1. Biology of Sarcomas
“The first thing that the general medical oncologist has to realize is that the parallel word to sarcoma is actually carcinoma, not, say, breast cancer or lung cancer. Sarcomas represent a group of up to 100 different diseases, depending on how they count them – some benign, some heavily aggressively malignant – that all have different biology, have underlying different genetics and actually are just, frankly, very different diseases with different approaches. And so as you kind of get down to the next level of ‘what do they have in common,’ the only thing they have in common is the mesenchymal origin.”
Brian A Van Tine, MD, PhD

2. Management of Sarcomas
One would not administer a single agent for prostate, lung and breast cancer as a whole and expect to see a lot of activity.
However, this is what has been traditionally done in sarcoma with agents like doxorubicin, resulting in low response rates.
Brian A Van Tine, MD, PhD

3. Management of Sarcomas
One would not administer a single agent for prostate, lung and breast cancer as a whole and expect to see a lot of activity.
However, this is what has been traditionally done in sarcoma with agents like doxorubicin, resulting in low response rates.
According to the NCCN Guidelines, “Prior to the initiation of therapy, all patients should be evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma.”
I believe that this is really important.
Brian A Van Tine, MD, PhD

4. Results from the Phase II Trial of Olaratumab and Doxorubicin in Sarcoma
Olaratumab + doxorubicin
(n = 66)
Olaratumab until progression
Eligibility (n = 133)
Advanced soft tissue sarcoma
ECOG PS ≤2
No previous anthracycline R
Optional olaratumab until progression
Doxorubicin
(n = 67)
Outcome
Olaratumab + doxorubicin
Doxorubicin HR
p-value
Median OS
26.5 mo
14.7 mo
0.46
0.0003
OS = overall survival
Phase III ANNOUNCE trial of olaratumub/doxorubicin is ongoing
Tap WD et al. Lancet 2016;388(10043):

5. Treatment Options for Sarcoma
Stage I sarcoma tumors are usually more appropriate for surgery.
In Stage II and III sarcoma, the first question is diagnosis. Depending on the diagnosis, treatment may involve neoadjuvant therapy, radiation therapy and/or surgery.
This is why experience with multidisciplinary team planning of the appropriate treatment approach is so important.
For Stage IV disease, several questions need to be answered, such as the type of Stage IV sarcoma, how extensive the disease is and how therapy can be personalized.
Brian A Van Tine, MD, PhD

6. Mechanism of Action of Trabectedin
Trabectedin is a marine alkaloid isolate with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings:
Two of these rings provide the framework for covalent interaction with the minor groove of the DNA double helix.
The third ring protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins.
Several clinical studies of the combination of trabectedin with other anticancer agents are ongoing.
D'Incalci M, Galmarini CM. Mol Cancer Ther 2010;9(8):

7. Phase III ET743-SAR-3007 Trial: Incidence of  Select Adverse Events with Trabectedin for Metastatic Liposarcoma or Leiomyosarcoma After Chemotherapy
Trabectedin (n = 340)
Dacarbazine (n = 155)
All grades
Grade 3 or 4
Neutropenia
49%
37%
29%
21%
ALT increase
45%
26% 6% 1%
Anemia
39%
14%
12%
AST increase
35%
13% 5% 0%
Thrombocytopenia
30%
17%
36%
18%
Blood alkaline phosphatase increase
20% 7%
Demetri GD et al. J Clin Oncol 2016;34(8):

8. ET743-SAR-3007: Trial Schema and Results
Eligibility (n = 518)
Advanced liposarcoma or leiomyosarcoma
Failure of an anthracycline and ≥1 additional systemic regimen
Trabectedin
(n = 345) R
Dacarbazine
(n = 173)
Survival
Trabectedin
Dacarbazine HR
p-value
Median OS
12.4 mo
12.9 mo
0.87
0.37
Median PFS
4.2 mo
1.5 mo
0.55
<0.001
Demetri GD et al. J Clin Oncol 2016;34(8):

