Solid Tumor Panel Powered by Oncomine™ Solutions

Solid Tumor Panel Powered by Oncomine™ solutions

Now including microsatellite instability (MSI) analysis Powerful insights to help personalize treatment

The Solid Tumor Panel uses next-generation sequencing (NGS) technology to test for actionable somatic mutations in solid tumors.

This test, as part of a comprehensive care plan, is designed to help clinicians

Optimize treatment selection and planning

Identify relevant clinical trials

Provide prognostic information, where available

Determine treatment options if no effective standard-of-care is available

Efficiently test for actionable mutations when limited tissue is available

Designed to help identify appropriate targeted therapies and clinical trials for patients with solid tumors*

20+ genes found in 115+ genes included in 15+ genes associated with 15+ guidelines 800+ clinical trials 30+ targeted therapies

for solid tumor genetic testing worldwide that are approved by the FDA

Delivers highly accurate insights into a tumor’s genomic profile+

Sensitivity 99.6%

Specificity ≥99.6%

Positive predictive value 98.2%

Negative predictive value 97.1%

Overall agreement 97.8%

*Figures updated May 2019.

+Compared against a series of cases with known or previously-tested mutations by other NGS methods. Actionable insights into solid Testing includes microsatellite instability (MSI) analysis to identify patients tumor cancers who may be candidates for immunotherapy or MSI-indicated clinical trials • Designed for use in solid tumors The Solid Tumor Panel analyzes 161 of the most relevant cancer driver • May help identify Lynch Syndrome in colon and endometrial cancers genes for clinically significant mutations, including

• Single nucleotide variants (SNVs), insertions and deletions (indels), gene fusions, copy number alterations (CNAs), and certain splice variants using DNA and RNA Markers interrogated by the MSI analysis

• National Comprehensive Cancer Network (NCCN) and other guideline-recommended markers Multiplexed markers BAT-25, BAT-26, MONO-27, NR-21, NR-24

• Gene targets that are relevant for clinical trial selection

of mutations associated with FDA-approved therapies, standard-of-care >99% treatments, and investigational therapies in clinical trials* Results are interpreted and presented in a comprehensive report

