Next Generation Sequencing in Clinical Practice: Impact on Therapeutic Decision Making

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1 Next Generation Sequencing in Clinical Practice: Impact on Therapeutic Decision Making November 20, 2014 Capturing Value in Next Generation Sequencing Symposium Douglas Johnson MD, MSCI Vanderbilt-Ingram Cancer Center Vanderbilt-Ingram Cancer Center

2 Outline Precision medicine - overview Clinical considerations surrounding NGS Clinical implications of NGS

3 Traditional Model Pathology, Staging Treatment Precision/personalized Model DNA Testing FISH, gene expression, staining Treatment Pathology, Staging

4 Increasing impact of precision medicine Minimal impact Prognosis only Small subset benefits Large subset benefits Prostate ALL Breast Lymphoma GYN malignancies Kidney Pancreas Head and neck AML Colon Sarcomas Lung CML GIST Liver Myeloma Esophagus Melanoma Testicular Stomach Bladder Thyroid

5 Precision medicine in clinical practice Therapeutic examples: BCR-ABL fusion in CML (and ALL) KIT and PDGFR in GIST ER/PR/Her2neu in breast BRAF, KIT in melanoma BRAF in thyroid EGFR and ALK in lung PML-RARa(t:15,17) in acute promyelocytic leukemia KRAS in colon Her2neu in esophageal Newer targets Drukeret al Nature 2009 Sosman et al NEJM 2012 Shaw et al NEJM 2014

6 Precision medicine in clinical practice Goal of NGS: find an actionable genetic alteration and treat patient with a more selective, often less toxic approach

7 Outline Precision medicine - overview Clinical considerations surrounding NGS Clinical implications of NGS

8 Clinical Considerations Who do I test? Highly selected settings Selected cancers eligible for treatment/trials All metastatic cancers eligible for treatment/trials Single genes only All metastatic cancers Bad practice All cancers

9 Clinical Considerations What platform do I use? Multiplexed panels Small targeted NGS panel (20-50 genes) Large targeted NGS panel ( genes) Single gene testing Whole exome sequencing None Whole genome sequencing

10 Clinical Considerations How well does it perform? Frampton et al Nature Biotech 2013

11 Clinical Considerations How much does it cost? To patient To system

12 Clinical Considerations Other logistical questions Turn around time Amount of tissue required What do I do with the information?

13 Outline Precision medicine - overview Clinical considerations surrounding NGS Clinical implications of NGS

14 Targeted NGS Vanderbilt has been using a particular targeted NGS platform (FoundationOne TM ) Many other platforms available but will discuss our experience Sequence the coding regions (exons) of selected, cancer related genes Evaluates for mutations, amplifications, deletions, truncations, indels, some translocations Provides more information but also more complex

15 Example: melanoma No known mutations 60% No known mutations 35% NRAS 18% BRAF 40% BRAF 39% Single gene BRAF testing BRAF V600 NRAS KIT GNAQ/11 Atypical BRAF NF1 KRAS MAP2K1 CDKN2A/B CCND1/2 CDK4 TP53 MDM2 PTEN AKT1/2/3 PIK3CA FGFR1 RET ERBB3/4 CTNNB1 IGF1R NTRK3 KIT 2% GNA11 1% Melanoma SNaPshot ~1000 melanomas GNAQ 3% Mutation Deletion Amplification Fusion FoundationOne 44 melanomas (largely BRAF WT)

16 Clinical Implications Now that we are moving to targeted NGS: What patients are getting tested? What are we finding? Is testing changing management? Genetically-targeted treatments being prescribed?

17 Vanderbilt Experience Study design 431 patients from VICC have had NGS testing Collected Baseline characteristics Testing results Subsequent therapy (targeted vs. non-targeted, reasons) for first 103 patients

18 Demographics Table. Demographics and baseline clinical characteristics (N=431) Variable Classification Result, n (%) Age, yr Median 54 years Range years Gender Female 259 (60) Male 172 (40) Tumor Type Breast 100 (23) CNS 10 (2) GI 100 (23) GYN 23 (5) Head and neck 42 (10) Heme 3 (1) Lung 36 (8) Melanoma 46 (11) Renal/GU 15 (3) Sarcoma 28 (6) Unk Primary 17 (4) Other 11 (3)

19 Testing results (n=431) Testing results Variable Classification Result, n (%) Genetic alterations Any detected 411 (95%) Median 3 Range 0-13 Potentially actionable alterations Any detected 386 (89%) 1 alteration 85 2 alterations alterations alterations 121 Mutations that fit one of the below criteria: 1. There is an approved therapy targeting that mutation 2. There is a clinical trial targeting that mutation

