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A Personalized Approach: Molecular Testing and Targeted Therapy – Hussein Tawbi, MD, PhD

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Hussein Tawbi, MD, PhD provides information on molecular testing and targeted therapy for melanoma at the 2017 MD Anderson Melanoma Patient Symposium held in Austin, TX on May 6, 2017.

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A Personalized Approach: Molecular Testing and Targeted Therapy – Hussein Tawbi, MD, PhD

  1. 1. MDACC Melanoma  Patient Symposium Austin, Texas May 5th, 2017 Targeted Therapy for Melanoma: A Personalized Approach Hussein Tawbi, M.D., Ph.D. Associate Professor, Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center CCR, 2012 Day 1 Day 15 Flaherty NEJM, 2010
  2. 2. Disclosures • Research support from – Bristol Myers Squibb – Novartis – Roche/Genentech – Merck – GlaxoSmithKline • Advisory Board – Bristol Myers Squibb – Roche/Genentech – Novartis – EMD Serono
  3. 3. Targeted Therapy:  A Personalized Approach • What is targeted therapy? • Why do we use targeted therapy  for melanoma? • What have we learned & what are  we working on
  4. 4. A Brief History of Chemotherapy • WW I: Nitrogen mustards gas  • → 1946 1st successful systemic treatment of  cancer with chemotherapy • 1950s‐1980s most standard chemotherapies • 1977 First report of an oncogene • 1980s‐2000s  Oncogenes in most cancers Dr. Sidney Farber And Patient ‘Targeted Therapy’: Treat cancer by targeting the genes activated in cancer cells
  5. 5. MAPK and PI3K/AKT Pathways in Melanoma from genes to function Miller et al. NEJM, 2006
  6. 6. Melanocytes in the Basal Layer of the Skin Rigel DS, et al.
  7. 7. The Main Ingredient of Melanoma Rigel DS, et al. • Overall melanomas have more mutations than  any other type of cancer
  8. 8. MAPK and PI3K/AKT Pathways in Melanoma from genes to function Miller et al. NEJM, 2006
  9. 9. EUREKA!!!!...
  10. 10. Accumulation of Genetic “Hits” and Melanoma Progression Miller et al. NEJM, 2006
  11. 11. Cancer growth and i l BRAF MEK ERK BRAF Inhibitors, Targeted Therapy to  Block the Driver Oncogenic Signaling Adapted from Fecher et al, 2007; Xing, 2010; Weber, 2011.
  12. 12. Imatinib Mechanism BCR-ABL or KIT or PDGFR Adapted from Imatinib / CML Prescribing Guidelines, Novartis Signals for growth, survival BCR-ABL or KIT or PDGFR
  13. 13. Ras GTP Baseline pERK cyclin D Ki67 Day 15 Cyclin D BRAFV600 MEK ERK P P Cell cycle (Ki67) PLX4032 RTK Y‐PY‐P GF Inhibition of MAPK Signaling in Biopsies of BRAFV600 Melanoma From Patients Treated With Vemurafenib Smalley et al, 2010; Flaherty et al, 2010b.
  14. 14. Responses to PLX4032
  15. 15. Effective for Brain Metastases Long et al, Lancet Oncology, 2013 BRAFi 32 Weeks
  16. 16. Clinical Activity of BRAF Inhibitors Tumor Grew Tumor Shrank • 50% of patient achieve a “clinical response” • 90% achieve disease control, usually very quickly (<1 month) • KEY: Only work in patients that have a BRAFV600 mutation • If don’t have a mutation they will make the tumors grow faster FDA‐Approved BRAF Inhibitors • Vemurafenib, 2011 • Dabrafenib, 2013 Champman et al, NEJM, 2011
  17. 17. All grades n (%) Grade 3 n (%) Grade 4 n (%) Overall 130 (99) 79 (60) 5 (4)† Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity reaction 69 (52) 4 (3) – Fatigue 56 (42) 2 (2) – Alopecia 48 (36) – – Pruritus 38 (29) 3 (2) – Skin papilloma 38 (29) – – cuSCC / KA‡ 34 (26) 34 (26) – Nausea 30 (23) 2 (2) – Elevated liver enzymes 23 (17) 8 (6) § 4 (3)¶ Toxicity of BRAF InhibitorsToxicity of BRAF Inhibitors
  18. 18. Baseline 2 Weeks 16 Weeks Resistance to BRAF Inhibitors Average response duration ~6 months
  19. 19. BRAFi: Why Does Resistance Happen MAPK & PI3K Pathway Re‐Activated MAPK  Pathway Re‐Activated Unknown Mechanism  of Resistance Shi,… Lo, Cancer Discovery, 2013 → Rationale to combine BRAF with other MAPK inhibitors 70% of Patients: MAPK Pathway is Back On
  20. 20. Mechanisms of Resistance to BRAF Inhibitors Survival BRAFV600E MEK ERK P P BRAF inh PDGFRb or IGF1R PI3K AKT MEK-independent progression NRASQ61 COT CRAF MEK-dependent progression Adapted from Poulikakos et al, 2011; Shi et al, 2012; Nazarian et al, 2010; Villanueva et al, 2010; Johannessen et al, 2010; Wagle et al, 2011. MEKi PI3Ki or AKTi
  21. 21. Combinations to Overcome Resistance: Targeted Therapy + Targeted Therapy ‐100 ‐80 ‐60 ‐40 ‐20 0 20 40 60 80 100 Tumor Shrank BRAFi + MEKi • ~100% disease control rate • Average response duration  11 months (~2X BRAFi) • Less skin toxicity than BRAFi alone Flaherty et al, NEJM, 2012
  22. 22. A New Hypothesis: Combining BRAF Inhibitors & Immunotherapy BRAF Inhibitors • Almost all patients respond • Responses but not cures Immunotherapies • Some patients respond  • Responses can → cures Can BRAF Inhibitors + Immunotherapy →  High rate of cures?
  23. 23. Combinations to Overcome Resistance: Targeted Therapy + Immune Therapy Liu, …Hwu, CCR, 2013 Frederick,…Wargo, CCR, 2013 BRAF Inhibitor: In Mice BRAF Inhibitor: In Patients → Clinical trials of targeted therapy + immune therapy ongoing & planned
  24. 24. Targeted Therapy for Melanoma: What Have We Learned & What Are We Working On
  25. 25. Targeted Therapy: What We Have Learned • Virtually all patients with cutaneous melanomas  have many DNA mutations • BRAF‐Mutant Melanoma (~ 50%) – Inhibi ng driver oncogenes can → benefit – Right patient, right drug, right dose – Combinations can be even better! • Have to identify ways to understand, prevent &  overcome resistance
  26. 26. THANK YOU

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