Sema4 Solid Tumor Panel report for Jane Doe. Date of Birth: 07/20/1969 MRN #: 7654321 Sex: F Lab #: 12345678O1 Sema4 Solid Tumor Panel report for Jane Doe. Genes interrogated by the Solid Tumor Panel Date of Birth: 07/20/1969 MRN #: 7654321 Referring Provider Sample(s) Collection Method Specimen Site Specimen Detail Block ID SSeemx:a F4 SolidL Taubm #o: r1 2P3a4n5e6l 7re8pOo1rt for Jane Doe. Tumor Right hemicolectomy Right colon and Genomic DNA BlockXnHZKTDY P. Freund terminal ileum Practice of Dr. P. Freund Date of Birth: 07/20/1969 MRN #: 7654321 Spring�eld Medical Of�ces 123 Main St. Sample(s) Collection Method Specimen Site Specimen Detail Block ID Referring Provider Sex: F Lab #: 12345678O1 Normal Blood Draw Peripheral Blood Genomic DNA Block12345 Eugene , OR , 97403 Tumor Right hemicolectomy Right colon and Genomic DNA BlockXPnhHoZnKeT (D55Y5) 555-55P5.5 Fre Fuanxd (555) 555-5555 terminal ileum Practice of Dr. P. Freund Depending on the case and findings, AKT1, AKT2, AKT3, ALK, AR, ARAF, AXL, BRAF, BTK, CBL, CCND1, CDK4, CDK6, CHEK2, CSF1R, Sample(s) Collection Method Specimen Site Specimen Detail Block ID Spring�eld MedicRael fOefr�rcinegs P12ro3v Midaeirn St. Normal Blood Draw Peripheral Blood Genomic DNA Block12345 Eugene , OR , 97403 P. Freund Test Tumor Right hemicoIlnedctiocmatyionRight colon and GOennocmoitcr DeNe ACode BlockXnTHPuZhmKoTonDer Y(C55e5ll) u5l5a5r-i5t5y55 Fax (555) 555-5555 Sema4 Solid Tumor Panel plus MSI Invasive moderate to poorltye drmiffinearel nilteiuamted COAD Per Requisition: 70P%ractice of Dr. P. Freund adenocarcinoma Per Sema4 PathologisStp: 7ri0n%g�eld Medical Of�ces 123 Main St. the report provides insight into CTNNB1, DDR2, EGFR, ERBB2, ERBB3, ERBB4, ERCC2, ESR1, EZH2, FGFR1, FGFR2, FGFR3, FGFR4, Normal Blood Draw Peripheral Blood Genomic DNA Block12345 Eugene , OR , 97403 Test Indication Oncotree Code PThuomneo (5r 5C5e) 5ll5u5l-a5r5i5t5y Fax (555) 555-5555 Sema4 Solid Tumor Panel plus MSI Invasive moderate to poorly differentiated COAD Per Requisition: 70% Hotspot regions FLT3, FOXL2, GATA2, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HNF1A, HRAS, IDH1, IDH2, JAK1, adenocarcinoma Per Sema4 Pathologist: 70% Interpretation Test Indication Oncotree Code Tumor Cellularity Sema4 Solid Tumor Panel plus MSI Invasive moderate to poorly differentiated COAD Per Requisition: 70% sequenced Next-generation sequencing analysis of DNA and RNA from this patient’s colonic adenocarcinoamdae nidoecnatric�iendo mclainically signicant variants in XPO1, MSH2, Per Sema4 Pathologist: 70% Appropriate targeted therapies JAK2, JAK3, KDR, KIT, KNSTRN, KRAS, MAGOH, MAP2K1, MAP2K2, MAP2K4, MAPK1, MAX, MDM4, RAF1, SETD2, PIK3RIn1t, TePrp53re atnadt PioTnEN genes. The tumor is KRAS wild-type and anti EGFR monoclonal antibodies, Cetuximab and Panitumumab, are FDA‑approved and the NCCN Guidelines® for Colon Cancer Version 2.2019 recommend Cetuximab or Panitumumab, alone or as part of combination therapy options, for the treatment of certain colorectal cancer patients with wild‑type KRAS and NRAS (NCCN Guidelines®). There are no FDA-approved or NCCN GuidelinesN®e x-rt-egceonmemraetniodne sde tqhueernacpiinegs atanragleytsiinsg o tfh DeN oAth aenrd v RarNiaAn ftrso imn tthiiss ipnadtiiceanttio’sn c. oClloinica ald Terniaolcsa arrcein aovmaail aidbelen.t i�ed clinically signicant variants in