20 Testing results Percentage of samples with alterations 50% 40% 30% 20% 10% 0% MAP2K1 MAP2K4 BRAF GNAQ/GNAS RICTOR RPTOR NF2 AKT3 TSC1 AKT2 AKT1 NF1 PTEN HRAS PIK3CG NRAS PIK3R1/2 ALK IGF1R RET ERBB3/4 ERBB2 MET KIT CCNE1 CCND3 CCND2 CCND1 CDK6 CDK4 KRAS PIK3CA EGFR CDKN2A/B/C FGFR1 MDM2 TP53 KDR EWSR1 BRCA2 BRCA1 ATR ATM MYC AURKA JAK1/2 CTNNB1 Ras/MAPK PI3K/MTOR RTKs/GFs Cell Cycle p53 Other

21 Potentially actionable alterations Level of evidence for genes (modified and adapted with permission from the NCI Match Trial): Level 1: Gene variants credentialed for selection of an approved therapy in a particular malignancy (i.e. vemurafenib in BRAF V600E mutant melanoma) Level 2: Gene variants credentialed for selection of an approved therapy in any malignancy but robust data for efficacy is lacking in that tumor type (i.e. vemurafenibin BRAF V600E mutant lung adenocarcinoma

22 Potentially actionable alterations Level of evidence for genes (modified and adapted with permission from the NCI Match Trial): Level 3: Gene variant is an eligibility criteria for a clinical trial or published evidence of clinical efficacy with an investigational agent Level 4: Gene variant with only preclinical support for using an investigational therapy

23 Testing Results Category 4: Experimental therapy, pre-clinical only 3% No actionable alterations 10% Category 1: Approved therapy 20% Category 3: Experimental therapy, evidence of activity 32% Category 2: Approved therapy in another malignancy 35%

24 No actionable alterations 17% Results -Treatment Actionable alteration identified 83% Other trial options selected 10% Rapid progression and death 13% No evidence of disease 12% Other 9% Received genotype directed therapy 21% Standard options selected 35% Johnson et al The Oncologist 2014

25 Results -Treatment

26 Results Specific cases 60 yo with T-cell PLL s/p Campath, CHOP, Pentostatin, Pralatrexate, and Romidepsin JAK1 V658F mutation. Started on ruxolitinib improved counts and decreased transfusions x 5 mos. 37 yo woman with metastatic melanoma s/p ipilumumab/nivolumab BRAF V600E mutation (not detected by SNaPshot due to low allele frequency), started on dabrafenib with dramatic clinical improvement. 28 yo woman with melanoma s/p anti-pd-l1 antibody, ipilumumab BRAF fusion. Unfortunately expired. Led to clinical trial

27 Update lung cancer Table. Demographics and baseline clinical characteristics (N=36) Variable Classification Result Age, year Average 62 years Range years Gender Female 17 Male 19 Tumor Type Adenocarcinoma 20 Squamous cell 4 NSCLC, NOS 9 Other 3 Performance Status Prior therapies Median 1 Range 0-5

28 NF2 NF1 HRAS KRAS AKT2 PTEN PIK3CA ERBB3 ERBB2 RET MET FGFR1 ALK EGFR CCND1 CDK4 CDKN2A Ras/MAPK PI3K/MTOR RTKs/GFs Cell Cycle None KRAS EGFR RET ALK AKT2 PIK3CA HRAS ERBB2 MET

29 Therapy assignments No actionable mutation 8% Standard/no therapy 43% Other trial options 14% Received targeted therapy 18% Rapid progression 17% Heavily pre-treated lung mucoepidermoid carcinoma, EML4- ALK fusion identified, minor PR/SD for >1 year EGFR T790M, PIK3CA H1047L identified after erlotinib, received afatanib/cetuximaband a PIK3CA inhibitor with brief SD RET fusion identified, ongoing SD with cabozantinib EGFR T790M, brief SD to experimental EGFR inhibitor MITF amplification, no response to crizotinib ERBB2 amplification, no response to taxol and trastuzumab

30 Other Studies Phase II study by von Hoff et al Performed gene expression profiling on 108 patients with previously treated cancers 66 received molecularly determined treatment Primary outcome: PFS on targeted therapy compared to previous therapy, ratio >1.3 Von Hoff et al JCO 2011

31 Other Studies 18 patients with favorable PFS ratios Several partial responses Highlights promise and need to understand more Von Hoff et al JCO 2011

32 Other studies 1007 lung adenocarcinomas subjected to SNaPshottesting (KRAS, ALK, EGFR, BRAF, PIK3CA, NRAS, ERBB2, MET, ROS1, PIK3CA, AKT1) 64% with potentially actionable alteration 275 treated with genetically targeted therapy, 318 were not Kris et al, JAMA 2014

33 Stay tuned Prospective trials treating with a number of therapies based on patient genotyping NCI MATCH trial Lung MAP trial Melanoma Su2C GEMM trial All ongoing or starting in 2015

34 Resources

35 Conclusions Targeted NGS identifies potentially actionable mutations with variable clinical implications Critically important in a few patients As additional genotype directed trials are opened, we will increase the proportion who receive genotype directed therapy Tissue agnostic trials will be a useful tool

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