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Targeted Therapy Clinical Trial Update - 2019 CURE OM Symposium

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Targeted Therapy Clinical Trial Update - 2019 CURE OM Symposium

  1. 1. Marlana Orloff, MD Assistant Professor Thomas Jefferson University Department of Medical Oncology Clinical Trial Update Targeted Therapies Eyes on A Cure Patient & Caregiver Symposium 4.6.19
  2. 2. Disclosures • BMS: Speaker, consultant, advisory board, research funding • Immunocore: Consultant, advisory board
  3. 3. Targeted Therapy • What is “targeted therapy” • Can think of it as drugs that interfere with specific molecules or targets that are involved in the growth, progression, or spread of cancer • Typically we think of it differently than other types: • Immunotherapy* (i.e. ipilimumab, nivolumab, pembrolizumab) • Cytotoxic chemotherapy (i.e. carboplatin, paclitaxel, dacarbazine) • Hormonal therapy (i.e. tamoxifen, leuprolide) National Cancer Institute: Targeted Therapies
  4. 4. • MANY MANY MANY molecular targets • GNAQ and GNA11 mutations found in about 85% of cases of UM • BAP1 mutations • Other mutations SF3B1 and EIFAX
  5. 5. What Makes it a Good Target? • Present in a decent amount of tumors • Can be a mutation or overexpression • Plays a key role in growth and survival • Present in cancer cells but not normal cells • Can target it safely without too much toxicity National Cancer Institute: Targeted Therapies
  6. 6. Why Should We Get Excited About Targeted Therapy? • Success in other cancers when the right target / right drug has been discovered • Imatinib for BCR-ABL mutations in AML • Vemurafenib, dabrafenib, encorafenib for BRAF mutations in cutaneous melanoma • Traztuzumab for HER-2 overexpression in breast cancer • Gefitinib and erlotinib for EGFR mutations in lung cancer
  7. 7. Wagle et al 2011
  8. 8. Targeted Attempts in Uveal Melanoma Krantz et al 2017 Yang et al 2018 PKC Inhibition AEB071 ORR: 3% PFS: 15.2 weeks MEK Inhibition Selumetinib Phase 2 ORR: 14% PFS: 15.9 weeks Selumetinib Phase 3 ORR: PFS: Trametinib ORR: 0% PFS: 7.8 weeks MEK + AKT Trametinib + GSK795 ORR: 5% PFS: 15.7 weeks MEK + PI3K AEB071 + BYL719 ORR: 0% PFS: 7.6 weeks RAF Sorafenib ORR: 0% 24 Week PFS: 31% Mouriax et al 2016
  9. 9. Ardisia Crenata • AKA Coral Berry, Christmas Berry, Australian Holly • Primrose family of plants • Compound FR900359 extracted from this plant • In cell culture (NOT HUMANS) has been shown to inhibit the GNAQ/GNA11 mutations • Ways away from in human clinical trials • Don’t eat this plant
  10. 10. Epigenetics … The Indirect Target • What is epigenetics? • “If DNA is like the hard drive that contains the information to guide every cellular function, then epigenetic modulation acts as software that regulates the packaging of DNA to guide potential for gene expression patterns.” (Ahuja et al 2016) • Pros of manipulating the epigenome (the stuff that regulates the genes) • Can indirectly target the un-targetable • Reverse, re-program, silence, unsilence …
  11. 11. Cancer Research Product Guide Edition 3, 2015.
  12. 12. Currently Available Clinical Trials Drug Target Phase Disease State LXS196 PKC Phase 1 Metastatic BDV-523 ERK Phase 2 Metastatic Selumetinib MEK Phase 1b Metastatic PLX2853 BET Phase 1 Metastatic Neraparib DNA MM Phase 2 Metastatic Sunitinib KIT/VEGF Phase 2 Adjuvant Vorinostat HDAC POC Adjuvant
  13. 13. THANK YOU