True or False? Nearly twice as many SLNB negative compared to SLNB positive patients will ultimately die of metastatic melanoma.

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1 qrt-pcr Based Methods for Prognosis of Melanoma Pedr am Gerami MD Pr ofessor of Dermatology, Pathology and Pediatrics Nor thwestern University Dir ector Melanoma Program, Northwestern Skin Cancer Institute Disclosures: I have been a consultant to Abbott Molecular, Neogenomics, Castle Biosciences, Myriad Genomics, and Derm Tech Int. True or False? MSLT-1: Twice as many node-negative patients died compared to nodepositive Initial Report Final Report Nearly twice as many SLNB negative compared to SLNB positive patients will ultimately die of metastatic melanoma. Answer: True Less than half of N1a patients will die from melanoma by 5 years. Answer: True Sentinel-node negative (8 3 events) Sentinel-node positive (4 1 events) Morton, N Engl J Med, 2006; Morton, N Engl J Med,

2 T2b- T4b, N0, M0 Any T, N1-3, M0 % metastasis free Clinical Need in Early Stage Melanoma Somewhere between 80-65% of patients that die of melanoma have thin or node-negative tumors AJCC Analysis (Jan 2010) MSLT-1 (NEJM, 2006 / NEJM, 2014) AJCC Survival by Stage # Deceased at 5 years / Total Incidence Melanoma Specific Survival by Stage Stage 5-year Stage 5-year Stage I (T1a /b, T2a) N0, M0 Stage II Stage III 91-97% 53-82% 1,740 5,220 / 58,000 1,692 4,418 / 9,400 # Deceased at 5 years II 90% 62 / % 1,144 3,120 / 5,200 III 72% 32 / 41 All newer therapies and regional interventions are effective in metastatic melanoma Within Stage IV use and resected Stage III disease, early intervention is consistently shown to be a significant (or the most significant) predictor of response 1-10 Stage at Diagnosis While AJCC clinicopathologic Excludes Stage IV factors are good majority of deaths occur in early stage Stage II Stage III disease % 7% Stage II Prognostic accuracy needs to be Stage 13% I 80% improved as it has direct implications on patient follow up Stage I 80% Deaths by Stage at Diagnosis Excludes Stage IV Stage III 24% Stage II 35% Stage I 41% AJCC v7, Morton, N Engl J Med, 2006; Morton, N Engl J Med, H odi et al., 2010.NEJM; 2 Joseph et al.,2014. J Clin Onc; 3 Lyle et al.,2014. J Clin Onc (ASCO abstract); 4 Menzies et al., PLoSOne; 5 Nishino et al., J Immunother Cancer; 6 Steinman et al., J SurgOnc; 7 Del Vecchioet al., 2015.Future Oncology; 8 Kaufman etal., J ClinOnc (ASCO abstract); 9 Ts ai etal., J Clin Onc; 10 Ribas et al JAMA; 11 AJCC v7, (2010) Journal of Clinical Oncology; 12 SEER data 2012; 13 Morton, et al NEJM; 14 W hiteman, DC et al J Invest Dermatol; 15 Shaikh, WRet al JNatlCancer Inst Interrogating the Genome DNA analysis: 1) CGH or FISH for gene copy number changes 2) Next Gen Seq for Mutational Status mrna expression profiling Immunohistochemistry and now Proteomics to analyze Proteins Where we started: Gene expression profiling in uv eal melanoma 15-gene expression profile test Prospective clinical validation study 1 Strong separation of metastatic risk by class Months Class 1 (low risk) Class 2 (high risk) Adopted by >95% of ocular oncologists as standard of care Achieved a market penetration of 70% Transformed care by enabling personalized treatment planning 2 1 Onken, 2012, Ophthalmology 2 Aaberg, 2014, Clinical Ophthalmology 12 2

