MenariniSearch Training July 2024 PDF

MenariniSearch Training July 2024 M_DOC_023 Rev. 5 CMD_MKT_025 Rev.3  Breast Cancer M_DOC_023 Rev. 5 2 CMD_MKT_025 Rev.3  Patient Journey:...

MenariniSearch Training July 2024 M_DOC_023 Rev. 5 CMD_MKT_025 Rev.3  Breast Cancer M_DOC_023 Rev. 5 2 CMD_MKT_025 Rev.3  Patient Journey: Example Metastatic Breast Cancer Patient Pathology tests for disease classification, prognosis and therapy selection Palliative/best supportive care All stages Genetic ER/PR 1st visit Refers to Counselor MDT Surgery Initial breast HER2 PCP / A+E Surgeon Regular cancer diagnosis Cytokeratin Ki-67 1L therapy monitoring Physical gBRCA1/2 USS Stage IV Patient exam personal/ mammogram, AP by H+E (mets) presentation family history Needle core biopsy, Disease BRCA1/2 Progression or relapse Lymph node staging PD-L1 assessment PIK3CA mTOR NTRK +/- Bone Physical, Re-biopsy possible? MSI-H/dMMR metastasis CT/MRI, Bone (Tissue and/or blood) scan, Yes No Radiographs Extract new tissue Use original and/or liquid biopsy Dx biopsy TNBC BRCA1/2 BRCA 1/2 HR+ Evaluate NTRK Key PIK3CA (HER2-) ER/PR/HER2 status MSI-H/dMMR NTRK TMB Surgery Lab tests Routine tests MSI-H/dMMR TMB 2L therapy and Diagnosis/ Therapy subsequent lines classification Source: Menarini Stemline Oncology  Applications of MSB Tests in BrCA Pathway Pathology tests for Surgery disease Progression or relapse classification, prognosis and 1L therapy therapy selection Re-biopsy possible? +/- Bone Physical, CT/MRI, (Tissue and/or blood) metastasis Bone scan, Radiographs Yes No Extract new Use original Dx biopsy tissue and/or liquid biopsy BRCA1/2 Evaluate TNBC NTRK HR+ ER/PR/HER2 MSI-H/dMMR status TMB BRCA 1/2 PIK3CA (HER2-) ESR1, NTRK Palliative/best MSI-H/dMMR TMB supportive 2L therapy and care subsequent lines M_DOC_023 Rev. 5 4 CMD_MKT_025 Rev.3  Selling CTC HER2 & MenariniSearch M_DOC_023 Rev. 5 CMD_MKT_025 Rev.3  DNA, RNA, Protein Our cells contain RNA is created from Proteins are created from DNA, the instructions DNA and contains the RNA and have many that tell our bodies instructions for how to important functions in the how to work. build proteins body M_DOC_023 Rev. 5 6 CMD_MKT_025 Rev.3  ERBB2 GENE Chromosomes are Chromosome made up of DNA 17q12 DNA are made ERBB2 up of genes Amplification DNA Gene are made up of introns and exons ERBB2 ERBB2 Mutations (HER2) RNA is created from DNA Gene and typically contains information from the ERBB2 RNA exons Splicing RNA serves as a template to make Protein Overexpression proteins M_DOC_023 Rev. 5 7 CMD_MKT_025 Rev.3 Positioning MenariniSearch  The Only CLIA Lab That Offers CTCs + Comprehensive Genomic Profiles in Most Cancers Circulating Tumor Cell and Biomarker Testing in cfDNA/cfRNA Tandem Liquid Biopsy Testing in Solid Tumors and Multiple Myeloma Solid Tumors and Hematological Malignancies Insights from CTCs and cfDNA/cfRNA is The Future of Liquid Biopsy & Oncology Management Example: Testing CTC-HER2 & MenariniSearch in Tandem Treatment / Monitoring 2L 3L 4L 5L 6L 7L TESTING TREATMENT Faster to Treatment HER2 Targeted TAT ~2 Days Therapy Positive Re fle x >1 HER2 CTC Cell Combination Targeted HER2 CTCs Therapy Therapy Liquid Biopsy cfDNA / cfRNA Biomarker Testing TAT 1600 genes Colorectal Leukemia Brain (CHIP, AML, ALL, CLL, CML, HCL, PH-Like ALL) Prostate Lymphomas Liver Myelodysplastic syndromes Bladder (MDS-MLD, - SLD, -RS, -EB, del5q, -U) Sarcoma Myeloproliferative Neoplasms Kidney DNA RNA Histiocytic and Dendritic Melanoma 434/ 302 genes >1600 genes Cell Neoplasms Gynecological Clonal Evolution Tissue Biopsy Tissue Bone Biopsy Marrow Pancreatic Cancer of Unknown Primary Origin  Overview of MenariniSearch MSearch provides a broad genetic overview of the tumor, revealing additional actionable mutations like PIK3CA and ESR1. Unlike our competitors like GH, FM, Caris, Tempus – Msearch uniquely combines comprehensive cfRNA assessment with cfDNA. This dual approach increases sensitivity of our liquid biopsy assay to provide a more complete molecular profile of tumors, offering deeper insights into cancer biology and enabling more precise, personalized treatment strategizes. When it comes to BrCa – our tests can detect amplifications, mutations, gene expressions, Exon skipping, fusions, chromosomal structural