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Bone and Soft-tissue Sarcomas Precision Sarcoma Sarcoma Alliance

Jon Trent, MD, PhD Professor of Medicine Director, Bone and Soft-tissue Sarcoma Associate Director, Clinical Research The University of Miami, Sylvester Comprehensive Cancer Center jtrent@med.miami.edu @ JTrentMDPhD. Bone and Soft-tissue Sarcomas Precision Sarcoma Sarcoma Alliance.

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Bone and Soft-tissue Sarcomas Precision Sarcoma Sarcoma Alliance

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  1. Jon Trent, MD, PhD Professor of Medicine Director, Bone and Soft-tissue Sarcoma Associate Director, Clinical Research The University of Miami, Sylvester Comprehensive Cancer Center jtrent@med.miami.edu @JTrentMDPhD Bone and Soft-tissue SarcomasPrecision SarcomaSarcoma Alliance

  2. Current Classification of Sarcomas • Vascular STSs • Angiosarcoma • Hemangiosarcoma • Lymphangiosarcoma • Hemangioendothelioma • Hemangiopericytoma • Kaposi’s Sarcoma • Neural STSs • Malignant Peripheral Nerve Sheath Tumor • Malignant Paraganglioma • Neuroblastoma, Neuroepithelioma • Granular Cell Tumor • Adipose STSs • ALT • Myxoid/Round cell Liposarcoma • Dedifferentiated Liposarcoma • Pleomorphic STSs • Lipo, MFH • Neuromuscular STS • GI Stromal Tumor • Unclassified • Smooth Muscle STSs • GI, GU, Cutaneous, Vascular • Skeletal Muscle STSs • ARMS, ERMS, Pleomorphic RMS • Fibrous STSs • Fibrosarcoma • Fibromyxoid Sarcomas • Desmoid Tumor • Dermatofibrosarcoma • Inflammatory myofibroblastic tumor • Unknown Tissue • Synovial Sarcoma • ASPS • Epithelioid Sarcoma • Bone Sarcomas • Osteosarcoma (+ variants) • Chondrosarcoma (+ variants) • Giant Cell Tumor of Bone • Ewing’s Sarcoma Family of Tumors • Extraskeletal Bone Sarcomas • Osteosarcoma • Ewing’s Sarcoma Chondrosarcoma N>200

  3. Molecular Sarcomagenesis • Point mutations • GIST: KIT, PDGFR, RAF • Myxoid Liposarcoma: PTEN, PI3K, AKT • Gene Amplification • Dediff Liposarcoma: MDM-2, CDK4 • Neuroblastoma: n-myc • Gene Deletion • Osteosarcoma: p53 • Retinoblastoma: RB1 • Translocation • Ewing’s Sarcoma: EWS-FLI1 • Dermatofibrosarcoma: Col1A-PDGFB • Protein Overexpression • Desmoid Tumor: ER

  4. Adriamycin Ifosfamide DTIC, Temozolomide Gemcitabine Docetaxel, Paclitaxel Irinotecan Vincristine VP-16 Trabectedin High-dose ifosfamide Soft-tissue SarcomasActive Systemic Agents • Imatinib, sunitinib, regorafinib • Pazopanib • Eribulin • Celebrex, sulindac • Interferon-alpha • Denosumab • mTOR inhibitors • Tamoxifen • Olaratumab

  5. Precision Medicine • Testing • Next-Generation Sequencing (NGS) • Circulating Tumor DNA • Diagnosis • Treatment • Match patient to optimal therapy

  6. Strategic Alliances (Networks) Components of SCCC Precision Medicine Precision Medicine Clinical Trials Precision Medicine Clinic Molecular Tumor Board NGS Results (EPIC and Syapse) Software Solutions (Syapse) Next Generation Sequencing (NGS) NGS Ordering (EPIC)

  7. DePICT Protocol Overview Patients with advanced, refractory cancer(s) ICF and eligibility review Ineligible Eligible Existing sequencing available Tissue for analysis Standard of Care Weekly Disposition Meeting/Molecular Tumor Board SCCC Clinical Trials Group A: actionable mutation Group B: No actionable mutation Refusal NCI MATCH Options Drug Screening Platform Targeted Drug Other external clinical trials Follow-up at Investigator discretion (non-targeted therapy) Targeted Drug FDA Approved (Off-Label) via n-of-1

  8. Gastrointestinal Stromal Tumor (GIST) Overview • Most common GI sarcoma • 0.2% of all GI tumors, but 80% of GI sarcomas • Distinct clinical and histopathologic entity • Highest incidence in the 40-60 year age group • Similar male/female incidence • About 5,000 newly diagnosed GIST patients per year in the US • Clinical presentation is variable • pain, hemorrhage, anemia, anorexia, nausea, bleeding • High recurrence rate after surgery (>50%) • No effective chemotherapy