XPO1, MSH2, MED12, MET, MTOR, MYC, MYCN, MYD88, NFE2L2, NRAS, NTRK1, NTRK2, NTRK3, PDGFRA, RAF1, SETD2, PIKI3nRt1e,r TpPr5e3t antido PnTEN genes. The tumor is KRAS wild-type and anti EGFR monoclonal antibodies, Cetuximab and Panitumumab, are 87 genes PLEASE NOTE: TheF tDuAm‑oarp pprreosveendt sa ansd ttwheo NdiCffCerNe nGtu sidueblcilnoense®s wfohri Ccho mloann Cifaensctes ri tVserlfs iionn d 2if.f2e0r1e9n tr evcaormiamnte anldle Clee ftruaxcitmioanbs .o Trh Pea mniatujomr usumbacblo, anleo fneea otur raess part of combination therapy options, for the treatment of certain colorectal cancer patients with wild type KRAS and NRAS (NCCN Guidelines®). There are no FDA-approved variants in XPO1, RAF1, PIK3R1 and NPTeExNt-,g aennde trhaeti omni nsoerq suuebncclionnge a fneaaltyusries so af dDdNitAio annadl mRNutAa ftrionms tihni M‑s pSaHti2e, nStE’sT cDo2lo annidc aTdPe5n3o. Tcahrisc itnuommoar aidlseon thia�rebdo crlsi nai chaigllhy signicant variants in XPO1, MSH2, Relevant clinical trials or NCCN Guidelines® -recommended therapies targeting the other variants in this indication. Clinical Trials are available. number of variants in combination wRitAh Fa1 s,i SgEnTi�Dc2a,n Pt IMK3SRH12, TvPar5i3a natn, da PfeTaEtNur gee anlesos. a Tshseo ctiuamteodr wisi KthR rAigSh wt-isldid-teydp teu amnodr sa,n tthie ErGefFoRr em foonlloocwlo unpa tl easnttiinbgo tdoie cso, nC�ertmuximab and Panitumumab, are PDGFRB, PIK3CA, PIK3CB, PPP2R1A, PTPN11, RAC1, RAF1, RET, RHEB, RHOA, ROS1, SF3B1, the potential high tumor mutation burden is recommended, to determine the eligibility for immunotherapy. PLEASE NOTE: TFhDe Atu‑mapoprr porveesde natnsd a tsh tew NoC dCifNfe Greunitd seulibncelso®ne fso wr Chioclho nm Canainfceesrt sV ietrsseilofn in 2 d.2i0ff1e9r erenct ovmarmiaenntd a Cllelteu fxriamcatibo nosr .P Tahnei tmuamjourm saubb,c alolonnee f oera atusr peasrt of combination therapy options, for the treatment of certain colorectal cancer patients with wild type KRAS and NRAS (NCCN Guidelines®). There are no FDA-approved These results were vreavriaenwtesd in a XndP Oin1te, RrpArFe1te, Pd IbKy3 ARn1d arnedw P PToElNlo,c akn, dL athbeo rmatinooryr sDuibrecclotonre. Ffeoar tinuqreusir aiedsd aitbionuat lt mhius traetpionrts, pi‑nle MasSeH c2a, lSl E1T-8D323 a-4n8d6 T-P65236.0 T. his tumor also harbors a high number of varianotsr iNn CcoCmNb Ginuaidtieolnin wesit®h a-r seicgonmi�mcaenntd MedS Hth2e vrapriiaenst t, aar fgeeattinugre t haels ot ahsesro vcaiaritaendt ws iinth t hriigsh int-dsiicdaetdio tnu.m Colirnsi,c tahle Trreifaolsre a froel laovwa iulapb tlees. ting to con�rm the potential high tumor mutation burden is recommended, to determine the eligibility for immunotherapy. SMAD4, SMO, SPOP, SRC, STAT3, TERT, TOP1, U2AF1, XPO1 PLEASE NOTE: The tumor presents as two different subclones which manifests itself in different variant allele fractions. The major subclone features MSI status These results wervea rreiavnietsw iend X aPnOd 1in, RteArFp1re, PteIKd 3bRy1 A annddre PwT EPNo,l laoncdk ,t Lhaeb morinaotor rsyu Dbcirloencteo fre. Faotur rineqs uaidrideisti aobnoaul mt tuhtias trieopnosr itn, pMleSaHs2e, cSaElTl D1-28 a3n3d-4 T8P65-632. T6h0i.s tumor also harbors a high number of variants in combination with a signi�cant MSH2 variant, a feature also associated with right-sided tumors, therefore follow up testing to con�rm the potential high tumor mutation burden is recommended, to determine the eligibility for immunotherapy. Clinically Relevant Findings These results were reviewed and interpreted by Andrew Pollock, Laboratory Director. For inquiries about this report, please call 1-833-486-6260. ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, CDK12, CDKN1B, CDKN2A, CDKN2B, CHEK1, Immunotherapy Resistance markers All coding exons Biomarker Clinically Relevant FindiRnegssult Potential Therapies † Clinical Trials Tier I: Pembrolizumab, Nivolumab, Ipilimumab Trials Available MSI ImmHunigoht (hBeArTa-p25y,BAT-26,NR-21,NR-24) Tier II: N/A See below CREBBP, FANCA, FANCD2, FANCI, FBXW7, MLH1, MRE11, MSH2, MSH6, NBN, NF1, NF2, NOTCH1, Biomarker Result Potential Therapies † Clinical Trials sequenced Clinically Relevant Findings Tier I: Pembrolizumab, Nivolumab, Ipilimumab Trials Available MSI ImmunHoigthhe (BraApT-y25,BAT-26,NR-21,NR-24) Contraindicated/Resistance Clinically relevant negative results NOTCH2, NOTCH3, PALB2, PIK3R1, PMS2, POLE, PTCH1, PTEN, RAD50, RAD51, RAD51B, RAD51C, Gene VariantBiomarker Potential Therapies † Result TierT IIh: eNr/aApies PoteCnltiinailc Tahl Teriaaplsies † See below Clinical Trials Tier I: Pembrolizumab, Nivolumab, Ipilimumab Trials Available MSI Tier I : High (BAT-25,BAT-26,NR-21,NR-T24ie)r I : Contraindicated/Resistance Tier II: N/A See below 48 genes Gene Wild-Type VaCreiatnuxtimab, PanitumumaPbotential TheNra/Apies † TherapiesTrials Available Clinical Trials RAD51D, RB1, RNF43, SETD2, SLX4, SMARCA4, SMARCB1, STK11, TP53, TSC1, TSC2 KRAS/ NRAS VAF = 100% Tier II : Tier II : See below Patient prognosis N/A Tier I : N/A Tier I : Contraindicated/Resistance Gene Wild-Type VariCanetuximab, PanitumumPaobtential TheraNp/iAes † Therapies Trials Available Clinical Trials KRAS/ NRAS VATF i=e r1 0I :0% Tier II : Tier I : Tier II : See below p.E571K N/A N/A TieNr/ AI : N/A Tier TI r:ials Available XPO1 Missense Wild-Type Cetuximab, Panitumumab N/A See below Trials Available VAF = 26K%RAS/ NRAS Tier II : Tier II : VAF = 100% See below AKT1, AKT2, AKT3, ALK, AR, AXL, BRAF, CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, N/A Tier I : TieNr/ AII : Tier I : Tier II : p.E571K N/A N/A N/A N/A Trials Available Copy number XPO1 Missense See below VAF = 26% Tier II : Tier II : N/A Tier I : N/A Tier I : EGFR, ERBB2, ESR1, FGF19, FGF3, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R, KIT, KRAS, MDM2, p.E571K N/A N/A Trials Available XPO1 Missense variations queried Tier II : Tier II : See below VAF = 26% MDM4, MET, MYC, MYCL, MYCN, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB, PIK3CA, PIK3CB, N/A N/A 43 genes Mail: 1 Commercial Street Page 1 of 16 CLIA#: 07D2101517 PPARG, RICTOR, TERT Branford, CT 06405 CT Lic#: CL-0830 T: 833-486-6260 www.sema4.comMail: 1 Commercial Street Page 1 of 16 F: 516-953-8154 CLIA#: 07D2101517 Branford, CT 06405 CT Lic#: CL-0830 T: 833-486-6260 www.sema4.coMmail: 1 Commercial Street Page 1 of 16 F: 516-953-8154CLIA#: 07D2101517 Branford, CT 06405 CT Lic#: CL-0830 AKT2, ALK, AR, AXL, BRAF, BRCA1, BRCA2, CDKN2A, EGFR, ERBB2, ERBB4, ERG, ESR1, ETV1, T: 833-486-6260 Rearrangements www.sema4.com F: 516-953-8154 or fusions queried ETV4, ETV5, FGFR1, FGFR2, FGFR3, FGR, FLT3, JAK2, KRAS, MDM4, MET, MYB, MYBL1, NF1, NOTCH1, NOTCH4, NRG1, NTRK1, NTRK2, NTRK3, NUTM1, PDGFRA, PDGFRB, PIK3CA, PPARG, 51 genes PRKACA, PRKACB, PTEN, RAD51B, RAF1, RB1, RELA, RET, ROS1, RSPO2, RSPO3, TERT