changes, viruses, TMB and more. We Differentiate with RNA M_DOC_023 Rev. 5 17 CMD_MKT_025 Rev.3 Collection and Shipping 18  MenariniSearch Specimen Requirements Liquid Biopsy Bone Marrow or Tissue Biopsy Peripheral Blood Cerebrospinal Fluid Peripheral blood: 10 mL. CSF: 7-10 mL. EDTA tube is preferred. No preservative tube Ship in room temp Ship with cold pack (2-4ºC) Important Note: Important Note: EDTA tube: CSF samples: RNA stability is optimal 48-72 hours There is a higher chance of QNS for RNA from blood draw. when transported in tubes with no DNA stability is 7 days from blood draw. preservatives. Our lab will repeat the extraction process if the quality or amount Samples received beyond 72 hours may does not pass our QC. In some cases we may include only DNA results request a redraw. M_DOC_023 Rev. 5 19 CMD_MKT_025 Rev.3 Sample Types for MenarniSearch Profiles Sample Type Tube Amount /Condition Kit Select One Test MenariniSearch Liquid Trace – Heme EDTA Blood 8-10mLs MenariniSearch Liquid Trace – Solid Tumor 7-10mL. optimal MenariniSearch Liquid Clear tubes (5 mL. minimum) Trace – Solid Tumor CSF Ship with cold pack (2-4ºC) MenariniSearch LiquidTrace - Heme MenariniSearch Bone Marrow EDTA 5mLs Hematological Profile Plus 6-8 unstained slides Tissue OR 1 H&E slide MenariniSearch Solid Or Tumor Plus FFPE Block  How TO Order Tests and Kits M_DOC_023 Rev. 5 21 CMD_MKT_025 Rev.3  Two Ways To Order MenariniSearch Test Paper Requisition Online Portal Access Patient Reports Through The Portal M_DOC_023 Rev. 5 22 CMD_MKT_025 Rev.3  Benefits of RNA Analysis M_DOC_023 Rev. 5 23 CMD_MKT_025 Rev.3  Comprehensive RNA Insights Matter Gene Expression Tumor Profiling Heterogeneity Alternative Predict Drug Splicing Detection Response Identify Monitor Treatment Fusions We Sequence More than Response 1600 RNA/cfRNA genes Detect MORE Mutations through “Targeted” RNA sequencing than the conventional whole transcriptome & DNA sequencing M_DOC_023 Rev. 5 24 CMD_MKT_025 Rev.3  Benefits of cfDNA & cfRNA Real-Time Monitoring and Prediction of Therapeutic Assessment of Treatment Evolution of Tumor Targets and Resistance Response and Resistance Mechanisms The combined analysis of cfDNA and cfRNA analysis can reveal overexpressed The expression levels of certain genes, cfRNA allows for real-time monitoring genes or pathways that are potential detectable through cfRNA, can serve of how tumor evolves under targets for therapy, which might not be as dynamic markers of response to therapeutic pressure, providing evident from cfDNA analysis alone. treatment. Additionally, cfDNA can insights into the mechanisms of Conversely, cfDNA can identify genetic identify emerging mutations that confer resistance and enabling adaptive mutations responsible for drug resistances, resistance to therapies, allowing for a treatment strategies providing a complete picture for optimizing more nuanced understanding of treatment strategies treatment efficacy over time cfRNA Helps in Evaluating the Entire Immune System M_DOC_023 Rev. 5 25 CMD_MKT_025 Rev.3  Benefits of cfDNA & cfRNA Enhanced Detection of Improved Mutations & Increase Tumor Heterogeneity Sensitivity Gene Expression Diagnostic Yield Comprehensive tumor Complementary detection cfDNA analysis primarily Some genetic alterations dynamics: Tumors are highly methods: Certain types of detects genetic mutations, may be undetectable by heterogeneous and can be alterations are more readily copy number variations, cfDNA due to low temporal and spatial. cfDNA detected in cfRNA, such as gene and methylation patterns. captures the genetic abundance or technical fusions and specific expression cfRNA complements this heterogeneity across different limitations profiles indicative of early-stage by providing data on gene tumor sites, while cfRNA offers cfRNA can increase the cancer. Combining cfDNA and expression levels, fusions insights into the heterogeneity diagnostic yield, particularly cfRNA analyses can improve the genes, alternate splicing of gene expression, enabling a sensistivity and specificity of that play crucial roles in for aberrations that effect more comprehensive monitoring cancer development and gene expression without understanding of tumor biology progression altering the DNA sequence M_DOC_023 Rev. 5 