1. Melanoma Nati Lerman MD Division of Hematology/Medical Oncology MD Anderson Cancer Center at Cooper September 2016

2. Epidemiology SEER data

3. Epidemiology

5. Survival curves from the AJCC Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for stages I and II melanoma. Balch C M et al. JCO 2009;27:6199-6206 ©2009 by American Society of Clinical Oncology Depth Ulceration Nodes: Number Macro/Mi cro

6. Localized Melanoma (I-II) Wide Excision to appropriate margins (0.5;1;2) SNLBx (consider in >0.76mm) Monitoring Risk reduction

7. Locally Advanced Melanoma (III) Lymph node management --  Completion dissection in SNL positive - MSLT-II (2022)  Dissection in clinically positive nodes Adjuvant Interferon IFN, peg-IFN PFS benefit, no survival benefit Toxicities Adjuvant Ipilimumab

8. MSLT-1 SLNBx vs Observation

9. 5 yr OS ~60% both IFN and observation or vaccine Median DFS ~25  36 mo Adjuvant Therapy: Interferon Alpha OS DFS

10. Better Outcomes with Autoimmunity n = 200 26% autoimmune phenomena (antibodies, vitiligo, others) Adjuvant Therapy: Interferon Alpha

11. Adjuvant Ipilimumab 10mg/kg q3W x4 Then q3M x 3 years

12. Adjuvant Ipilimumab - Toxicities

13. Metastatic Melanoma – Chemotherapy and First Generation Immunotherapy (1 st gen) Immunotherapy (IL-2, IFN) known for decades to produce sometimes dramatic responses in a small minority of patients High Dose IL-2 can produce longstanding remission in ~5% of patients, with substantial potential toxicity Chemotherapy – several options exist with response rates in 10-20%, none long lasting, all with toxicities Chemoimmunotherapy – many combinations of chemotherapy and various schedules of IFN and IL2 have been described. Overall there is no apparent survival benefit to combinations. Higher response rate higher toxicity

14. Chemotherapy Nab-Paclitaxel DTIC/TMZ Carbo/Taxol

15. 2015 Nivolumab Nivolumab with Ipilimumab Ipilimumab adjuvant T-Vec 2016 Vemurafenib and Cobimetinib Interferon alpha Drugs approved for metastatic melanoma over 46 years - Progress where the need is greatest

16. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) with monoclonal antibodies enhances T-cell activation.22-28 (A) Antigen presentation and costimulation signals results in T-cell activation and proliferation. Fong L, Small E J JCO 2008;26:5275-5283 ©2008 by American Society of Clinical Oncology

17. Immunotherapy – CTLA-4 inhibition Ipilimumab +/_ gp100 Hodi et al. NEJM 2010,363;8

18. Immunotherapy – CTLA-4 inhibition DTIC +/- Ipilimumab Robert et al. NEJM 2011,364;26 2 year survival 17.9  28.5% Median survival 9.1  11.2 mos

19. Ipilimumab patterns of response

20. Immunotherapy – CTLA-4 inhibition -Toxicities Diarrhea/Colitis LFT elevation/Hepatitis Rash Hypophisitis/Endocrinopathy All / Grade 3 /Grade 4: 80/20/5 Unusual immune mediated events 14 drug related deaths (of 676) in Hodi trial, no DRD’s in subsequent trials

21. CTLA-4 inhibitor –Toxicity kinetics

22. Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy. Ribas A. N Engl J Med 2012;366:2517-2519. PD-1/PD-L1 inhibition

24. Nivo AND Ipi vs Nevo OR Ipi

25. Toxicities of Nivolumab with Ipilimumab

26. IIIc or M1aIIIc or M1b/c

27. Metastatic Melanoma – Molecular Evolution Arlo et al., NEJM 2006

28. Melanoma – Targets for Therapy Alterations in MAPK pathway in Melanoma Arkenau et al., BJC 2011;104

29. Targeting is not so easy…

30. Metastatic Melanoma – Targeted Therapy – BRAFi Vemurafenib Vs. DTIC Vem DTIC Vem

31. Unintended consequences of BRAF inhibition Neoplastic squamous skin lesions reported in ~20% of patients treated with BRAFi

32. MEK inhibition Trametenib Vs. DTIC – METRIC trial Flaherty et al. NEJM 7/2012, 367;2

33. Dabrafenib and Trametinib

34. Vemurafenib and Cobimetinib

35. cKIT Inhibition in Mutated/Amplified Melanoma Carvajal et al., JAMA 6/2011;305

36. Metastatic Melanoma – Targeted Therapy - cKIT Carvajal et al., JAMA 6/2011;305

37. What to do first? Factors to consider: BRAF status – if wild type only immunotherapy is available (NRAS, cKIT) Disease Burden:  if quick reduction in tumor volume is required – targeted agents are first line.  If disease burden is low – start with immunotherapy, may provide long term responses Patient status  Good PS – consider combination therapies (consider testing for PD-L1 expression)  Poor PS – single agents, no Ipilimumab Trials ongoing

38. Tissue Analysis DNA RNA MiRNA Protein Target A Target B Target C Relapse immunotherapy

39. Melanoma 2016– new tools based on new understanding Immunotherapy (PD-1 inhibitors, CTLA-4 inhibitors, IL- 2, IFN) Targeted Therapies (BRAF, MEK, KIT) 10 new approved therapies and combinations since 2010 Incorporating new therapies in the adjuvant setting Combinations Management of resistance Sequencing of therapies Molecularly guided therapy (and Biomarkers) Future Directions:

40. Thank You!