*Based on an analysis of actionable alterations from OncoKB. For additional information, please see Chakrevarty D, Gao K, Phillips S, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precision Oncology. 2017. Advanced technology meets Specimen requirements a simplified workflow For all testing, provide a solid tumor tissue specimen

• Preferred specimen: 9 unstained slides at 10 μm thickness and one matching H&E Powered by Oncomine solutions stained slide. A minimum of 5 unstained slides and one matching H&E stained slide is required for testing. Optimal volume of >10 mm2 with ≥50% tumor content. At least The Oncomine Comprehensive Assay v3 used in our Solid Tumor Panel is an advanced next- 10% tumor content is required for testing generation sequencing solution, based on Ion AmpliSeq technology • Accepted specimen: 200 ng of extracted DNA and 200 ng of extracted RNA from Delivers proven performance with high specificity, sensitivity, and reproducibility tumor tissue with a concentration of 10 ng/μl each

Allows for concurrent DNA and RNA analyses To add MSI analysis, please also provide one of the following normal tissue specimens Used by leading global research institutions and for clinical trial matching • Preferred specimen: 4 unstained slides at 10 μm thickness and one matching H&E stained slide. Optimal volume of 10 mm2 • Preferred specimen: 2 mL of whole blood in EDTA tube (lavender top) or ACV tube Designed to integrate into your workflow • Accepted specimen: 20 ng of extracted DNA from normal tissue or blood with a Sema4 is dedicated to providing a seamless experience for providers and patients—from specimen concentration of >1 ng/μl pick up, to test ordering, to results reporting. Additional requirements • All specimens must be labeled with two unique identifiers. Slides should also be Order the Solid Tumor Panel through your electronic medical record, Sema4 provider labeled with a block label identity that corresponds with the surgical pathology report 1 portal, or fax. • Please include a surgical pathology report with specimen submission

Sema4 works with your preferred pathology department to ensure a formalin-fixed 2 paraffin-embedded (FFPE) tissue sample is prepared. Other sample types may also be Turnaround time accepted. If you would like MSI analysis, please also include a normal tissue specimen. • Approximately 2 weeks from receipt of specimen by Sema4 • If a paired normal sample is not received within 10 days of tumor sample receipt, MSI Final results expected in ≤2 weeks from the time of specimen receipt. Once available, 3 results may not be reported concurrently with the Solid Tumor Panel and may require you can view and print a comprehensive report via electronic medical record or portal, or separate ordering of the MSI test receive it via fax.

To learn more about the Solid Tumor Panel, please call 833-486-6260 or email [email protected] At Sema4, we are dedicated to helping every patient access advanced genetic testing

Our billing specialists will contact a patient’s insurance company to verify eligibility and obtain precertification or pre-authorization to ensure, to the fullest extent possible, insurance coverage of this test.

We appeal coverage determinations on behalf of patients if precertification or pre-authorization requests are denied. In order to do so, we will need a copy of relevant medical records from the ordering provider’s office. In some cases, Sema4 may also send the patient a form that requests their consent to perform the appeal on their behalf.

We are committed to ensuring that all patients can access testing. Payment plans, self-pay pricing, and other financial assistance options are available for patients who are uninsured or do not meet criteria for reimbursement for testing.

Sema4 is contracted with all major national payors, and is in network for >200 million lives.

If patients have any questions about the explanation of benefits from their insurance provider or their Sema4 bill, our billing specialists are here to help.

800-298-6470 [email protected]

Oncomine is a trademark of Thermo Fisher Scientific Inc. All rights reserved. No clinical claims, sponsorship, endorsement, or affiliation by Thermo Fisher Scientific is implied herein. The data generated by Sema4 is the sole responsibility of Sema4. The Oncomine Comprehensive Tumor Profiling Assay was developed by leading cancer institutes and regulatory agencies, and distributed by Thermo Fisher to support the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial. To learn more, please see Lih CJ, Harrington RD, Sims DJ, et al. Analytical Validation of the Next-Generation Sequencing Assay for a Nationwide Signal-Finding Clinical Trial Molecular Analysis for Therapy Choice Clinical Trial. J Mol Diagn. 2017; 19: 313-327.

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