26 CMD_MKT_025 Rev.3  RNA-Seq is Superior Than DNA in Detecting Fusions The vast majority of genomic rearrangements occur in introns Detection of fusions from DNA require intron sequencing Using RNA allows exon-to-exon sequencing RNA-based Fusions DNA-based Fusions RNA sequencing detects fusions from known and novel DNA-based fusion testing relies on the detection of transcripts structural alterations in the DNA, which may not always result in the formation of functional fusion transcript It can differentiate between functionally significant fusion events and passenger mutations DNA-based testing may detect fusion events that are not actively expressed in the tumor, leading to false positives RNA-based fusion detection is more accurate in identifying active fusion events because it detects mRNA It may miss some fusion events that are only detectable transcripts at the RNA level M_DOC_023 Rev. 5 27 CMD_MKT_025 Rev.3  Miscellaneous M_DOC_023 Rev. 5 28 CMD_MKT_025 Rev.3  Variant Allele Frequency The VAF represents the fraction of variant reads out of the total number of reads at that position A somatic mutation in 50% of reads A heterozygous germline variant M_DOC_023 Rev. 5 29 CMD_MKT_025 Rev.3  HER2 Amplification, Overexpression, Mutations Assessing HER2 amplification, ERBB2 overexpression refers to the increased production of overexpression and mutations is the HER2 protein on the surface of cancer cells. It is due to crucial for a precise diagnosis, HER2 gene amplification, which occurs in 18% to 20% of optimal treatment planning and patients with breast cancer. effective monitoring of breast Impact – Associated with more aggressive tumor behavior and poorer outcomes without HER2-targeted therapy cancer. This comprehensive approach ensure that patients receive the most appropriate and effective therapies, HER2 somatic mutations are present in improving outcomes and quality of life approximately 2–5% of primary breast cancers M_DOC_023 Rev. 5 30 CMD_MKT_025 Rev.3  Chromosomal structural changes can drive cancer What is the development and progression. Identifying these changes can uncover potential therapeutic targets and provide prognostic information, helping to tailor treatment chromosomal strategies and anticipate potential challenges in patient management structural changes Chromosomal changes such as amplifications or deletions can play a significant role in BrCa. in cancer? Example: Amplification of ERRB2 (HER2) gene which occurs in ~20% of BrCa patients leads to overexpression of HER2 protein and is associated with aggressive tumor behavior. This information is important to guide patient to appropriate therapy ( Trastuzumab or Herceptin) M_DOC_023 Rev. 5 31 CMD_MKT_025 Rev.3  Tumor Heterogeneity Tumor heterogeneity is critical as it affects treatment response How Tumor and resistance. By understanding the different subpopulations within a tumor you can design combination therapies that target Heterogeneity is multiple pathways, improving likelihood of treatment success and reducing the risk of relapse. important in cancer Tumor Heterogeneity in breast cancer can impact treatment efficacy. For instance, a tumor that shows HER2 Expression management? may require a combination of HER2-targeted therapies and other treatments to address the different tumor cell populations effectively, improving overall all treatment outcomes. M_DOC_023 Rev. 5 32 CMD_MKT_025 Rev.3  HLA genotyping is crucial as it can guide immunotherapy HLA: treatments. Understanding a patient's HLA type helps in predicting their response to immune checkpoint inhibitors and can aid in selecting the most effective How does HLA immunotherapy options genotyping In breast cancer, understanding a patient’s HLA type can help predict their response to certain immunotherapies. For information help in instance, HLA genotyping can identify patients who are more cancer treatment? likely to benefit from immune checkpoint inhibitors, which can be particularly useful in triple-negative breast cancer (TNBC) where treatment options are limited. M_DOC_023 Rev. 5 33 CMD_MKT_025 Rev.3  Assessing clonality helps in understanding tumor Clonality: evolution and resistance mechanisms. Knowing the clonal architecture of a tumor allows for better prediction of disease progression