3 Cellular functions represented in GEP signature 54 g enes initially assessed and then narrowed to 28 with 3 additional controls Migration/chemotaxi s/metastasis Chemokine/secreted molecules Gap junction/cellular adhesion Lymphocytic invasion Gerami, Clin Cancer Res 2013 CXCL14 SPP1 CLCA2 S100A9 S100A8 CCL14 MGP SPP1 GJA1 DSC1 PPL LTA4H Differentiation/ proliferation Cell surface receptors Structural proteins Angiogenesis regulator Transcription factor TRIM29 Extracellular functions CRABP2 SPRRIB BTG1 TACSTD2 CLCA2 ROBO1 MGP SPP1 CST6 CXCL14 KRT6B KRT st intended use: Identify the node negative patients who have aggressive disease Patients with Stage I and II melanoma Quantifies expression of 31 genes from primary tumor Applies a validation algorithm Classifies patients as low vs high risk with strong accuracy Class 1 test result: Low risk of metastasis within 5 years Class 2 test result: High risk of metastasis within 5 years Identification of high risk patients allows them the opportunity to access further evaluation, treatment, and monitoring with the goal of improving long-term survival 14 Validation Study #1: Background demographics Characteristics Training Set (n = 164) Validation Set (n = 104) Age, median yrs (range) 61 (23-89) 58 (18-94) Follow-up, median yrs (range) 4.9 ( ) 5.7 ( ) AJCC Stage n (%) n (%) 0 15 (9%) 0 (0%) I 63 (38%) 56 (54%) II 67 (41%) 34 (33%) III 18 (11%) 12 (11%) IV 1 (1%) 2 (2%) Breslow Thickness Median mm (range) 1.86 ( ) 1.4 ( ) 1mm 46 (28%) 45 (43%) > 1mm 101 (62%) 58 (56%) Mitotic Index 1/mm 2 43 (26%) 29 (28%) > 1/mm 2 82 (50%) 53 (51%) Ulceration Absent 104 (63%) 65 (63%) Present 46 (28%) 28 (27%) Growth Pattern Superficial spreading 75 (46%) 56 (54%) Nodular 47 (29%) 25 (24%) Desmoplastic/lentigo maligna/ 25 (15%) 10 (10%) acral lentiginous Gerami, Clin Cancer Res 2015 Censor date: May GEP A ccuracy: Disease-free survival prediction all cases n=164 Tr aining Set n=104 5-yr DFS Class 1 = 91% Class 2 = 25% ROC = Accuracy = 83% Sensitivity = 85% Gerami, Clin Cancer Res 2015 Censor Date: May, 2013 n=104 Validation Set 5-yr DFS Class 1 = 97% Class 2 = 31% ROC = Accuracy = 86% Sensitivity = 89% 16 SLNB v s. GEP 1 st and 2 nd Validation Studies with SLNB pr ocedure Patients with SLN Procedure (n=217) SLN Results GEP Results SLN positive = 58 SLN negative = 159 Class 2 = 141 Class 1 = 76 Met = 37 Met = 70 Met = 91 Met = 16 Non = 21 Non = 89 Non = 50 Non = 60 PPV = 64% NPV = 56% PPV = 65% NPV = 79% 3

4 % free of metastasis % free of metastasis DecisionDx-Melanoma Improves Prediction Over SLNB Negative Status for Distant Metastasis-Free Survival Previously unreported validation cohort of 523 patients 100% SLNB DecisionDx in SLNB- Patients 100% Class 1/ SLNB- 75% 75% SLNB- 50% 25% SLNB+ n=217 0% Time (years) SLNB- (n=159) SLNB+ (n=58) Events yr 64% 42% 50% Class 2/ SLNB- 25% n=159 0% Time (years) Class 1/SLNB- Class 2/SLNB- (n=67) (n=92) Events yr 86% 49% Cox Regression Analysis of 523 Patients Comparison of GEP and SLN in 523 patients GEP plus SLN in combination Independent Validation of 357 Previously Unreported Stage I and II patients 4

5 % free of metastasis RFS in validation cohort of 264 previously unreported stage I patients Independent cohort of 93 previously unreported stage II cases 166 previously unreported stage III patients DecisionDx-Melanoma Identifies ~70% of SLNB Negative Patients who had Distant Metastasis by SLN Status DecisionDx in SLNB- Patients SLNB- SLN- 5-yr Events n=216 80% 42 Class 1/SLN- (n=106) 5-yr Events 90% 13 SLNB+ SLN+ 5-yr Events Class 2/SLN- (n=110) 71% 29 Identified ~70% (29/42) events n=368 n=152 53% 69 Time (years) Zager et al. J ClinOncol 2016;34 (suppl; abstr 9581); manuscript in preparation University Affiliated Private Dermatology Practice Independent, Prospective, Single-Center Study Independent single-center study Used prospectively-collected melanoma registry with chart review 214 (84%) Class Class 1A 21 Class 1B Total of 375 patients were consented 256 successfully tested 42 (16%) Class 2 16 Class 2A 26 Class 2B 119 eliminated (lack adequate residual tumor tissue, exhausted FFPE blocks) Independent, Prospectiv e Single-Center Study Confirms Prev ious Studies Class 2A/2B patients were 22 times more likely to develop metastatic disease 76.9% of metastatic patients were correctly identified as high risk Metastatic Disease DecisionDx No % Yes % Total p-value Class 1A, 1B % 3 1.4% 214 < Class 2A, 2B % % 42 Total % % % Confidence Limits Sensitivity Specificity Negative Predictive Value Positive Predictive Value Odds ratio Greenhaw et al. Presented at ACMS Greenhaw et al. Presented at ACMS

