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Melanoma: Where Do We Go from Here? – Michael A. Davies, MD, PhD

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Michael Davies, MD, PhD discusses where we go from here in the melanoma field to conclude the 2017 MD Anderson Melanoma Patient Symposium held in Austin, TX on May 6, 2017.

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Melanoma: Where Do We Go from Here? – Michael A. Davies, MD, PhD

  1. 1. MD Anderson Cancer Center – Melanoma Research Foundation  Melanoma: Where Do We Go From Here? Michael A. Davies, M.D., Ph.D. Associate Professor, Deputy Chairman, Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center Austin, Texas May 6, 2017
  2. 2. Disclosure Information I have the following financial relationships to disclose: • Advisory Board member:  • GlaxoSmithKline, Roche/Genentech, Novartis,  Bristol Myers Squibb, Sanofi‐Aventis, Vaccinex • Grant/Research support from:  • GlaxoSmithKline, Roche/Genentech, AstraZeneca,  Merck, Oncothyreon, Myriad, Sanofi‐Aventis
  3. 3. New Agents for Stage IV Melanoma US Approval 1975 DTIC 1998 HD‐IL2 1998 ‐ 2011 Pre‐1998 Approvals w/o (+) randomized trials 1998‐2011  No approvals → Personalizing clinical management & understanding/overcoming resistance 2011‐2015 10 approvals 2011 Ipilimumab Vemurafenib 2012 2013 Dabrafenib Trametinib 2014 Dabrafenib  +Trametinib Pembrolizumab Targeted TherapyImmunotherapy 2015 Nivolumab Vemurafenib +Cobimetinib Nivolumab +  Ipilimumab T‐VEC
  4. 4. Melanoma, 2017: Where Do We Go From Here? • Overcoming Resistance • Extending Advances to Earlier Stages of Disease • Attacking Melanoma Through Prevention
  5. 5. Melanoma, 2017: Overcoming Resistance
  6. 6. Understanding Resistance to Immunotherapy: The Immune Response Anti‐PD1 Treatment:  On‐Treatment Biopsies Responders versus  Non‐Responders • Early on‐treatment biopsies can accurately predict clinical response – More accurate than biopsy taken before the start of treatment: possible new paradigm Chen et al, Cancer Discovery, 2016 • Molecular & immune analyses: why non‐responding tumors don’t become inflamed – Goal: identify rational new approaches to improve outcomes in Non‐Responders
  7. 7. Targeted Therapy or Immunotherapy‐ or Both? BRAFi  • antigen expression on tumors • immunosuppressive cytokines • tumor infiltrating lymphocytes •Synergy in preclinical models Fold ↑ vs Baseline MEKi PD0325901 MEKi U0126 BRAFi PLX4720 Boni,…Wargo, Cancer Res, 2010 Liu, …Hwu, CCR, 2013 Preclinical Frederick,…Wargo, CCR, 2013 Patients Multiple clinical trials now  ongoing to evaluate the safety  and efficacy of combining approved, effective immune  and targeted theraies
  8. 8. Understanding Resistance to Immunotherapy: Oncogenic Pathways In Vivo: Anti-PI3KβiPatients: Anti-PD-1 Peng et al, Cancer Discovery, 2016 • PTEN Loss → ↓T-cell infiltration, ↓ sensitive to T-cell killing, and ↓ response to PD-1 • Identified actionable strategies to overcome resistance • PTEN: a tumor suppressor that is lost in ~25% of melanomas • Discoveries → new clinical trials • Anti-PD-1 + PI3Kβ Inhibitor trial: Opened for patient enrollment ~1 year after publication of results
  9. 9. Laboratory Testing of Immune & Targeted Therapy  Combinations  Long‐Term Cures Goal Identify short‐term treatments that  have high rates of long‐term cures Day 19 Targeted therapy Day 4 Day 10 Immunotherapy Day 19 Tumor growth (Fig. 1) Survival (Fig. 1) 100-400mm3 Tumors 8x105 BRAFV600EPTEN-/- Tumor cells (s.c.) Targeted therapy (Daily - oral) Dabrafenib/Trametinib Immunotherapy (Twice/wk - i.p.) α-OX86 α-CTLA-4 α-PD-1 α-CTLA-4/α-PD-1 α-OX86/α-PD-1 Tumor Tumor Flow cytometry (Fig. 2) Immunohistochemistry (Fig. 2) Gene expression profiling (Fig. 3) C57BL/6 Mice Day 60 Platform to assess positive & negative effects of combinations → New clinical trials on the way Reuben, CCCT Platform, Davies, Lazar, Tetzlaff, Wargo 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) 0 20 40 60 0 2000 4000 6000 8000 Days post treatment TumorVolume(mm^3) Tumor Growth DT DT + α-CTLA-4 DT + α-OX86 DT +α-PD-1 DT + α-CTLA-4/α-PD-1 DT + α-OX86/α-PD-1 0/12 NED 0/12 NED 2/12 NED 0/12 NED 3/12 NED 5/12 NED 4/12 NED 10/12 NED 7/7 NED* 10/12 NED 12/12 NED 12/12 NED Vehicle α-CTLA-4 α-OX86 α-PD-1 α-CTLA-4/α-PD-1 α-OX86/α-PD-1b c d e f g h i j k l m IMT Only IMT  +  Targeted Tx IMT #1 IMT #2 IMT #3 IMT #1 + #3 IMT #2 + #3No Treatment TT+ IMT #1 TT+ IMT #2 TT + IMT #3 TT + IMT #1 + #3 TT + IMT #2 + #3Targeted Tx Alone
  10. 10. FecalBuccal Start of  therapy Clinical  assessment &  restaging n=233 Initial                   oral & gut  microbiome  sampling Repeat oral &  gut microbiome sampling Tumor  biopsy Gopalakrishnan et al, 2017 ASCO‐SITC  A Exciting New Player: The Microbiome High Low NRR Set1Set2Set3 Diversity & composition of the gut microbiome are associated with  differential responses to PD‐1 therapy in patients with metastatic melanoma Can we improve outcomes by changing the microbiome (i.e. probiotics)
