Incorporating Genomic Science into the Community Oncology SettingModerator: Carla Balch, President, NantCare

Panelists:Robert Green, M.D., M.S.C.E., Senior Vice President, Clinical Oncology, Flatiron Health

Todd Hembrough, Ph.D., President, Proteomics NantOmics, LLC

Jonathan Hirsch, President and Founder, Syapse

Tracey Weisberg, M.D., President, New England Cancer Specialists

Incorporating Genomic Science into the Community Oncology Setting

• Robert Green, M.D., M.S.C.E, Senior Vice President, Clinical Oncology, Flatiron Health

NSCLC: Comparison of FIH-FMI CG Data to TCGA Data

FIH-FMI CG Data: Genomic Landscape of NSCLCDATA FROM FH-FMI NSCLC CG Registry

Reproduces and extends findings of the The Cancer Genome Atlas project

Patient example: FMI testing reveals MET splice alteration

DETAILED ALTERATION INFORMATION* Exon 14 Splice Site Mutation* High Mutant Allele Frequency (38%)

Foundation Medicine clinician-facing testing results for a patient with advanced NSCLC:

Supplemental information available in the FH-FMI Clinico-Genomic Registry:DETAILED SAMPLE INFORMATION* Tumor Mutation Burden (TMB): 1.8 / Mb (low)* Microsatellite Instability (MSI): MSI Stable

Journey of a Patient on Targeted Therapy After NGS

7 © 2015 Flatiron Health, Inc. Proprietary and confidential.© 2015 Flatiron Health, Inc. Proprietary and confidential. 7

Diagnosed with Stage IA

NSCLC

Develops metastatic

disease

Tested for EGFR and ALK: both negative

Undergoes surgery for early-

stage disease

Starts 1L Therapy

(Erlotinib)

Undergoes profiling by FoundationONE: MET splice site mutation

(high allelic freq) and EGFR amp discovered →

2L Crizotinib

Progresses on 1L after 10

mo

Ongoing therapy without evid. of

progression, now 7 months

• Patient age• Gender• Race• Insurance• TNM staging

• Sites of metastases

• Biopsy date• Type of test

conducted • Turnaround

time for test• Number of

unsuccessful tests

• Test result, if successful

• Type of EGFR mutation

• Regimen name

• Duration of therapy

• Dosage• Concomitant

meds

Structured EMR dataUnstructured EMR dataFMI Genomic DataFMI Advanced Analytics

• Biopsy date• Site of biopsy• Alterations• Alteration class• Harmonized alteration

interpretation• List of VUS• Tumor mutation burden

(mutation load)• Microsatellite instability• Copy number• Minor allele frequencies

• Initial response to therapy

• Maximal response to therapy

• Maximal response to therapy

• Progression free survival

• Evidence for progression seen in the chart

Merging Genomics and Proteomics to Guide Patient Care

Todd Hembrough, Ph.D., President, Proteomics NantOmics, LLC

Tumor tissue is biopsied, and sent along with blood for preparation for Omics analysis

Sample is micro-dissected, and DNA & RNA are extracted

DNA and RNA libraries are prepared for sequencing

Whole genome sequencing followed by genomic, transcriptomic and proteomic analysis

Disrupted pathways, prognostic markers and potential therapies presented to the oncologist in a straightforward report

1 2 3 4 5

GPS CancerTM Process: Rapid Turnaround for Clinical Utility

From Tissue to Report: Less than 21 days

DNA and RNA sequencing

Quantitative proteomics

1 2 3 4 5Identification of tumor cells from 2 FFPE slides by pathologist

Non-contact laser-based dissection from DIRECTOR® slide

Liquid Tissue® processing releases DNA and protein into solution

Multi-protein quantitation by mass spec and DNA mutation analysis by NGS

Receive patient-specific objective guidance to personalize therapies

2/24/2017 9

Breast Carcinoma w/ left axillary LN mets

10

• Case: 44 yo Female• Topoisomerase 1 – 1895 amol/ug (protein)