6 # p a tie n ts # p a tie n ts Hsueh Independent, Prospective, Single-Center Study 159 consecutive patients underwent SLNB mapping and successful DecisionDx- Melanoma testing (November 2013 through September 2015) Median follow-up time 18 months Age Breslow s thickness yrs 1.325mm ( mm) Ulceration status Absent: 76% Present: 24% SLN Status Negative: 87% Positive: 13% DecisionDx- Melanoma Class Class 1 (low risk): 74% Class 2 (high risk): 26% Rate of recurrence in Class 2, SLN negative patients was consistent with previous studies (Gerami 2015; Zager ASCO 2016) 18 patients (11%) showed disease recurrence (in transit, nodal and distant metastases) Classification SLN Status: Recurrence Events(Rate) Negative (n=139) 10 (7%) Positive (n=20) 8 (40%) DecisionDx-Melanoma class: Class 1 (n=117) 2 (1.7%) Class 2 (n=42) 16 (38%) 89% (16/18) of all recurrences were identified as Class 2 10 node negative patients had recurrences, 8 were Class 2 8 node positive patients had recurrences, all were Class 2 NPV for Class 1 = 98% Hsueh Independent, Prospective, Single-Center Study: DecisionDx-Melanoma Class Correlates with DFS Disease-Free Survival Time (months) Class 2 Class 1 Hsueh et al. J Clin Oncol 2016;34 (suppl; abstr 9565) Hsueh et al. J Clin Oncol 2016;34 (suppl; abstr 9565) Earlier Detection with Lower Tumor Burden is Associated With Better Response to Therapy Author Therapy Investigated Summary Menzies et al Steinman et al Joseph et al Nishino et al Del Vecchio et al Hodi et al Lyle et al Kaufman et al Tsai et al Ribas et al Dabrafenib + trametinib Isolated limb infusion Ipilimumab + bevacizumab Vemurafenib Ipilimumab T-VEC Metastases achieving complete response (CR) vs. non-cr were significantly smaller (except those in lymph nodes ) More CRs associated with lower tumor burden; lower tumor volume is significant predictor of response Baseline tumor size is strongest independent prognostic factor for overall survival (OS) Better progression free survival (PFS) and OS significantly associated with baseline tumor diameter Lower tumor burden (M1a) stage associated with better PFS and OS Fewer deaths in lower M1 stage at diagnosis in patients treated with ipilimumab alone Individual mets achieving CR were smaller than non- CR mets Baseline tumor size was prognostic for OS, durable response, and overall response (OR) Patients with liver metastases exhibit a reduced response Patients with baseline tumor burden below the median had a higher objective response rate SLNB+/- trends are similar in thin melanomas ( 1.0mm) Ranieri 2006 Wong 2006 Wright 2008 Yonick 2011 H inz 2012 H an 2013 Cooper 2013 M ozzillo 2013 # Pts with SLNB Total SLNB+ patients (N, percent) Events in SLNB- (N) Events in SLNB+ (N) M edian follow-up (months) # S L N B + P ts # E v e n ts in S L N B - # E v e n ts in S L N B + S L N B in th in m e la n o m a s (< = 1.0 m m ) 0 Barlett , 6.5% 8, 3.6% 31, 4.9% 16, 11% 5, 4.1% 65, 5.2% 3, 1.6% 24, 4.9% 29, 3.1% 1 (death) (death) 1 (death) (death) NA SLNB+/- trends are similar in thin melanomas ( 1.0mm) Combined C results bined Results from Nine from Studies N ine on Studies Thin Melanomas on TM (7 6 % ) 74 y/o male with a 0.7 mm melanoma with 2 mitoses/mm2 Negative SLNB 3 3 (2 4 % ) t1bn0mx Castle Class II T o t a l # E v e n t s # E v e n t s S L N B + # E v e n t s S L N B - 1Ranieri, 2006; 2Wong, 2006; 3Wright, 2008; 4Yonick, 20121; 5Hinz, 2012; 6Han, 2013; 7Cooper, 2013; 8Mozzillo, 2013; 9 Barlett, Negative baseline imaging and negative repeat imaging at 6 months 6

7 Current and Near Term Collaborative Centers Emory University (Lawson, Delman, Russell) UMMC (Lyle) Kelsey-Seybold Foundation (Greisinger, Jackson) UCDenver (Gonzalez, Amaria) Northwestern (Gerami) St Thomas Path (Robbins) Baylor College of Medicine (Rosen) FL Hosp Mem Med Ctr (Windham) University of Arizona (Cramner) Moffitt (Sondak, Zager) UPMC (Ferris) Cleveland Clinic (Gastman) Others at contract / IRB stage 38 7