  9. Kit Receptor Structure Extracellular Domain (exon 9, 10.2%) Juxtamembrane Domain (exon 11, 66.1%) ATP Tyrosine Kinase Domain I (exon 13/14, 1.2%) Tyrosine Kinase Domain II (exon 17, 0.6%) = common mutation site

  10. Kit Receptor Phenotype ADP + P ATP Proliferation Survival Adhesion Invasion Metastasis Angiogenesis

  11. Kit Receptor Phenotype ATP Imatinib Proliferation Survival Adhesion Invasion Metastasis Angiogenesis = imanitib contact point

  12. Molecular Subtypes of GIST Optimal management of GIST patients requiresmolecular analysis • Kit exon 11 • Kit exon 9 • PDGFR: D842V et al • SDH-B deficiency • Raf V600E • NF-1 • Ras • PI3K • KIT secondary mutations • Exon 13 (ATP binding site) • Exon 17 (A-loop)

  13. GIST Patient Initial TherapyPDGFR D842V Mutation Treatment with RAF inhibitor

  14. AvapritinibPDGFR D842V Mutant GIST ASCO 2017. Abstract no: 11011

  15. GIST Patient Initial TherapyRAF V600E Mutation Treatment with RAF inhibitor Vemurafenib Falchook, Trent, Heinrich Oncotarget. 2013 Feb;4(2):310-5.

  16. Secondary Mutations in KIT ATP/ADP Binding Site (V654) EXON 13 Gate Keeper (T670) Activation Loop (D820) EXON 17 Chen, Trent, et al. Cancer Res 2004;64:5913-5919

  17. Differential Sensitivity to TKI Trent, CTOS 2017; Serrano BJC 2018 Gramza et al, Clinical Cancer Research 15:7510, 2009 Heinrich et al, ASCO 2013 Poster/Abstract 10509

  18. KIT D820Y (exon 17). Radiographic and metabolic response on REGO Baseline Pre-REGO biopsy KIT ex 11 + ex 17 (D820Y) C4D21

  19. Jon Trent, MD, PhD GIST SubtypesMolecularly Determined Therapy • Kit exon 11: Imatinib 400mg • Kit exon 9: Imatinib 800mg • PDGFR D842V: anti-PDGFR trial • SDH-B deficiency: Sunitinibor Regorafenib? • Raf V600E: Raf inhibitor • NF-1: Raf inhibitor? • Ras: Raf inhibitor? • PI3K:PI3K or mTOR inhibitor • IGF overexpressed: IGF-1R inhibitor trial • KIT secondary mutations • Exon 13 (ATP binding site): Sunitinib • Exon 17 (A-loop): Regorafenib or Panotanib • Exon 17 D816 A/G: Panotanib

  20. Precision Oncology Sarcomas other than GIST

  21. PDGFR Inhibitors in Dermatofibrosarcoma Collagen1A PDGF-B Col-PDGFB PDGF Transcription Translation intracellular 17 PDGF Receptor 22 Ring Chromosome Tibes, Trent, Kurzrock. Ann Rev Pharmacol Toxicol. 2005;45:357-84

  22. Autocrine CSF1 CSF1R CSF1R t(1;2) COL6A-CSF1 Paracrine CSF1 CSF1R CSF-1 in Pigmented Villonodular Synovitis (PVNS/TGCT-TS)Autocrine and Paracrine effects of CSF1 Tibes, Trent, Kurzrock. Ann Rev Pharmacol Toxicol. 2005;45:357-84 Adaptedfrom West et al. PNAS 2005

  23. Autocrine CSF1 CSF1R CSF1R t(1;2) COL6A-CSF1 Paracrine CSF1 CSF1R CSF-1 Inhibitors in PVNS/TGCT-TS Pexidartinib Anti-CSF-1 Antibody Y X X X X X Tibes, Trent, Kurzrock. Ann Rev Pharmacol Toxicol. 45:357-84 Adaptedfrom West et al. PNAS 2005

  24. PexidartinibCan Produce a Significant Response in PVNS as Early as 2 Months Baseline 8 weeks This patient underwent margin negative resection and remains free of disease at 22 months off imatinib.

  25. Autocrine RANK-L RANK RANK Paracine RANKL RANK RANKL in Giant Cell Tumor of Bone (GCTB)Autocrine and Paracrine effects of RANKL Tibes, Trent, Kurzrock. Ann Rev Pharmacol Toxicol:357-84

  26. Autocrine RANKL RANK RANK RANKL Paracrine RANK RANKL Inhibitor in GCTB Denosumab Y X X X X X Tibes, Trent, Kurzrock. Ann Rev Pharmacol Toxicol;45:357-84

  27. Radiologic Response to Denosumab Pre-Treatment Week 13 Post-Treatment

  28. Sarcoma With TRK Fusion

  29. CT PET Baseline Day 5 (53% ) Day 54 (85% ) mTOR inhbitor: antitumor activity in PI3K-mutant MRCL

  30. Mutant IDH Metabolism MITOCHONDRIA CYTOPLASM ISOCITRATE ISOCITRATE TCA Cycle NAD + NADP+ NADP + IDH2 IDH3 IDH1 NADH CO2 NADPH CO2 NADPH CO2 α-KETOGLUTARATE α-KETOGLUTARATE m-IDH2 m-IDH1 2 – HYDROXYGLUTARATE KDM PDH Histone hypermethylation Tet2 HIF1-α DNA hypermethylation Li, Wilky, Trent et al. PLOSone 2015 Tinoco, Wilky and Trent. ASCO 2016

