By David A Liebner, MD June 18, 2016

1. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
2016 ASCO Update:
Sarcoma
David A Liebner, MD
June 18, 2016

2. Ewing Sarcoma
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3. EURO-E.W.I.N.G. 99
§ Large, multicenter study of Ewing Sarcoma open to all newly
diagnosed patients with Ewing Sarcoma <50 yrs
§ Initial study design 1997
§ Stratified by risk-category at presentation:
§ R1: Standard-risk localized disease (Le Deley et al., JCO 2014)
§ R2Loc: High-risk localized disease
§ R2Pulm: Metastatic to lung only
§ R3: Disseminated multifocal disease (Ladenstein et al., JCO
2010)
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4. EURO-E.W.I.N.G. 99
R2Loc
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5. EURO-E.W.I.N.G 99: High-Risk Localized Dz
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6. 6
EURO-E.W.I.N.G 99: R2Loc
Treatment Randomization

7. EURO-E.W.I.N.G 99: R2Loc
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8. EURO-E.W.I.N.G 99: R2Loc
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9. EURO-E.W.I.N.G 99: R2Loc
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10. Subset analyses
§ Suggests benefit may be
greatest in patients <25 yrs
§ Not statistically significant
(p=0.12)
§ Similar to other studies of dose-
intensification in EwS
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11. EURO-E.W.I.N.G 99: R2Loc
Acute Toxicites
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12. EURO-E.W.I.N.G. 99: Rationale R2Loc
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13. Take Home: EURO-E.W.I.N.G. 99 (R2Loc)
§ Consolidation with BuMel x1 is associated with
improvements in EFS (HR = 0.64) and OS (HR = 0.60) in
patients with:
1. High-risk localized disease (R2Loc)
2. Treated with induction chemotherapy with VIDE x 6 cycles
3. Who are candidates for high-dose chemotherapy with
stem-cell rescue
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14. Discussion
§ Challenges to generalization of EURO-E.W.I.N.G. 99 results:
1. VIDE induction chemotherapy is not the standard backbone
for EwS in the United States
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15. AEWS0031: Dose-Dense Therapy in Localized
Ewing Sarcoma
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16. AEWS0031: Impact on EFS and OS
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5-yr EFS: 73% vs 65%
HR = 0.74 (p = 0.048)
5-yr OS: 83% vs 77%
HR = 0.69 (p = 0.056)

17. Discussion
§ Challenges to generalization of EURO-E.W.I.N.G. 99 results:
1. VIDE induction chemotherapy is not the standard backbone
for EwS in the United States
2. Among patients eligible for treatment on the R2Loc protocol,
only 216 of 477 were randomized (45%)
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18. EURO-E.W.I.N.G. 99 R2Loc:
Challenges to Accrual
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19. Discussion
§ Challenges to generalization of EURO-E.W.I.N.G. 99 results:
1. VIDE induction chemotherapy is not the standard backbone
for EwS in the United States
2. Among patients eligible for treatment on the R2Loc protocol,
only 216 of 477 were randomized (45%)
3. Patients > 25 yrs did not clearly benefit
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20. Take Home: EURO-E.W.I.N.G. 99 (R2Loc)
§ Impact of BuMel x 1 on EFS and OS is NOT clear for:
1. Patients treated with an alternative induction regimen (e.g.,
VDC/IE), particularly dose-dense therapy
2. The subset of patients with R2Loc disease who did not
meet study criteria or who elected not to enroll (~55% of
eligible subjects)
3. Patients >25 yrs did not clearly benefit
§ Standard-of-care in the U.S. will likely remain dose-dense
VDC/IE
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21. EURO-E.W.I.N.G. 99
R2Pulm
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22. EURO-E.W.I.N.G 99: Pulmonary Metastases
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23. EURO-E.W.I.N.G 99: R2Pulm
Treatment Randomization
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24. Discussion: Challenges to Generalization
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25. EURO-E.W.I.N.G 99: R2Pulm
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26. EURO-E.W.I.N.G 99: R2Pulm
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27. EURO-E.W.I.N.G 99: R2Pulm
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28. Subset analyses
§ Suggests possible impact of
histologic response on optimal
consolidation regimen:
§ VAI + WLI better in patients
with a suboptimal response to
induction therapy with VIDE
§ BuMel better for patients with a
good response to induction
therapy
§ Possible association with
patient age as well
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29. EURO-E.W.I.N.G 99: R2Pulm
Acute Toxicites
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30. Take Home: EURO-E.W.I.N.G. 99 (R2Pulm)
§ Consolidation with BuMel x1 is NOT associated with
improvements in EFS or OS in patients with:
1. Pulmonary metastatic disease (R2Pulm)
2. Treated with induction chemotherapy with VIDE x 6 cycles
3. Who are candidates for high-dose chemotherapy with
stem-cell rescue
§ Subset analyses suggest:
1. A possible benefit to BuMel x 1 in patients with the best
responses to induction chemotherapy (<10% viable cells)
2. A possible benefit to VAI + WLI in patients with the worst
responses to induction chemotherapy (>30% viable cells)
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31. Take Home: EURO-E.W.I.N.G. 99 (R2Pulm)
§ Impact of BuMel x 1 on EFS and OS is difficult to generalize
to:
1. Patients treated with an alternative induction regimen (e.g.,
VDC/IE)
2. The subset of patients with R2Pulm disease who did not
meet study criteria or who elected not to enroll (~54% of
eligible subjects)
§ Long-term follow-up will be needed given concerns for
potential long-term toxicities of WLI and BuMel with stem-
cell rescue
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32. Immunotherapy
in Sarcoma
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33. An Ode to Coley!
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Nature Reviews Cancer 9, 361-371 (May 2009)