9. ET743-SAR-3007 and E7389-G000-309 Phase III Trials for Patients with Soft Tissue Sarcomas
Trabectedin
(n = 345)
Dacarbazine
(n = 173) HR
p-value
Median OS
12.4 mo
12.9 mo
0.87
0.37
Median PFS
4.2 mo
1.5 mo
0.55
<0.001
E7389-G
Eribulin
(n = 228)
(n = 224)
13.5 mo
11.5 mo
0.77
0.0169
2.6 mo
0.88
0.23
E7389-G trial2: Median OS with eribulin versus dacarbazine was longer for patients with liposarcoma (median OS 15.6 vs 8.4 mo) than for those with leiomyosarcoma (12.7 vs 13.0 mo).
1 Demetri GD et al. J Clin Oncol 2016;34(8):786-93;
2 Schoffski P et al. Lancet 2016;387(10028):

10. Results from the REGOSARC Phase II Trial for Advanced Soft Tissue Sarcomas
Regorafenib
Placebo HR
p-value
Liposarcomas
n = 20
n = 23
Median PFS
1.1 mo
1.7 mo
0.89
0.70
Leiomyosarcomas
n = 28
3.7 mo
1.8 mo
0.46
0.0045
Synovial sarcomas
n = 13
n = 14
5.6 mo
1.0 mo
0.10
<0.0001
Other sarcomas
n = 27
2.9 mo
0.0061
Mir O et al. Lancet Oncol 2016;17(12):

11. Perspective on the Utility of Pazopanib in the Management of Sarcoma
“I think pazopanib is a really useful drug. I think it’s got some dosing complications in the soft tissue sarcoma realm that I think are soon to be addressed with new trials. But I think it causes diarrhea. I think it causes fatigue. And I think that there’s a hepatotoxicity that has a black box warning. But beyond that, if you can get the dosing right — I personally use a dose escalation that’s not on label to get the tolerability in my patients to where it needs to be. I think it’s a good drug. And there is a subset of patients where that is a really good drug.”
Brian A Van Tine, MD, PhD

12. Results from the Phase II Trial of Olaratumab and Doxorubicin in Sarcoma
Olaratumab + doxorubicin
(n = 66)
Olaratumab until progression
Eligibility (n = 133)
Advanced soft tissue sarcoma
ECOG PS ≤2
No previous anthracycline R
Optional olaratumab until progression
Doxorubicin
(n = 67)
Outcome
Olaratumab + doxorubicin
Doxorubicin HR
p-value
Median OS
26.5 mo
14.7 mo
0.46
0.0003
Tap WD et al. Lancet 2016;388(10043):

13. Ongoing Phase III ANNOUNCE Trial Schema
Olaratumab + doxorubicin
Olaratumab until progression
Eligibility (n = 460)
Advanced unresectable soft tissue sarcoma
ECOG PS ≤1
No previous anthracycline therapy R
Placebo + doxorubicin
Placebo
until progression
Primary endpoint: Overall survival
NCT (Accessed April 2017).

14. Olaratumab/doxorubicin (n = 64)
Phase II Trial: Select Side Effects of Olaratumab/Doxorubicin versus Doxorubicin Alone
Event
Olaratumab/doxorubicin (n = 64)
Doxorubicin
(n = 65)
Any grade
Grade ≥3
Nausea
73% 2%
52% 3%
Neutropenia
58%
53%
35%
33%
Mucositis 5%
Vomiting
45% 0%
18%
Diarrhea
34%
23%
Febrile neutropenia
13%
14%
Tap WD et al. Lancet 2016;388(10043):

15. Risk Factors and Types of Sarcoma
Risk factors that predispose to sarcoma:
Li-Fraumeni syndrome
Adults with a childhood history of retinoblastoma
Several other genetic syndromes
Types of sarcoma:
Genetically complex sarcomas, including undifferentiated pleomorphic sarcomas and leiomyosarcoma
Genetically simple translocation-associated sarcomas, including myxoid/round cell liposarcoma, synovial sarcoma and alveolar soft part sarcoma
Others, such as dedifferentiated liposarcoma
Seth M Pollack, MD

16. What are the therapeutic options?
Case Discussion
A 55-year-old woman with Li-Fraumeni syndrome
History of sarcoma: 2 sarcoma diagnoses as a child and as an adolescent
Previous anthracycline-based chemotherapy, radiation therapy and several surgical procedures
At 53, she developed a 12-cm high-grade, unresectable dedifferentiated liposarcoma in her mediastinum
What are the therapeutic options?