  31. Mutant IDH Metabolism MITOCHONDRIA CYTOPLASM ISOCITRATE ISOCITRATE TCA Cycle NAD + NADP+ NADP + IDH2 IDH3 IDH1 NADH CO2 NADPH CO2 NADPH CO2 α-KETOGLUTARATE α-KETOGLUTARATE m-IDH2 m-IDH1 2 – HYDROXYGLUTARATE KDM PDH Histone hypermethylation Tet2 HIF1-α DNA hypermethylation Li, Wilky, Trent et al. PLOSone 2015 Tinoco, Wilky and Trent. ASCO 2016

  32. MRI Response of Chondrosarcoma To IDH Inhibitor 12/22/17 MRI With Contrast 1/15/15 MRI With Contrast

  33. Precision Medicine Immunotherapy

  34. Checkpoint Inhibitors – Unleash the Brakes on the Immune System APC APC Anti-CTLA4 drug

  35. Dendritic Cell Vaccine Protocol Primary endpoints: • Maximally tolerated dose • Safety and toxicity Secondary endpoints: • Tumor response • Progression-free survival Correlative endpoints: • Peripheral blood sampling for immune monitoring

  36. Additional projects • Compassionate use partnership with Agenus (Boston, MA) for administration of customized vaccine protocols • Site for Adaptimmune NY-ESO-1 engineered TCR adoptive cell therapy (granted breakthrough designation by FDA) for synovial sarcoma and liposarcoma (upcoming) • 60% of the 10 patients receiving the target dose of cells responded, and there was a 50% percent overall response rate in 12 patients receiving any dose of cells • Site for industry-sponsored novel phase I CTLA-4 inhibitor AGEN1884

  37. Precision Medicine Targeted Immunotherapy

  38. Axitinib plus Pembrolizumab for soft tissue sarcomas (Pembr-Ax) Axitinib – more favorable safety profile in combination with PD-1 blockade vs sunitinib or pazopanib Active as single agent in refractory soft tissue sarcomas (AXI-STS trial – EORTC)

  39. Sarcoma Targeted Therapy Trials • Phase II ASCO TAPUR • Phase II NCI MATCH • GRAIL, DEPICT • Phase II IDH-1 inhibitor for Chondrosarcoma and other solid tumors • Phase II IDH-2 inhibitor for Chondrosarcoma and other solid tumors • Phase III Plexxicon CSF1-R TKI Phase III Registration Study • Phase Ib Plexxicon 9937 + 4986/sunitinib in metastatic GIST • Phase III Avapritinib metastatic GIST (Phase III vs. regorafenib) • Phase III Ripretinib metastatic GIST (Phase III vs. sunitinib) • Phase III Gem/docetaxel +/- anti-PDGFR antibody (Olaratumab) • Phase I • Phase II axitinib sequential with pembrolizumab • Phase I Agenus C-500 PD-1 inhibitor in advanced STS • Phase I Agenus C-700 CTLA-4 inhibitor in advanced STS

  40. Sylvester Comprehensive Cancer CenterSarcoma Team • Interventional Radiology • Prashoon Mohan • Shree Venkat • Gynecologic Oncology • Brian Slomovitz • Marilyn Huang • Clinical Research • Chinar Singh • Melissa Serna • Mirna Gonzalez • Lab Research • Joanna DeSalvo • Luyuan Li • Karina Galoian • Josie Eid • Medical Oncology • Jon Trent • Gina D’Amato • TBA • Pathology • Andrew Rosenberg • Jay-Lou Velez • Radiology • Ty Subhawong • Jean Jose • Nurse Practitioner • Morgan Smith • Solange Sierra • Yolanda Roper • Nursing • Sara Perez • Social Work • Lisa Merheb • Marlene Morales • Abby Solomon • Orthopedic Oncology • Sheila Conway • Frank Eismont • Juan Pretell • Mo Al Maaieh • Surgical Oncology • Nipun Merchant • Alan Livingstone • Neha Goel • Radiation Therapy • Raphael Yechieli • Aaron Wolfson • Head & Neck Surgery • Zoukaa Sargi • Frank Civantos • Thoracic Surgery • Dao Nguyen • Nestor Villamizar

  41. Bone and Soft-tissue SarcomasPersonalized SarcomaSarcoma Alliance Jon Trent, MD, PhD Professor of Medicine Director, Bone and Soft-tissue Sarcoma Associate Director, Clinical Research The University of Miami, Sylvester Comprehensive Cancer Center jtrent@med.miami.edu @JTrentMDPhD

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