Targets

18. Soft Tissue Sarcoma:
Biological Key Players & Possible Targets
Kumar R et al. Mol Cancer Ther 2007;6:2012; Sonpavde G & Hutson TE. Curr Oncol Rep 2007;9:115;
GlaxoSmithKline. VOTRIENT® (pazopanib) SPC. 2012; 4. Kumar R et al. Br J Cancer 2009;101:1717.
Significant Anti-Angiogenic Effect

19. Matching placebo
(n=123)
Registration trial; PALETTE phase III:
Study design
Disease assessment
• At week 4, 8, 12, 20 and at 8-week intervals thereafter
VOTRIENT* (800 mg QD)
(n=246)
Secondary
endpoints
Primary
endpoint
OS
ORR
QoL
Safety
TTR
DoR
PFS by
independent
review
(RECIST v 1.0)
2:1n=369
R
A
N
D
O
MI
Z
E
DoR, duration of response; ORR, overall response rate; PFS, progression-free survival; QoL, quality of life;
QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response
*Until disease progression, unacceptable toxicity, withdrawal of consent for any reason or death
Van Der Graaf W et al. Lancet 2012;19:1879)

20. PALETTE: Included/excluded histological
subtypes
Included:1,2
● Fibroblastic
● Fibrohistiocytic
● Leiomyosarcoma
● Synovial sarcoma
● Malignant peripheral nerve sheath
tumours
● Sarcoma not otherwise specified (NOS)
● Vascular STS
● Malignant glomus tumours
20
References: 1. Van Der Graaf W et al. Lancet 2012;19:1879; 2. Van Der Graaf W et al. ASCO 2011; abstract LBA10002: oral presentation.
Excluded:1,2
• Adipocytic sarcoma
• Osteosarcoma
• Inflammatory myofibroblastic sarcoma
• Chondrosarcoma
• Dermatofibrosarcoma protuberans
• Mixed mesodermal uterine tumour
• GIST
• Mesothelioma
• Ewing’s sarcoma/PNET
• Non-alveolar and non-pleiomorphic
rhabdomyosarcoma

21. PALETTE: Patient demographics
PLACEBO
(n=123)
PAZOPANIB
(n=246)
Age
Median (years) 51 56
Range (years) (18–78) (20–83)
Performance status
(WHO)
0 60 (49%) 118 (48%)
1 63 (51%) 128 (52%)
Histology (by central
pathology or local if
unavailable)
Leiomyosarcoma 49 (40%) 109 (44%)
Synovial sarcoma 13 (11%) 25 (10%)
Other type 61 (49%) 112 (46%)
Grade at initial
diagnosis (local)
I / low 3 (2%) 24 (10%)
II / intermediate 30 (24%) 63 (26%)
III / high 90 (73%) 159 (65%)
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

22. PALETTE: Prior systemic therapies
PLACEBO (n=123) PAZOPANIB (n=246)
Prior (neo)adjuvant therapy 45 (37%) 74 (30%)
Prior systemic
therapy for
advanced disease
1st line 110 (89%) 232 (94%)
2nd line 67 (54%) 132 (54%)
3rd line 28 (23%) 51 (21%)
4th line 9 (7%) 16 (7%)
Including: Doxorubicin 121 (98%) 242 (98%)
Ifosfamide 93 (76%) 164 (67%)
Gemcitabine 42 (34%) 85 (35%)
Docetaxel 35 (28%) 69 (28%)
Trabectedin 22 (18%) 38 (15%)
mTOR inhibitor(s) 3 (2%) 11 (4%)
22
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

23. PALETTE: Median PFS nearly 3 times
greater than placebo at 20 weeks
REGULATORY
ANALYSIS
PLACEBO
(n=123)
VOTRIENT
(n=246)
Median PFS (weeks) 7.0 20.0
Median PFS (months) 1.6 4.6
Hazard ratio (95% CI) 0.35 (0.26, 0.48); p<0.001
CI, confidence interval; PFS, progression-free survival
1.0
Placebo
VOTRIENT
Time since randomization (weeks)
Estimatedsurvivalfunction
0.8
0.6
0.4
0.2
0.0
0 20 40 60 80 100

24. PALETTE: Progression-free survival
according to subgroup
24
Hazard ratio (95% CI)
Favours
pazopanib
Favours
placebo
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
Primary analysis (n=369)
Prior lines 0/1 (n=162)
Prior lines 2+ (n=207)
WHO PS 0 at baseline (n=178)
WHO PS 1 at baseline (n=191)
Recruited from US (n=43)
Recruited from Europe and Australia (n=245)
Recruited from Japan and Korea (n=81)
Leimoyosarcoma (n=158)
Other STS histology (n=173)
Synovial sarcoma (n=38)
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

25. PALETTE: Progression-free survival by
prior lines of treatment
Number of prior
lines of therapy
Median PFS (weeks),
95% CI
Hazard ratio,
95% CI p valuePlacebo Pazopanib
0/1
(n=162)
7.6
(4.3, 9.1)
24.7
(19.6, 27.4)
0.31
(0.19, 0.50)
<0.001
2+
(n=207)
6.1
(4.3, 8.1)
18.9
(11.9, 20.1)
0.39
(0.26, 0.57)
<0.001
Stratified log rank test and Pike estimator, independent reviewer, adjusted for WHO PS
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

26. PALETTE: Overall survival
26
REGULATORY ANALYSIS
PLACEBO
(n=123)
PAZOPANIB
(n=246)
Median OS (weeks) 46.5 54.8
Hazard ratio (95% CI) 0.87 (0.67, 1.12); p=0.256
CI, confidence interval; OS, overall survival
Placebo
Pazopanib
1.0
0.0
0.2
0.4
0.6
0.8
Estimatedsurvivalfunction
0 5 10 15 20 25 30 35
Time since randomization (months)
Reference: GlaxoSmithKline. VOTRIENT® (pazopanib) SPC. 2014; Sharma S et al. BMC Cancer 2013;13:385. Additional file 4.