34. Ongoing Trials of Immunotherapy in Sarcoma
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35. SARC 028
Pembrolizumab
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36. SARC 028: Pembrolizumab in Sarcoma
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37. SARC 028: Pembrolizumab in Sarcoma
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38. SARC 028: Pembrolizumab (STS)
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39. SARC 028: Pembrolizumab (STS)
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40. SARC 028: Pembrolizumab (STS)
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41. SARC 028: Pembrolizumab (STS)
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42. SARC 028: Pembrolizumab (Bone Sarcoma)
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43. SARC 028: Pembrolizumab (Bone Sarcoma)
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44. SARC 028: Pembrolizumab (Bone Sarcoma)
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45. NCI-2014-02403
Nivolumab in uLMS
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46. Nivolumab in Uterine Leiomyosarcoma (uLMS)
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§ ≥1 response (RECIST 1.1) in stage 1 (n=12) required to open Stage 2

47. Nivolumab in uLMS
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• No objective responses noted:
(ORR = 0%)
• Median PFS = 1.8 mo

48. Take Home: PD-1 inhibitors in Sarcoma
§ PD-1 inhibitor therapy in bone and soft-tissue sarcoma was
well-tolerated with no unexpected toxicities
§ Response rates (RECIST) appear to vary by histology
though sample sizes are small and definitive conclusions are
not possible at this phase:
§ Soft-tissue sarcoma (SARC 028): 19% (7/37)
§ Bone sarcoma (SARC 028): 5% (2/38)
§ Uterine leiomyosarcoma: 0% (0/12)
§ Ongoing assessment of efficacy on trial is strongly
preferred
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49. Promising Signal of PD-1 Inhibition in STS
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KEYNOTE-001 (NSCLC)SARC 028 (STS)
ORR = 19%
Median PFS = 4.2 mo
ORR = 19.4%
Median PFS = 3.7 mo

50. TKIs in Soft-
Tissue Sarcoma
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51. Regorafenib in
non-GIST Sarcoma
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52. Regorafenib in non-GIST Sarcoma
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• Placebo-controlled cross-over study of regorafenib in doxorubicin pre-treated
STS (4 cohorts) conducted in France/Austria

53. Regorafenib in non-GIST Sarcoma
§ Relatively few patients had received a prior TKI (pazopanib)
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54. Regorafenib in non-GIST Sarcoma: PFS
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55. Regorafenib in non-GIST Sarcoma: PFS
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56. Take Home
§ Regorafenib is associated with improved PFS (HR = 0.36)
compared to placebo in patients with non-adipocytic soft-
tissue sarcoma
§ Median PFS improved by 3 months (4.0 mo vs 1.0 mo) which
is comparable to the results seen in the phase 3 PALETTE
study which led to the approval of pazopanib for non-adipocytic
STS
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57. Take Home
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PALETTE trial
(Lancet. 2012 May 19;379(9829):1879-86.)

58. Take Home
§ Regorafenib is associated with improved PFS (HR = 0.36)
compared to placebo in patients with non-adipocytic soft-
tissue sarcoma
§ Median PFS improved by 3 months (4.0 mo vs 1.0 mo) which
is comparable to the results seen in the phase 3 PALETTE
study which led to the approval of pazopanib
§ The study was not designed to detect any improvement in OS
§ Efficacy of regorafenib in patients with pazopanib-
refractory disease is unknown due to small sample size
§ Pazopanib remains the preferred 1st line TKI in non-
adipocytic STS
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59. PAPAGEMO:
Pazopanib ± Gemcitabine
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60. PAPAGEMO: Pazopanib +/- Gemcitabine in STS
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61. PAPAGEMO: Pazopanib +/- Gemcitabine in STS
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62. PAPAGEMO: Primary Endpoint (PFS)
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63. PAPAGEMO: Secondary Endpoint (OS)
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64. PAPAGEMO: Toxicity
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65. Take Home: PAPAGEMO
§ Combination therapy with pazopanib + gemcitabine is
associated with improved PFS compared to pazopanib
alone (HR = 0.58)
§ There is no impact on OS
§ Combination therapy was more toxic (SAE 54% vs 16.3%)
and potentially associated with 2 toxic deaths
§ Combination therapy cannot be recommended at this time
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66. Thank You
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