and the development of Why should we resistance, enabling more strategic and adaptive treatment approaches consider clonality In breast cancer, assessing tumor clonality can provide in treatment insights into tumor progression and treatment resistance. It can identify subclones that might be resistant to current decisions? treatments, allowing oncologists to adjust therapy plans accordingly. M_DOC_023 Rev. 5 34 CMD_MKT_025 Rev.3  Gene Expression Gene expression profiling provides insights into the How does gene tumor's biology and behavior, identifying which genes are actively driving cancer growth. This information can expression data guide the selection of targeted therapies and predict treatment responses, leading to more personalized and help in treating effective treatment plans. cancer? M_DOC_023 Rev. 5 35 CMD_MKT_025 Rev.3  Multiple Myeloma M_DOC_023 Rev. 5 36 CMD_MKT_025 Rev.3  Comprehensive RNA & DNA Profiles Powered by Artificial Intelligence and Reviewed by Pathologists Detects guideline-recommended biomarkers and more Developed by a team of Hematopathologist Solid Tumor pathologists Scientists and Statisticians 37 Multiple Technologies in One Test MenariniSearch includes SNVs, Fusions, InDels, Gene Expression, CNV, HPV, T&B-cell Clonality, HLA Genotyping Liquid Biopsy OR Tissue Biopsies  Beyond the Ordinary: Liquid Biopsy For Clinical Use PB / CSF Tumor Fraction Mut/mL Assay Sensitivity < 0.1% 0.01%* - Tumor informed cfDNA/cfRNA Hematological Malignancies >1000 Solid Tumors Samples Clinically Validated  What is the Chromosomal structural changes can drive cancer development and progression. Identifying these changes can uncover potential therapeutic chromosomal targets and provide prognostic information, helping to tailor treatment strategies and anticipate potential challenges in patient management structural changes in Chromosomal structural changes, such as deletions, translocations, and amplifications, are common in multiple myeloma and have cancer? significant prognostic and therapeutic implications. For example, the presence of del(17p) (deletion of part of chromosome 17) is associated with a poor prognosis and may prompt the use of more intensive treatment strategies or participation in clinical trials for novel therapies. M_DOC_023 Rev. 5 40 CMD_MKT_025 Rev.3  Tumor Heterogeneity Tumor heterogeneity is critical as it affects treatment response and How Tumor resistance. By understanding the different subpopulations within a tumor you can design combination therapies that target multiple Heterogeneity is pathways, improving likelihood of treatment success and reducing the risk of relapse. important in cancer Tumor heterogeneity in multiple myeloma can affect treatment outcomes. For instance, intratumoral heterogeneity can lead to varied management? responses to treatment, where some subpopulations of myeloma cells might be sensitive to a specific therapy while others are resistant. Understanding this heterogeneity can help in designing combination therapies that target multiple pathways. M_DOC_023 Rev. 5 41 CMD_MKT_025 Rev.3  Gene expression profiling provides insights into the Gene Expression: tumor's biology and behavior, identifying which genes are actively driving cancer growth. This information can How does gene guide the selection of targeted therapies and predict treatment responses, leading to more personalized and expression data effective treatment plans. help in MM? Gene expression profiling in multiple myeloma can identify high-risk genetic signatures, such as the overexpression of genes like MMSET/FGFR3 (associated with the t(4;14) translocation). This information can guide the choice of more aggressive treatment regimens for patients with high-risk profiles. M_DOC_023 Rev. 5 42 CMD_MKT_025 Rev.3  HLA genotyping is crucial as it can guide immunotherapy HLA: treatments. Understanding a patient's HLA type helps in predicting their response to immune checkpoint inhibitors and can aid in selecting the most effective How does HLA immunotherapy options genotyping HLA genotyping is important in multiple myeloma (MM) for guiding information help in allogeneic stem cell transplantation. Matching HLA types between donors and recipients is crucial for reducing the risk of cancer treatment? graft-versus-host