27. PALETTE: Summary of best confirmed
response by independent review
● The median time to response* by independent review in the
pazopanib arm was 8.4 weeks (95% CI 4.7, 19.1)
● Median duration of response was 38.9 weeks (95% CI 16.7,
40.0) for pazopanib in the responder population
27
PLACEBO
(n=123)
PAZOPANIB
(n=246)
Response rate (complete
response + partial response)
0 (0%) 11 (4%)
Partial response 0 (0%) 11 (4%)
Stable disease 33 (27%) 134 (54%)
Progression 76 (62%) 66 (27%)
* Time to response was defined as the time from the start of treatment until the first documented evidence of complete response or partial response, whichever status was
recorded first
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

28. PALETTE: Adverse event overview
28
PLACEBO
(n=123)
PAZOPANIB
(n=240)*
On-therapy AEs by maximum grade
All Grades 110 (89%) 237 (99%)
Grade 3 23 (19%) 118 (49%)
Grade 4 7 (6%) 23 (10%)
Grade 5 4 (3%) 8 (3%)
All SAEs† 29 (24%) 99 (41%)
Fatal SAEs† 6 (5%) 8 (3%)
Discontinuations due to AEs‡ 3 (2%) 41 (17%)
Discontinuations due to drug-related AEs 1 (<1%) 34 (14%)
On-therapy treatment-related AEs (all grades) 78 (63%) 219 (91%)
AE, adverse event; SAE, serious adverse event
* Six patients (pazopanib arm) were excluded from safety population as they did not begin investigational product.
† Includes off therapy SAEs
‡ Primary reason for discontinuation
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

29. PALETTE: Newly identified serious
adverse events
ON-THERAPY AND
POST-THERAPY
ADVERSE EVENTS
PLACEBO
(n=123)
PAZOPANIB
(n=240)
Any
grade Grade 3 Grade 4
Any
grade Grade 3 Grade 4
Myocardial dysfunction* 6 (5%) – – 21 (9%) 3 (1%) 1 (<1%)
Venous thromboembolic
events
† 3 (2%) 1 (<1%) 2 (1%) 13 (5%) 5 (2%) 1 (<1%)
Pneumothorax – – – 8 (3%) – 1 (<1%)
SAEs with a higher incidence in the pazopanib-treated aSTS population
than in the pazopanib-treated aRCC population
29
* Grouping of MedDRA terms, including left ventricular dysfunction, cardiac failure, restrictive cardiomyopathy and
pulmonary oedema
† Fatal pulmonary embolus occurred in two of 240 patients treated with pazopanib
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

30. PALETTE*:Health-related quality of life
(HRQoL)
Patients receiving treatment with Pazopanib did not experience a clinically
meaningful or statistically significant deterioration in HRQoL compared with
placebo (p=0.291)1,3
Adapted from Sharma S et al. 2013 - Additional file 4.2
HRQoL was measured using the EORTC QLQ-C30 Global Health Status/HRQoL score
†For EORTC QLQ-C30, data were collected at baseline, week 4, week 8 and week 12.4
MID: Minimally important difference, 5 to 10. SE: Standard error. ITT: Intention to treat
1. van der Graaf W et al. Lancet 2012; 379: 1879-1886; supplementary appendix published online; 2. Sharma S et al. BMC Cancer 2013; 13: 385. Additional
file 4; 3. Sharma S et al. BMC Cancer 2013; 13: 385; 4. FDA Oncology Drug Advisory Committee Briefing Document, March 2012. Available at
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM296303.pdf(Accessed
February 2015)
*Phase III study excluded selective STS subtypes such as GIST and adipocytic sarcoma
Pazopanib (n=246)
Placebo (n=123)
Change from baseline in health-related quality of life (HRQoL, ITT population) 1,2†

31. Take Home Message:
● Soft-tissue sarcoma (STS) is a rare disease that encompasses over
50 separate histological subtypes with varying sensitivity to systemic
treatment
● Although Ifosfamide and doxorubicin remain important treatment
options in STS, therapy is increasingly tailored towards different
histological subtypes
● In post-Imatinib era; Targeted therapies such as tyrosine kinase
inhibitors will become increasingly important as we further define the
molecular basis of sarcomagenesis.
● Pazopanib is a recently approved option for advanced refractory STS
with significant prolongation of PFS and perfect compliance.
● Clinical trials remain a challenge due to the rarity and heterogeneity of STS
and international collaboration is critical to achieve high quality clinical trials
stratified by histological subtype.