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

Epidemiology SEER data

Epidemiology

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: ©2009 by American Society of Clinical Oncology Depth Ulceration Nodes: Number Macro/Mi cro

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

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

MSLT-1 SLNBx vs Observation

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

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

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

Adjuvant Ipilimumab - Toxicities

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

Chemotherapy Nab-Paclitaxel DTIC/TMZ Carbo/Taxol

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

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

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

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

Ipilimumab patterns of response

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

CTLA-4 inhibitor –Toxicity kinetics

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

Nivo AND Ipi vs Nevo OR Ipi

Toxicities of Nivolumab with Ipilimumab

IIIc or M1aIIIc or M1b/c

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

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

Targeting is not so easy…

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

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

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

Dabrafenib and Trametinib

Vemurafenib and Cobimetinib

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

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

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

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

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:

Thank You!