• Very high expression likely responder to irinotecan

• ERCC1 – 216 amol/ug (protein)– unlikely responsive to Platinum drugs

• TUBB3 – 4010 amol/ug (protein)– Very High expression unlikely to respond to

taxanes• P53 R248Q CN LOH (DNA)• Germline PMS2 Loss (DNA)

• Potential response to immunomodulatory agents

• 3.31 mut/Mb (DNA)• Above cutoff for response to checkpoint inh

• PD-1, CTLA-4, LAG-3 overexpressed (RNA)• Likely to respond to nivo/pembro, ipi

NantOmics | Confidential – Do Not Distribute

TUBβ3

Docetaxel

FRα

Pemetrexed Nivolumab

PD-L1

ALKhENT1

Gemcitabine

Crizotinib

Addressing the Question:“Doctor, what information do you have from my tumor

tissue that will help inform you that the treatment you are about to prescribe has a probability of being effective?”

GPS GuidedCancer Treatment

Kaplan Meier curves of randomized TASTE Trial patients receiving cisplatin plus pemetrexed

selected by ERCC1 proteomics levels

ERCC1

Cisplatin

GPS CancerTM: Enable utilization of lower cost chemotherapy with knowledgeof quantitative proteomic chemo-resistance biomarkers before treatment begins.

ERCC1 Not Detectable

ERCC1 Detected

11

2/24/2017

Confidential | Do Not Distribute

Breast Carcinoma w/ liver mets

12

• Case: 56 yo Female • hENT1 – 194 amol/ug (protein)

• Likely to respond to gemcitabine• ERCC1 – 302 amol/ug (protein)

– Very high expression: unlikely responsive to platinum drugs• Topoisomerase 1 – 5100 amol/ug (protein)

• Very high expression: likely responder to irinotecan• Topoisomerase 2a – 1635 amol/ug (protein)

– Likely to respond to anthracyclines• Flt1, Flt3 amplified and expressed; PIK3C2G amplified and

overexpressed (DNA & RNA)• Potential enrollment in clinical study

• FGFR1 – 349.6 tpm (RNA)• Likely to respond to anti-FGFR agents (clinical study)

• IDO overexpressed (RNA)• Potential response to IDO inhibitor (clinical study)

NantOmics | Confidential – Do Not Distribute

``

Herceptin (HER2 >1825) + Chemotherapy

Herceptin (HER2 <1825) + Chemotherapy

Chemotherapy Alone

Herceptin (HER2 >1825) + Chemotherapy

Herceptin (HER2 <1825) + Chemotherapy

Chemotherapy Alone

Cohort 2: HER2-positive patients treated with chemotherapy alone

HER2-Positive Gastric Cancer Patients Randomized Trial: Predictive Value of GPS Cancer for Herceptin Use

Gastric Cancer, Metastatic Setting

Cohort 1: HER2-positive patients treated with Herceptin (trastuzumab) and chemotherapy GPS Cancer HER2 Cutoff:

1825 amol/µg Tissue

13Ock et al. Quantitative measurement of HER2 levels by multiplexed mass spectrometry to predict survival in gastric cancer patients treated with trastuzumab. J Clin Oncol 33, 2015 (suppl; abstr 4050).

2/24/2017 Confidential | Do Not

Inaccurate ERBB2 Calls From a 328 Gene Panel

Nucleus (DNA)

Cytoplasm (RNA)

Cell Surface (Protein)

Expressed Protein Peptide Receptor

DNA

+~20,000 Genes

Gene Expression

Whole Genome

GPS Cancer~20,000 Genes

3 Billion Base Pairs

Genes in 328 Gene Panel

Per

cent

age

of A

ltera

tions

(DN

A a

nd/o

r R

NA

)

Potential False-Positive Calls (69% instances in 3,783 Patients)Potential False-Negative Calls (26% instances in 3,783 Patients)Potential Incorrect Calls From a Gene Panel (~95% of Patients)

RNA

117 PatientsERBB2

Positive DNANegative RNA

False PositiveBut No RNA

Over Expression

ERBB2 (n=237)