disease (GVHD) and improving transplant success rates. M_DOC_023 Rev. 5 43 CMD_MKT_025 Rev.3  Assessing clonality helps in understanding tumor evolution Clonality: and resistance mechanisms. Knowing the clonal architecture of a tumor allows for better prediction of disease progression and the development of resistance, Why should we enabling more strategic and adaptive treatment approaches consider clonality in treatment Assessing clonality in multiple myeloma helps understand disease progression and treatment resistance. MenariniSearch can identify clonal evolution, indicating which subclones are driving relapse and decisions? may be resistant to current therapies, thereby guiding adjustments in treatment plans. M_DOC_023 Rev. 5 44 CMD_MKT_025 Rev.3  Certain viruses, like HPV, EBV and TTV are linked to specific cancers. Identifying viral presence can influence cancer Viral: treatment and progression. The information is used in targeted therapies and preventive strategies, such as vaccines or What relevance antiviral treatments, which can significantly impact patient outcomes. do viral EBV and TTV can occur in multiple myeloma patients, particularly those findings have in undergoing stem cell transplantation or receiving certain immunosuppressive therapies. Monitoring viral status helps in early intervention and management to prevent complications from viral infections. MM? EBV – is known to proliferate B-cells and TTV plays a role in immune response to therapy M_DOC_023 Rev. 5 45 CMD_MKT_025 Rev.3  HLA - Genotyping HLA genotyping provides insights that can significantly impact cancer diagnosis, treatment, and management. By understanding a patient's HLA profile, clinicians can better tailor immunotherapies, improve transplant outcomes, develop personalized vaccines, and use HLA-related biomarkers for more accurate prognostication. M_DOC_023 Rev. 5 46 CMD_MKT_025 Rev.3  HLA Genotyping -Immunotherapy Response Prediction HLA genotyping can predict which patients are more likely to Checkpoint Inhibitors: respond to immune checkpoint inhibitors such as pembrolizumab or nivolumab. Certain HLA alleles are associated with better responses to these therapies, helping to personalize and optimize treatment plans. Donor Matching: In hematologic cancers like leukemia or multiple myeloma, HLA genotyping is crucial for matching donors and Allogeneic Stem Cell recipients in allogeneic stem cell transplantation. A close HLA match Transplantation reduces the risk of graft-versus-host disease (GVHD) and increases the chances of transplant success. Example - In multiple myeloma, finding an HLA-matched donor is essential for a successful stem cell transplant, which can be a curative treatment. M_DOC_023 Rev. 5 47 CMD_MKT_025 Rev.3  Competitive Comparison M_DOC_023 Rev. 5 48 CMD_MKT_025 Rev.3 The Most Comprehensive CTC and cfDNA/cfRNA Menu Liquid Biopsy Tissue Biopsy Liquid Bx – Liquid Bx – Tissue Bx – Tissue Bx – CTC CTC + ctDNA Solid Tumor Heme Solid Tumor Heme MSB Epic Sc Adaptive Biocept FMI GH Tempus Caris Market Differentiation Current Market Need Current Market In Development 49 Competition in Liquid Biopsy for Solid Tumors and Hematology CARIS Foundation MSearch Liquid Assure GH Liquid Bx Trace Medicine Liquid Tempus* Blood-based GH 360CDx 360CGP CDx profile DNA 284 311 523 23,000 54 83 RNA >1,600 No No No No Hematology √ √ No No No No Fusion >1,600 genes 4 genes, 10 genes No 4 genes 11 genes Cytogenetics/ No/CNV in 3 genes, No/CNV2 No/CNV in 19 √/√ No/7 gene/deletion 2 No CNV MET 14 mut, genes genes MSI √ - MSI High √ yes, if detected No No √ TMB √ √ No No No √ B+T clonality √ No No No No No EBV and HPV √ No No No No No Minimal residual √ No No No √ √ disease (MRD) HLA typing √ No No No No No 2X10 ml 2X10 ml Sample Type: PB 1X10 ml (EDTA) 2X 8 ml (preservative) 2X 8 ml (streck) No (Streck) (Streck) Sample Type √ No No No No No CSF 50  vs Guardant Health INTERNAL USE ONLY M_DOC_023 Rev. 5 51 CMD_MKT_025 Rev.3  Summary: Comparison Against Guardant’s 360CDx ▪ MenariniSearch CGP Liquid Biopsy test is for Solid Tumors and Heme Malignancies ▪ MSearch CGP will analyze 302 cfDNA genes and 1600 cfRNA genes vs Guardant’s 360CDx analyses ~80 genes for cfDNA ▪ Important to note: RNA sequencing is able to detect more mutations (13% more