  11. 11. The Significance of Clinical Factors • Women have better outcomes than men with melanoma • Obesity: associated with outcomes in many cancers 2-Year OS 64% Obese 35% Normal %Alive Months MenWomen Opportunity to understand the basis of gender-specific differences in melanoma → New therapeutic approaches 2-Year OS 60-65% Months Obese Overweight Normal %Alive Targeted Therapy: Dabrafenib +  Trametinib • Gender + BMI in Melanoma: • ↑BMI: markedly improved outcomes in men treated with targeted & immune tx
  12. 12. Melanoma, 2017: Extending Advances to Earlier Stages
  13. 13. Regional (Stage III) Disease: New Trials & New Approaches • Many adjuvant trials ongoing with PD1, BRAF+MEK: Likely to change SOC adjuvant therapy • New paradigm: Neoadjuvant Therapy for High‐Risk (Bulky) Stage III Disease • Clinical Benefits: Several advantages • Shrinking the tumor  decrease the morbidity of surgery • Rational selection of adjuvant therapy after surgery based on response • Immunotherapy may be more effective with more tumor to recognize • Research: Potentially powerful opportunity to study resistance & evaluate new agents Pathology Findings:  fibrosis only, no viable  tumor cells (pCR) Neoadjuvant BRAFi + MEKi 2 months Bulky Stage III Surgery
  14. 14. Neoadjuvant Targeted Therapy: 1st Randomized Trial versus Standard Surgery • 1st ever randomized clinical trial to compare neoadjuvant targeted therapy versus  standard‐of‐care surgery in advanced melanoma Standard Neoadjvuant:  No pCR Neoadjuvant:  + pCR Free of Distant Metastases Neoadjvuant Standard Free of Any Relapse
  15. 15. Evaluation of Clinical, Molecular and Immune Features in Earlier Stages of Disease • Molecular profiling now SOC for stage IV • Melanoma TCGA – Molecular and Immune analysis of bulky  lymph nodes and distant metastases • Unmet Need: In‐depth characterization of  microscopic LNs metastases & primary tumors – Challenge: Small amounts of tumor – Opportunities • Large & growing % of patients • Benefits to identifying Low‐ & Hi‐Risk  patients Exploratory Analyses: Mutations vs Outcomes Technical Validation: RNAseq on FFPE Next: RNAseq vs Nanostring & Immune IHC Jeff Gershenwald, AJCC Chair, TCGA Co‐Chair
  16. 16. Attacking Melanoma Through  Screening & Prevention
  17. 17. The Potential Impact of UVR Protection 50% reduction in indoor tanning in minors younger than 18 years is  expected to prevent 101,637 melanoma cases, avert 11,633 melanoma  deaths, and save more than $547 million in melanoma treatment over  the lifetime of 61.2 million youth age 14 years or younger in the US Guy et al, JAAD 2017
  18. 18. MDACC Melanoma Moonshot: Prevention Goal: To reduce UVR exposure in children, adolescents and young  adults through state‐of‐the‐art interventions and public policy Pre-K K-1 Middle school High school Colleges/ Universities UV photography protocol Tanning facility legislation & compliance research Skin cancer prevention toolkit Evidence-based preschool sun safety curriculum Sun safety curriculum expansion Collaboration with Cancer Control & Prevention Platform
  19. 19. Indoor Tanning Facility  Legislation: 2012 ‐ Present WA OR CA NV ID IL TX CO KS IA NB MT WY UT ND SD AZ NM MN OK AK HI LA AR MO WI IN MI MS AL FL MD PA OH WV KY TN NC GA SC NY NJ VT NH ME VA DE RI CT MA Source: NCSL/AIM at Melanoma Cancer Prevention and Control Platform  Under Age 18 effective (15 states*)  Under Age 18  proposed (11 states)  No 2016 tanning legislation MD Anderson engagement
  20. 20. Management of Melanoma, 2017: Summary Treatment 1 Treatment 2 Treatment 3 Treatment 4
  21. 21. Melanoma Management 2017 • Advances on many fronts • Improving understanding of  melanoma biology and immunology • Development of many new, highly  effective therapies • Promising investigations across the  melanoma continuum • Significant challenges remain • Predicting, understanding and  overcoming resistance – and toxicities • Personalizing care across the  continuum • Continued unmet needs for prevention  & early detection/screening
  22. 22. Making Continued Impact: The Role of the Melanoma Community • Public awareness • Significance of melanoma and ultraviolet radiation (UVR)  exposure • Giving hope • Many patients remain unaware of advances that have been  made and treatments that are available • Sharing of experiences and lessons among patients • Research • All research requires the participation and commitment of  volunteers
  23. 23. Thank you for your attendance, participation  and support! Michael Davies, M.D., Ph.D. Departments of Melanoma Medical Oncology and Systems Biology University of Texas M. D. Anderson Cancer Center mdavies@mdanderson.org

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