Pat

ient

#

Gene Panel328 Genes

1/100h of Whole Exome

15 PatientsFalse Negative

ERBB2

+ DNA- RNA

- DNA+ RNA

+ DNA+ RNA

132Potential Incorrect

Calls

HerceptinTM

2/24/2017

GPS CancerTM vs. Gene Panel in 237 ERBB2 Patients

14

Genomics, Transcriptomics, and Proteomics in the Clinical Setting: Integrating Whole Genome and RNA Sequencing With Quantitative Proteomics to Better Inform Clinical Treatment Selection (Abstract #11093) – Presented at ASCO 2015

Drug Analyte DNA RNA

QuantProtein

(amol/ug)

Efficacy Threshold

PembrolizumabMK-3475

PD-L1, MSI

No MSI No PD-L1 < 100 > 100

Paclitaxel TUBB3 Intact Expressed < 100 < 850

Trastuzumab HER2 Amplified Amplified 4,995 > 740

Doxorubicin TOPO2A Intact Expressed 472 > 1,530

Pemetrexed FRa Intact Expressed 10,500 > 1,510

GPS Cancer: Guided Cancer Therapy Predictive of Efficacy and Resistance2014-2016 Case Study: Metastatic Uterine Cancer

GPS Cancer

Green: Likely to respond; Red: Unlikely to respond

Standard of Care Treatment Options

Paclitaxel IfosfamideCarboplatin

CisplatinDoxorubicin Topotecan Radiation

Quantitative Proteomics (GPS Cancer)

A Universal Decision Support For All Cancer Drug Therapy

152/24/2017

Chemotherapy agents Biomarkercisplatin, carboplatin, oxaliplatin ERCC1gemcitabine RRM1, hENTirinotecan, topotecan TOPO1doxorubicin, etoposide TOPO2Apemetrexed, methotrexate FR-αtemozolamide MGMTpaclitaxel, docetaxel TUBB3enzalutamide, bicalutamide, flutamide Androgen Receptor (AR)cytoxan ALDH15-FU TS/TYMP

Targeted therapy Biomarkercetuximab, panitumumab EGFRtrastuzumab, T-DM1, pertuzumab,lapatinib HER2

trastuzumab, HER3 Targeted Clinical Trials HER3

crizotinib, ceritinib ALKpazopanib FGFR 1, 2, 3, 4cabozantinib, vendetanib RETtrametinib, dabrafenib KRASpembrolizumab, nivolumab PD-L1palbociclib p16

Differentiation markers BiomarkerEMT Transition E-Cadherin, Vimentin

Basic Clinical Trial Menu for Proteomics

16

Targeted Clinical Trials BiomarkerMET Targeted Clinical Trials METROS1 Targeted Clinical Trials ROS1IGF1R Targeted Clinical Trials IGF1RMSLN Targeted Clinical Trials MSLNAXL Targeted Clinical Trials AXL

Immuno-Oncology markers BiomarkerIDO1 inhibitors IDO1pembrolizumab, nivolumab PD-L1Immune cell infiltration CD8MSI markers MSH2, MSH6

Number of Molecules in Clinical Development and Preclinical Studies: Over 60 Molecules

Number of Phase I Trials Current (2016) & Planned (2017): 67 Phase I Studies

Number of Phase II Trials Current (2016) & Planned (2017): 26 Phase II Studies

Number of Registration Trials Planned in 2017-2019: 15 Registration Studies

Total Number Active & Planned Trials (2017-2018): 108 Total Studies

Issued IP & Pending: Term 2028 - 2035

Clinical Trial Site Management Organization Central IRB - 3,000 Provider Oncology Clinical Network

Biological & Cytotoxic GMP Manufacturing Facilities 2017 Completion: Vaccine, NK Therapy and Fusion Proteins

The Path to the Cancer Vaccine & The Memory T & NK Cell: QUILT TrialEntering the Era of Clinical Genomics & Proteomics to Deliver 21st Century Immuno Oncology

Neoepitope Immunotherapy for N=1

AdaptiveImmunotherapy

InnateImmunotherapy

Entering the Tumor Microenvironment

NKCells

NKExogenous

Off-the-ShelfNatural KillerNK-92 Cells

• aNK• haNK• Her2.taNK

T-Regs,MDSC & M2

MDSC T-Reg

M2Macrophage

• NB-AB• 5FU• Cytoxan• NB-GITR-L• NB-182• NB1 / GITR-L• NBt803 / GITR-L• NBt803 / OX40L / Anti CD25