based on widely published data) ▪ MSearch CGP will detect fusions via RNA this helps in detecting the fusion partner vs Guardan’t 360 CDx detects fusion from DNA which may not be able to detect fusion partners ▪ Gene expression is important for the new ADC class of drugs which are the next gen immunotherapies. Copy MSI- Tumor SNV InDels Fusions TMB PD-L1 HRD MRD HPV EBV TAT Other Capabilities Number High Fraction MSB’s Gene expression, exon skipping, 7-10 CGP alternative splicing, chromosomal Days changes Guardant 360CDX * * 7-10 Days Able Not Able Optional: If requested through tissue biopsy In the development roadmap for liquid biopsy * With tissue biopsy 52  Technical Comparison Shows MSB’s CGP Test is Comparable to Guardant’s 360CDx Alteration Type SNVs Alteration Type Indels (1-24bp) Liquid VAF% Reportable Analytical Analytical Liquid VAF% VAF Range Analytical Analytical Biopsy CGP Range Sensitivity Specificity Biopsy Reportable VAF Range Sensitivity Specificity CGP Range ≥ 0.01% From > 0.5% to 100% 100% 100% ≥ 0.01% From >0.5% to 100% 100% 100% MSB MSB ≥ 0.01% From 0.1% to 0.5% 64% 100% ≥ 0.01% From 0.1%-5% 96% 100% ≥ 0.04% From > 0.5% to 100% 100% 100% GH ≥ 0.06% From >0.5% to 100% 100% 100% GH From 0.1% to 0.5% 100% ≥ 0.04% From 0.1% to 0.5% 70.60% 100% 86% tia tor Differentiator: CGP with RNA Sequencing fe ren (ability to find fusion partner, unlike ctDNA based fusions) Alteration Type Copy Number Di f Alteration Type Fusions Liquid Copy Number Analytical Analytical CNV Reportable range Liquid Biopsy VAF% Reportable Analytical Analytical Biopsy CGP range Sensitivity Specificity VAF Range CGP Range Sensitivity Specificity MSB –Fusion 0.0000001 2-3 (RNA reads) 100% 100% (cfRNA assay) (RNA reads) MSB ≥ 2.16 Copies ≥ 2.14 Copies 100% 100% 0.1% to 0.5% 100% 100% GH ≥ 0.04% GH ≥ 2.18 Copies > 2.3 Copies 99.30% 100% (cfDNA assay) >0.05% to 0.3% 87.30% 100% 53  Competitive Position: Against Guardant Health vs MSB Sales: Position Heme profiles for high success rates against Guardant Health MSearch GH Battle Cards Liquid Bx Liquid Trace GH 360 CDx 360 CGP Key Attack Points against Guardant DNA 284 54 83 MSB Position Health RNA >1,600 No No Hematology √ No No GH’s CDx 360 is limited to only few MSearch liquid trace is pan-cancer panel for solid tumors indications and cancer types and hematological malignancies Fusion >1,600 genes 4 genes 11 genes Cytogenetics/ No/CNV in 19 FM’s liquid CDx is not available for MSearch liquid trace heme profile assess all hematological √/√ No/CNV2 genes hematological cancers malignancies. It also assess for B&T cell clonality CNV genes (?√) coming MSI No √ MSearch’s Liquid Trace analyzes a comprehensive set of soon RNA genes which detects known and novel fusion (?√) coming It does not include RNA insights TMB No √ transcripts. In addition to that is detects HPV counts in solid soon tumors and EBV viral count in Hematological malignancies. B+T clonality √ No No EBV and HPV √ No No GH Liquid CDx may not help a patient Minimal residual MSearch liquid trace profile is supported by Artificial √ √ √ become eligible for Antibody Drug disease (MRD) intelligence which provides the latest's insights to all the Conjugates clinical trials. It may need possible clinical trials based on the patient’s genomic HLA typing √ No No some follow up RNA profiling for alterations. expression level data Requirement 1X10 ml (EDTA) 2X10 ml (Streck) 2X10 ml (Streck)  Competitive Position: Against Guardant Health Tissue Biopsy vs MSB Sales: Position Heme profiles for high success rate against Guardant Health accounts Battle Cards Solid GH 360 Key Attack Points against MSearch MSB Position Tumors Tissue Next Foundation Medicine DNA 434 genes 84 genes GH 360 Tissue Next is available for NSCLC, breast, urothelial, RNA >1,600 No MSearch Solid tumor profile is a pan-cancer profile which includes assessing cancer of hepatobiliary, gastric, colorectal, unknown origin (CUP). pancreatic, and prostate cancers TBM √ √ MSI √ √ Fusions >1600 12 genes It does not include RNA insights MSearch’s Solid Tumor Profile Plus analyzes a comprehensive set of RNA genes thus may not provide full insights which detects known and novel fusion transcripts. In addition, to that is detects Cytogenetics/CNV √/√ No/√ to the possible genomic alterations. HPV