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Innovations in Sarcoma Treatment: Updates in Research and Therapies by Dr. Benjamin Powers, MD

Dr. Benjamin Powers, MD, presents key updates in sarcoma treatment, discussing off-label uses and non-approved drugs due to the rarity of the disease. Learn about recent studies, treatment options, and promising therapies in the field of sarcoma oncology.

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Innovations in Sarcoma Treatment: Updates in Research and Therapies by Dr. Benjamin Powers, MD

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  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 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?

  6. 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

  7. 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

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

  9. PDGFR-α expression • did not predict outcomes?!

  10. 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 1.) Why?

  11. 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)

  12. 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!

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

  14. 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)

  15. Bone: not so much?

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

  17. GIST • Next generation KIT/PDGFR inhibitors • Avapritinib • DCC2618

  18. 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….

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

  20. 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.

  21. 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%)

  22. 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.

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

  24. 2nd and 4th Thursdays at Indian Creek… • Tumor Board 7am • Ortho Onc, SurgOnc, Path, Radiology, Rad Onc, Med Onc, PT, SW, Cancer Registry • Multidisciplinary Sarcoma Clinic 8am • Ortho Onc, Rad Onc, Med Onc, SW

  25. 2nd Annual Race to Cure Sarcoma! Kansas City 9/15/2019 Shawnee Mission Park 9:00am curesarcoma.org

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