Incorporating Genomic Science into the Community Oncology Setting

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2 Incorporating Genomic Science into the Community Oncology Setting Moderator: 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

3 Incorporating Genomic Science into the Community Oncology Setting Robert Green, M.D., M.S.C.E, Senior Vice President, Clinical Oncology, Flatiron Health

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

5 FIH-FMI CG Data: Genomic Landscape of NSCLC DATA FROM FH-FMI NSCLC CG Registry Reproduces and extends findings of the The Cancer Genome Atlas project

6 Patient example: FMI testing reveals MET splice alteration Foundation Medicine clinician-facing testing results for a patient with advanced NSCLC: Supplemental information available in the FH-FMI Clinico-Genomic Registry: DETAILED ALTERATION INFORMATION * Exon 14 Splice Site Mutation * High Mutant Allele Frequency (38%) DETAILED SAMPLE INFORMATION * Tumor Mutation Burden (TMB): 1.8 / Mb (low) * Microsatellite Instability (MSI): MSI Stable

7 Journey of a Patient on Targeted Therapy After NGS Diagnosed Undergoes with Stage IA surgery for earlystage NSCLC disease Develops metastatic disease Tested for EGFR and ALK: both negative Starts 1L Therapy (Erlotinib) Progresses on 1L after 10 mo Undergoes profiling by FoundationONE: MET splice site mutation (high allelic freq) and EGFR amp discovered 2L Crizotinib Ongoing therapy without evid. of progression, now 7 months Patient age Gender Race Insurance TNM staging Structured EMR data Unstructured EMR data FMI Genomic Data FMI Advanced Analytics 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 Maximal response to therapy Progression free survival Evidence for progression seen in the chart 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 Flatiron Health, Inc. Proprietary and confidential. 7

8 Merging Genomics and Proteomics to Guide Patient Care Todd Hembrough, Ph.D., President, Proteomics NantOmics, LLC

9 GPS Cancer TM Process: Rapid Turnaround for Clinical Utility DNA and RNA sequencing Tumor tissue is biopsied, and sent along with blood for preparation for Omics analysis Sample is microdissected, 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 From Tissue to Report: Less than 21 days Quantitative proteomics Identification of tumor cells from 2 FFPE slides by pathologist Non-contact laserbased 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

10 Breast Carcinoma w/ left axillary LN mets NantOmics Confidential Do Not Distribute Case: 44 yo Female Topoisomerase amol/ug (protein) Very high expression likely responder to irinotecan ERCC1 216 amol/ug (protein) unlikely responsive to Platinum drugs TUBB 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 10

11 GPS Guided Cancer Treatment GPS Cancer TM : Enable utilization of lower cost chemotherapy with knowledge of quantitative proteomic chemo-resistance biomarkers before treatment begins. ERCC1 Not Detectable Pemetrexed Nivolumab FRα ERCC1 Detected Docetaxel PD-L1 TUBβ3 hent1 ERCC1 ALK Cisplatin Crizotinib Gemcitabine 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? Kaplan Meier curves of randomized TASTE Trial patients receiving cisplatin plus pemetrexed selected by ERCC1 proteomics levels Confidential Do Not Distribute 11 2/24/2017

12 Breast Carcinoma w/ liver mets Case: 56 yo Female NantOmics Confidential Do Not Distribute hent1 194 amol/ug (protein) Likely to respond to gemcitabine ` ERCC1 302 amol/ug (protein) Very high expression: unlikely responsive to platinum drugs Topoisomerase 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 FGFR tpm (RNA) Likely to respond to anti-fgfr agents (clinical study) IDO overexpressed (RNA) Potential response to IDO inhibitor (clinical study) ` 12

13 HER2-Positive Gastric Cancer Patients Randomized Trial: Predictive Value of GPS Cancer for Herceptin Use Gastric Cancer, Metastatic Setting Herceptin (HER2 >1825) + Chemotherapy Herceptin (HER2 <1825) + Chemotherapy Chemotherapy Alone Herceptin (HER2 >1825) + Chemotherapy Herceptin (HER2 <1825) + Chemotherapy Chemotherapy Alone Cohort 1: HER2-positive patients treated with Herceptin (trastuzumab) and chemotherapy Cohort 2: HER2-positive patients treated with chemotherapy alone GPS Cancer HER2 Cutoff: 1825 amol/µg Tissue Ock 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). 13 2/24/2017 Confidential Do Not