17. Patient received trabectedin on the expanded access trabectedin trial
Case Discussion
A 55-year-old woman with Li-Fraumeni syndrome
History of sarcoma: 2 sarcoma diagnoses as a child and as an adolescent
Previous anthracycline-based chemotherapy, radiation therapy and several surgical procedures
At 53, she developed a 12-cm high-grade, unresectable dedifferentiated liposarcoma in her mediastinum
Patient received trabectedin on the expanded access trabectedin trial

18. Case Discussion
A 55-year-old woman with Li-Fraumeni syndrome
History of sarcoma: 2 sarcoma diagnoses as a child and as an adolescent
Previous anthracycline-based chemotherapy, radiation therapy and several surgical procedures
At 53, she developed a 12-cm high-grade, unresectable dedifferentiated liposarcoma in her mediastinum
Trabectedin x 16 on the expanded access trabectedin trial  stable disease (SD) with several tolerability issues  disease progression  eribulin and SD for 12 months

19. Phase III E7389-G000-309 Trial for Patients with Soft Tissue Sarcoma
Outcome
Eribulin
(n = 228)
Dacarbazine
(n = 224) HR
p-value
Median OS
13.5 mo
11.5 mo
0.77
0.0169
Median PFS
2.6 mo
0.88
0.23
Median OS with eribulin versus dacarbazine was longer for patients with liposarcoma than for those with leiomyosarcoma:
Liposarcoma 15.6 mo versus 8.4 mo
Leiomyosarcoma 12.7 mo versus 13.0 mo
Schoffski P et al. Lancet 2016;387(10028):

20. Phase III ET743-SAR-3007 Trial Results
Eligibility (n = 518)
Advanced liposarcoma or leiomyosarcoma
Failure of an anthracycline and ≥1 additional systemic regimen
Trabectedin
(n = 345) R
Dacarbazine
(n = 173)
Survival
Trabectedin
Dacarbazine HR
p-value
Median OS
12.4 mo
12.9 mo
0.87
0.37
Median PFS
4.2 mo
1.5 mo
0.55
<0.001
Demetri GD et al. J Clin Oncol 2016;34(8):

21. Results form the Phase II Trial of Olaratumab and Doxorubicin in Sarcoma
Olaratumab + doxorubicin
(n = 66)
Olaratumab until progression
Eligibility (n = 133)
Advanced soft tissue sarcoma
ECOG PS ≤2
No previous anthracycline R
Optional olaratumab until progression
Doxorubicin
(n = 67)
Outcome
Olaratumab + doxorubicin
Doxorubicin HR
p-value
Median OS
26.5 mo
14.7 mo
0.46
0.0003
Median PFS
6.6 mo
4.1 mo
0.67
0.0615
Tap WD et al. Lancet 2016;388(10043):

22. Olaratumab/Doxorubicin
Phase II Trial: Select Side Effects of Olaratumab/Doxorubicin versus Doxorubicin Alone
Event
Olaratumab/Doxorubicin
(n = 64)
Doxorubicin
(n = 65)
Any grade
Grade ≥3
Nausea
73% 2%
52% 3%
Fatigue
69% 9%
Neutropenia
58%
53%
35%
33%
Anemia
41%
13%
37%
Leukopenia
36%
18%
17%
Diarrhea
34%
23% 0%
Tap WD et al. Lancet 2016;388(10043):

23. Ongoing Phase III ANNOUNCE Trial Schema
Olaratumab + doxorubicin
Olaratumab until progression
Eligibility (n = 460)
Advanced unresectable soft tissue sarcoma
ECOG PS ≤1
No previous anthracycline therapy R
Placebo + doxorubicin
Placebo
until progression
Primary endpoint: Overall survival
Secondary endpoints include PFS, response and quality of life
NCT (Accessed April 2017).

24. SARC 028: A Phase II Trial of the Anti-PD-1 Antibody Pembrolizumab in Advanced Soft Tissue Sarcoma
40 patients with soft tissue sarcoma enrolled on study
Sarcoma type PR SD
Undifferentiated pleomorphic sarcoma (n = 9)
4 (44%)
3 (33%)
Liposarcoma (n = 9)
2 (22%)
Synovial sarcoma (n = 9)
1 (11%)
Leiomyosarcoma (n = 10)
6 (60%)
Three patients have not reached first scan assessment.
Abdul-Hassan H et al. Proc ASCO 2016;Abstract