Updates in Sarcoma Benjamin Powers, MD June 2019

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

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

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

STRASS (EORTC 62092) study 3-year Abdominal Recurrence Free-Survival (ARFS) was 60.4% vs 58.7% (HR = 1.01, 95%CI 0.71-1.44, p=0.954) in RT/S versus S groups. In the liposarcoma subgroup, 3-year ARFS (sensitivity analysis) was 71.6% (61.3-79.6%) and 60.4% (49.8-69.5%) in RT/S versus S groups (HR = 0.64, 95%CI 0.40-1.01, p =0.049). Should we be using neoadjuvant radiation in retroperitoneal liposarcomas?

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

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

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

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

Initial rates of survival Median OS 26.5 months (O+D) vs 14.7 months (D alone) HR 0.46, 95% CI 0.30-0.71 39 dead in O+D arm = 38 from progression, 1 unknown 52 dead in D arm = 44 progression, 6 adverse events 1.) Why?

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: 1.01-1.50; p = 0.04)

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: 0.84-1.30; p = 0.69) FDA pulled approval of olaratumab Jan 2019!

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

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)

Bone: not so much?

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

GIST Next generation KIT/PDGFR inhibitors Avapritinib DCC2618

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….

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

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, 7–9. 2015.

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%)

MEK inhibition in NF1 Dombi et al. “Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas”. N Engl J Med. 2016 Dec 29;375(26):2550-2560.

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

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

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