counts in solid tumors and EBV viral count in Hematological malignancies. In addition, patient may not be HRD (LOH) √ √ The reports provide clinical matching information, which is constantly updated eligible for certain type of clinical B+T clonality √ No based on A.I algorithms that feeds/updates data from internal and external trials (e.g. Antibody drug sources EBV and HPV √ No conjugates trials) Required sample 6 unstained slides 11-15 unstained QNS rate 0.5% ??? Tumor cell of √ No origin HLA typing √ No  vs Caris Assure INTERNAL USE ONLY M_DOC_023 Rev. 5 56 CMD_MKT_025 Rev.3  KEY TAKEAWAYS 1 2 3 MenariniSearch is Highly Sample Types: MenariniSearch: Sensitive compared to CSF & Peripheral Blood Hematological Caris Assure Malignancies Menu MSB: Sensitivity 98.95% MenariniSearch is validated for Caris does not have a robust Caris: Sensitivity 93.8% CSF and Peripheral blood Hematological menu samples compared MSB. Caris Assure likely to miss more mutations than Caris does not offer CSF testing MenariniSearch is validated MenariniSearch for Leukemia, Lymphoma, Multiple Myeloma, MDS, MPN INTERNAL USE ONLY M_DOC_023 Rev. 5 CMD_MKT_025 Rev.3  MenariniSearch vs Caris Assure Liquid Biopsy Profile INTERNAL USE ONLY Caris Assure MenariniSearch Messaging Circulating Nucleic Acid Sequencing Technology Circulating Nucleic Acid Sequencing (cNAS) (cNAS) Biomarker Analysis (including resistance Biomarker Analysis (including Application mutations) resistance mutations) Plasma: cfDNA, cfRNA Plasma: cfDNA, cfRNA Biological Coverage White Blood Cells: gDNA, mRNA White Blood Cells: gDNA, mRNA Variant Coverage Tumor-Derived Incidental Germline† Tumor-Derived Incidental Germline† (pathogenic and likely Incidental CHIP Incidental CHIP pathogenic) 23,000+ (Clinical report covers only 275 23,000 genes make the profile less specific, it impacts the sensitivity of the assay as Genes DNA genes with limited amplifications and >1600 cfRNA + 302 cfDNA covers a lot of genes fusions on RNA) 8,000x (raw average for clinically relevant Depth genes) 25,000x - 30,000x 1 Next Generation Whole Exome Whole Exome Sequencing Whole Transcriptome Targeted RNA seq SNV INDEL CNA Fusions Alterations SNV INDEL CNA Fusions Gene Expression 2 Due the depth of coverage we can confidently provide gene expression information bTMB and MSI in liquid biopsy is questionable as it requires high tumor burden to accurately assess TMB and MSI. We performed multiple studies and majority of the HLA Genotype, HRD Genomic Signatures/Other bTMB (?) HLA Genotype MSI (?) liquid biopsy cases do not have high tumor burden compared to tissue biopsy. We did Viral (RNA) not feel confident in the data therefore we do not list this. However, in cases where there is high tumor burden we can report out TMB and MSI in liquid biopsy. 2 Tubes Whole Blood; 1 Tube Whole Blood ; Our profile is comprehensive and requires less blood volume (8-10mLs). Our profiles Sample Quantity NO CSF CSF (7-10 mLs) are validated on CSF sample type, which is important for CNS tumors Performance in Compared to matched tissue collected Advanced/Metastatic within 30 days; based on ≥5 ng of cNAS Patients input. Sensitivity 93.8% MenariniSearch is more sensitive and specific, it is likely to detect more mutations Sensitivity 98.95% Clinically Actionable SNV Specificity >99% and INDEL: PPV 96.8% Specificity 100% 3 and genomic alterations compared to Caris Assure. This is because of the targeted RNA approach. Our depth of sequencing for RNA is 25,000-30,000 which makes the LOD 0.1% on everything in this assay 0.01% on cases with a tissue/cell history (tumor informed) High Sensitivity: At >25,000x MenariniSearch offers extremely high sensitivity in detecting rare transcripts and low-frequency variants Increases Accuracy: Higher depth of coverage reduces the impact of sequencing errors, leading to more accurate quantification of gene expression levels Improved Detection of Isoforms: enables better differentiation and quantification of transcript isoforms which is essential for understanding alternative splicing events INTERNAL USE ONLY M_DOC_023 Rev. 5 59 CMD_MKT_025 Rev.3  cfRNA Provides More Accurate Quantification of Gene Expression Levels Read Depth of 25,000x Increases Accuracy From cfDNA BCL2 gene NM_000633.2:c.157C>T = 1.12 NM_000633.2:c.121G>C = 1.1 NM_000633.2:c.140G>A = 1.04 From cfRNA BCL2 gene NM_000633.2:c.157C>T = 75 NM_000633.2:c.121G>C = 73.94 NM_000633.2:c.140G>A = 73.26 INTERNAL USE ONLY M_DOC_023 Rev. 5 60 CMD_MKT_025 Rev.3  MenariniSearch Offers Extremely High Sensitivity Sample Report -Breast Cancer Sensitivity 93.8% Sensitivity 98.95% Specificity >99% Specificity 100% LOD 0.1% VAF LOD 1600 23,000 Tissue is like gold in oncology. Labs should find ways to preserve tissue as much as Cytogenetics/CNV √/√ No/√ possible for further assessment of the tissue. Some labs have a locked protocol and cannot make updates therefore requires a lot of tissue to reach the appropriate Do you have to send in a lot of tissue HRD (LOH) √ √ sensitivity. for a result? B+T clonality √ No With MenariniSearch we have mastered the extraction process for both DNA and RNA and thus are able to work will less tissue without compromising the sensitivity and EBV and HPV √ (?Can) specificity of the test. We require 6-8 slides compared >20 slides with Caris’s test Required sample 6 unstained slides 8 slides QNS rate 0.5% 2-7% √ (special Tumor cell of origin √ request) HLA typing √ √ INTERNAL USE ONLY M_DOC_023 Rev. 5 CMD_MKT_025 Rev.3  Competitive Position: Against Caris vs Battle Cards Hematology MSearch CARIS Key Attack Points against Foundation MSB Position DNA 302 No Medicine MSB offers comprehensive Hematological profile for bone marrow biopsy and liquid biopsy. RNA >1,600 No MenariniSearch Heme Profile – analyses all the CD markers to differentiate sub classification of Heme Malignancies Cytogenetics/CNV √/√ No Tumor Fraction – with MenariniSearch Heme Profile you gain insights to the tumor fraction – allowing you to monitor B+T clonality √ No Caris does not have a robust Hematological patients from baseline or after treatment profile EBV and HPV √ No FISH, Flow and Cytogenetics technologies are all combined into one test. Chimerism Analysis √ No For Multiple Myeloma patients - once CGP is performed you HLA typing √ No could monitor your patients with Circulating Multiple Myeloma cell (CMMC) tests. Our CMMC test comes with a Lymphoma very quick TAT (1600 (cfRNA) 523 105 SNV Yes Yes Yes INDELS Yes Yes Yes Fusions (Gene Rearrangements) 1600 genes Limited to 10 genes only Limited to 7 genes only CHIP Yes Yes No Gene Expression Yes No No Clonality Yes No No Copy Number Variations Gains and Deletions (302 genes) Limited to gains (7 genes only) Limited to gains (6 genes only) MSI-h Yes Yes Yes bTMB Yes Yes Yes PD-L1 Yes Yes Yes HLA – Genotyping Yes No No Tumor Fraction (Mutant/mL) Yes No No Virus (HPV, EBV, TTV) Yes No No Sample Type: Peripheral Blood Peripheral Blood Peripheral Blood Peripheral Blood Sample Type: CSF CSF No No Coverage 25,000x - 30,000x >5000x 20,000X 0.1% VAF 0.01% when Tumor Informed (Baseline Tissue or Liquid >0.25% >0.25% Biopsy) TAT 7 to 10 10 7  KEY TAKEAWAYS MenariniSearch provides comprehensive molecular profiling, enabling the identification of chromosomal structural changes, specific mutations, gene fusions, gene expression and other high-risk features in most solid tumors and hematological malignancies. It covers all the guideline recommended biomarkers that have therapy or clinical trials associated with it. 1 2 3 MenariniSearch is Highly Sample Types: MenariniSearch: Sensitive compared to CSF & Peripheral Blood Hematological Tempus Malignancies Menu Increase your chances against Tempus by positioning MenariniSearch for CSF testing and for Hematological Malignancies INTERNAL USE ONLY MenariniSearch Resources 68  To be Successful in Reimbursement Seek Medical/Clinical Notes from Physicians Test requisition built to seek medical necessity information Two touch points to seek Patient attestation 1st is online portal/email 2nd – form included in every collection kit Prior Authorization will be required for private payers (signed form before the sample is collected) Soft-Launch Resources MSearch Profiles – Solid Tumors Sample Reports MSearch Profiles – Heme Soft Launch Resources Contd… 71 MenariniSearch Collection Kits 72 Components Inside MenariniSearch Collection Kits Patient Attestation included to increase success rate of receive patient consent Will help shipping department/clinical department to identify MSearch cases 73