• NB-v41BBL+vCombo• NB-vOX40L+vCombo• NB-vGITRL+vCombo• NB-vNB1-OX40L+Anti

CD25

Co-Stim Signal 2

T-CellDendritic

Cell

• NB-vCEA• NB-vHer2• NB-vHer3• NB-vMUC1• NB-vBrachyury• NB-vHPV• NB-vPSA• NB-vTRIAD

Tumor Associated

Signal 1

NeoepitopesNB-vNeoepitope

MemoryT-Cell

Type 1 Interferon STING Pathway

NB-vLMP1-IPS1

Entering the Tumor Microenvironment

• Abraxane• NB-AB• NB-ABC• NB-AR• NB-AT• NB-AA• NB-AE• NB1 / CXCL• NB1 / NB-803• NB-011

Immunogenic ModulationCombination Therapy

• Low Dose Chemotherapy• Low Dose Radiation• Endocrine Deprivation• Small-Molecule Inhibitors• Monoclonal Antibody

• Fusion Proteins

• NB-337• NB-MYC9• NB-KRAS4562• NB-FGFR4523• NB-DR5• NB-102• NB-201• NB-Ganitumab

Checkpoints

• Anti PD-L1• Anti PD-1• Anti CTLA4

MemoryNK

NKEndogenous

Autologous NKFusion Protein

Superkine

• IL-15• IL-18• IL-12

PersistentMemory

GPS Guided Immuno Induction Phase

NK Transplant Phase

Immune Synapse Consolidation Phase

ImmuneMaintenance Phase

Converting Cold Tumor to Hot Tumor

Fusion Proteins

• NB-803• NB-801• NB-PDL1• NB-CTLA4• NB-PD1• NB-OX40L• NB-GITR-L• NB-41BBL• NB1 / OX40L• NB1 / GITR-L• NB1 / 41BBL• NBt803 / PDL1• NBt803 / IL12 / IL18• NBt803 / NB1

• NBt803 / HER2 / PDL1• NBt803 / CD20• NBt803 / CD19 / CD3• NBt803 / CD20 / CD3• NBt803 / CD33 / CD3• NBt803 / CD30 / CD3• NBt803 / 41BBL• NBt803 / GITR-L• NBt803 / OX40L / Anti CD25• NB-EGFR-mAb / CXCL• NBt803 / EGFR-mAb / CXCL

Quantum Oncotherapeutics

Tracey Weisberg, M.D.,

President, New England Cancer Specialists

The Incorporation of Genomic Science into the Market and Practice of Hematology and Medical Oncology• Evidence-based preferable• Highest value is when test result has been

linked to a definable therapeutic treatment o• Secondary value for prediction of prognosis• Highly problematic for patient when result

suggests an intervention for which there is no data or FDA clearance for payment of said agent. The lure to the unattainable cure.

The Use of Genomics and Proteomics in Community Oncology• Genomics is SOC in some treatment scenarios

• Integral aspect of many clinical research trials

• Proteomics has high potential for clinical utility but lacks prospective trials. This hinders insurance authorizations and payment.

Real-time Incorporation of Genomics and Proteomics into Clinical Decision Making

• Tissue acquisition and biopsy adequacy• Preauthorization turn around time• Time to run test (days better than weeks)• Tumor Boards most powerful for real-time

treatment planning

Genomics Impact on Clinical Outcome• Obvious big wins in breast, lung, colon and melanoma.• Testing in the Palliative Setting:

• Could testing nearer the end of life or in classically “futile” diagnoses direct care and help with counseling regarding treatment outcomes and reasonable options?• Could this type of testing eliminate therapy destined to never work and thus provide a significant cost savings in the final months of a patient’s cancer journey?

Current Usage in Community Oncology

• Genomics will soon be part of all clinical trials• Clinical trial opportunities (MATCH, TAPUR)• Classic biomarkers in initial management of all

cancers• Biopsy of metastatic sites to confirm DX and

reassess therapeutic • Metastatic patients of low ECOG status that

have been refractory to therapy• Prognostic panels