14 Expressed Protein Peptide Receptor Inaccurate ERBB2 Calls From a 328 Gene Panel GPS Cancer TM vs. Gene Panel in 237 ERBB2 Patients ERBB2 - DNA + RNA 15 Patients False Negative Cell Surface (Protein) Cytoplasm (RNA) Nucleus (DNA) Gene Panel 328 Genes 1/100 h of Whole Exome ~20,000 Genes 3 Billion Base Pairs Gene Expression RNA + ~20,000 Genes DNA Whole Genome GPS Cancer Percentage of Alterations (DNA and/or RNA) + DNA - RNA + DNA + RNA Genes in 328 Gene Panel Patient # 132 Potential Incorrect Calls 117 Patients ERBB2 Positive DNA Negative RNA False Positive But No RNA Over Expression ERBB2 (n=237) 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 /24/2017 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) Herceptin TM 14

15 GPS Cancer: Guided Cancer Therapy Predictive of Efficacy and Resistance Case Study: Metastatic Uterine Cancer Paclitaxel Ifosfamide Standard of Care Treatment Options Carboplatin Cisplatin Doxorubicin Topotecan Radiation GPS Cancer A Universal Decision Support For All Cancer Drug Therapy Drug Analyte DNA RNA Pembrolizumab MK-3475 Quantitative Proteomics (GPS Cancer) PD-L1, MSI Quant Protein (amol/ug ) Efficacy Threshold 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 2/24/2017 Green: Likely to respond; Red: Unlikely to respond 15

16 Basic Clinical Trial Menu for Proteomics Chemotherapy agents cisplatin, carboplatin, oxaliplatin gemcitabine irinotecan, topotecan doxorubicin, etoposide pemetrexed, methotrexate temozolamide paclitaxel, docetaxel enzalutamide, bicalutamide, flutamide cytoxan 5-FU Immuno-Oncology markers IDO1 inhibitors pembrolizumab, nivolumab Immune cell infiltration MSI markers Differentiation markers EMT Transition Biomarker ERCC1 RRM1, hent TOPO1 TOPO2A FR-α MGMT TUBB3 Androgen Receptor (AR) ALDH1 TS/TYMP Biomarker IDO1 PD-L1 CD8 MSH2, MSH6 Biomarker E-Cadherin, Vimentin Targeted therapy cetuximab, panitumumab trastuzumab, T-DM1, pertuzumab, lapatinib trastuzumab, HER3 Targeted Clinical Trials crizotinib, ceritinib Biomarker EGFR HER2 HER3 ALK pazopanib FGFR 1, 2, 3, 4 cabozantinib, vendetanib trametinib, dabrafenib pembrolizumab, nivolumab palbociclib Targeted Clinical Trials MET Targeted Clinical Trials ROS1 Targeted Clinical Trials IGF1R Targeted Clinical Trials MSLN Targeted Clinical Trials AXL Targeted Clinical Trials RET KRAS PD-L1 p16 Biomarker MET ROS1 IGF1R MSLN AXL 16

17 Quantum Oncotherapeutics Entering the Tumor Microenvironment GPS Guided Immuno Induction Phase Immunogenic Modulation Combination Therapy T-Regs, MDSC & M2 Checkpoints NK Cells NK Transplant Phase Memory NK Dendritic Cell Immune Synapse Consolidation Phase T-Cell Memory T-Cell Immune Maintenance Phase Fusion Proteins Abraxane NB-AB NB-ABC NB-AR NB-AT NB-AA NB-AE NB1 / CXCL NB1 / NB-803 NB-011 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 MDSC T-Reg NB-AB 5FU M2 Cytoxan Macrophage NB-GITR-L NB-182 NB1 / GITR-L NBt803 / GITR-L NBt803 / OX40L / Anti CD25 Anti PD-L1 Anti PD-1 Anti CTLA4 NK Exogenous Off-the-Shelf Natural Killer NK-92 Cells ank hank Her2.taNK NK Endogenous Autologous NK Fusion Protein Superkine IL-15 IL-18 IL-12 Tumor Associated Signal 1 NB-vCEA NB-vHer2 NB-vHer3 NB-vMUC1 NB-vBrachyury NB-vHPV NB-vPSA NB-vTRIAD Neoepitopes NB-vNeoepitope Co-Stim Signal 2 NB-v41BBL+vCombo NB-vOX40L+vCombo NB-vGITRL+vCombo NB-vNB1-OX40L+Anti CD25 Type 1 Interferon STING Pathway NB-vLMP1-IPS1 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 Entering the Tumor Microenvironment Converting Cold Tumor to Hot Tumor Innate Immunotherapy Adaptive Immunotherapy Persistent Memory The Path to the Cancer Vaccine & The Memory T & NK Cell: QUILT Trial Entering the Era of Clinical Genomics & Proteomics to Deliver 21 st Century Immuno Oncology Neoepitope Immunotherapy for N=1 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 : 15 Registration Studies Total Number Active & Planned Trials ( ): 108 Total Studies Issued IP & Pending: Term 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

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

19 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.

20 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.

21 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

22 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?

23 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