1. Updates in Sarcoma
Benjamin Powers, MD
June 2019

2. Disclosures: I have no relevant financial relationships
and/or affiliations to disclose
I will be discussing off-label uses
and/or non-approved drugs,
due to the rarity of sarcoma

3. Background “Sarcoma” – <1% adult malignancies
~70 different types though!
Standard of care = surgical disease!
radiation +/- systemic therapy second rate?
(doxorubicin most active historically)
Metastatic, stage IV survival: not great

4. STRASS (EORTC 62092) study
phase III randomized, multicenter, international study of preoperative radiotherapy (50.4 Gy) plus surgery (RT/S) versus surgery alone (S) for patients with retroperitoneal sarcoma 266 patients (198 with liposarcoma) between January 2012 and April 2017 Re-operation rate for any complication was 10.9% vs 9.4% in RT/S versus S

5. STRASS (EORTC 62092) study
3-year Abdominal Recurrence Free-Survival (ARFS) was 60.4% vs 58.7% (HR = 1.01, 95%CI , p=0.954) in RT/S versus S groups. In the liposarcoma subgroup, 3-year ARFS (sensitivity analysis) was 71.6% ( %) and 60.4% ( %) in RT/S versus S groups (HR = 0.64, 95%CI , p =0.049). Should we be using neoadjuvant radiation in retroperitoneal liposarcomas?

8. PDGFR
autocrine PDGF stimulation contributes to proliferation of some human tumors
PDGFRα overexpression in many cancer types (osteosarcoma, glioma, lung, ovarian, melanoma, prostate, GISTs, etc)
Olaratumab: recombinant human IgG1 monoclonal antibody that specifically blocks the PDGF ligand binding and inhibits PDGFRa activation and downstream signaling (PI3K and MAPK pathways…)
Loizos et al. Mol Cancer Ther. 2005;4(3):369–79

10. Randomized in 1:1 ratio in 21 day cycles x 8 cycles
a.) olaratumab 15mg/kg IV d1 + 8 and doxorubicin (75mg/m2 IV push d1) vs
b.) doxorubicin alone (75mg/m2 IV push d1)
*both groups could receive olaratumab monotherapy after disease progression or after all 8 cycles
Randomized to balance patients based on
ECOG performance status (0–1 vs 2)
histological tumour type (leiomyosarcoma vs synovial sarcoma vs other)
immunohistochemical PDGFR expression (positive vs negative)**
previous lines of treatments (0 vs ≥1) line of treatment

11. Progression Free Survival
Overall Response Rate:
18.2% Olaratumab + Doxorubicin
11.9% Doxorubicin alone

12. did not predict outcomes?!
PDGFR-α expression
did not predict outcomes?!
Consistent across subtypes, lines of treatment, etc

13. Initial rates of survival
Median OS
26.5 months (O+D)
vs 14.7 months (D alone)
HR 0.46, 95% CI
39 dead in O+D arm = 38 from progression, 1 unknown
52 dead in D arm = 44 progression, 6 adverse events
1.) Why?

14. ANNOUNCE study
randomized, placebo-controlled, double-blind, phase III trial of doxorubicin (dox) + olaratumab versus dox + placebo in advanced soft tissue sarcomas 509 pts (258 dox + olara vs 251 dox + placebo) Median PFS 5.4 vs 6.8 months (HR=1.23, 95% CI: ; p = 0.04)

15. ANNOUNCE study
randomized, placebo-controlled, double-blind, phase III trial of doxorubicin (dox) + olaratumab versus dox + placebo in advanced soft tissue sarcomas Median OS 20.4 vs 19.8 months (HR=1.05, 95% CI: ; p = 0.69) FDA pulled approval of olaratumab Jan 2019!

16. Undifferentiated pleomorphic!
Soft tissue
Undifferentiated pleomorphic!
Dedifferentiated liposarcomas?
**NO MSI, TMB, PDL-1
data published?

17. SARC 028 expansion
additional 30 pts for a total of 40 UPS and 40 LPS pts ORR in UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs) ORR in LPS cohort was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs)

18. Bone: not so much?

20. What about bone sarcomas?
Cabozantinib – CABONE trial Sorafenib +/- everolimus – Italian Sarcoma Group Regorafenib – SARC024 Still not good enough…

21. GIST
Next generation KIT/PDGFR inhibitors
Avapritinib
DCC2618

22. Other targeted therapies?
Milademetan?: oral MDM2 inhibitor in WD/DD liposarcomas
Tazemetostat?: oral EZH2 inhibitor in sarcomas with INI deletion
Larotrectinib!: TRK fusion inhibitor!
Children:
Infantile fibrosarcoma
Congenital nephroma
Adults:
Secretory cancers of breast, salivary gland
Otherwise, good luck….

23. “Benign” tumors Desmoid tumor
Nirogacestat – gamma secretase inhibitor
Tenosynovial giant cell tumor (PVNS, GCTTS)
Pexidartinib – CSF1R inhibitor
Neurofibromatosis 1
MEK inhibitors – selumetinib, trametinib

24. Nirogacestat
Oral, noncompetitive, reversible, gamma secretase inhibitor
Activation of WNT pathway through Beta-catenin or APC mutations appears to be primary driver in desmoid tumors
Hypothesis that cooperativity exists between WNT pathway activation and active NOTCH signaling.
Inhibition of NOTCH may reverse activation of B-catenin
Hughes, D. P. M. et al. , “New, Tolerable γ-Secretase Inhibitor
Takes Desmoid Down a Notch”. Clinical Cancer Research 21, 7–

25. Pexidartinib Oral CSF1-R inhibitor
ENLIVEN study - double-blind, randomized, global, multicenter, phase III study – 120 pts with PVNS to pexidartinib vs placebo
39% vs 0% overall response rate at week 25
Most frequent adverse events: hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%).
Hepatic toxicities were more frequent with pexidartinib:
AST/ALT ≥ 3× ULN: 33% Total bilirubin ≥ 2× ULN: 5%
Eight patients discontinued pexidartinib due to hepatic adverse events
In early phase studies using pexidartinib, 2 severe liver toxicity cases -- 1 required liver transplant, 1 was associated with death.
Clinically meaningful improvement in range of motion (+15% vs +6%, P = .0043), PROMIS physical function (+4.1 vs –0.9, P = .0019), worst stiffness (–2.5 vs –0.3, P < .0001), pain response (31% vs 15%)

26. MEK inhibition in NF1
Dombi et al. “Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas”. N Engl J Med Dec 29;375(26):

27. Ongoing/upcoming trials at KU
Trametinib for epithelioid hemangioendothelioma DART trial for rare tumors Auranofin window of opportunity trial!

28. 2nd and 4th Thursdays at Indian Creek…
Tumor Board 7am
Ortho Onc, Surg Onc, Path, Radiology, Rad Onc, Med Onc, PT, SW, Cancer Registry
Multidisciplinary Sarcoma Clinic 8am
Ortho Onc, Rad Onc, Med Onc, SW

29. 2nd Annual Race to Cure Sarcoma!
Kansas City
9/15/2019
Shawnee Mission Park
9:00am
curesarcoma.org