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Vanderbilt-Ingram Cancer Center Tumor-Genome-Directed Anti-Cancer Therapy: Using Lung Cancer and Melanoma as a Paradigm NCI Workshop on Next-Generation DNA Sequencing as a Tool for Clinical Decision-making in Cancer Patient Management May 4, 2012 Bethesda, MD William Pao, MD, PhD Professor of Medicine Director, Personalized Cancer Medicine Director, Division of Hematology/Oncology Vanderbilt-Ingram Cancer Center Nashville, TN

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Vanderbilt-Ingram Cancer Center Disclosure Information I have the following financial relationships to disclose: Patent licensed to MolecularMD for EGFR T790M testing (got total of $500.00 and no royalties) Consulting for MolecularMD, BMS, AstraZeneca, Symphony Evolution, Clovis Oncology Research funding from Xcovery, Enzon, AstraZeneca, Symphogen

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Vanderbilt-Ingram Cancer Center Traditional View of Cancer Adeno- carcinoma Squamous Large Small Lung Cancer Melanoma

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Vanderbilt-Ingram Cancer Center Oncogenic Driver Mutations Impact Anticancer Therapy in Humans IPASS NEJM 09 Ph II Trial PLX-4032 PASCO 09 Lung CancerMelanoma

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Vanderbilt-Ingram Cancer Center Pao and Girard 11 Evolution of Knowledge About Driver Mutations in Non-Small Cell Lung Cancer

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Vanderbilt-Ingram Cancer Center Li et al 11 Spectrum of Driver Mutations in 202 East Asian Never Smokers with Lung Adenocarcinoma

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Vanderbilt-Ingram Cancer Center Molecular Subsets Progress YearReferenceCriteriaOS (mos)Notes Lung Cancer 1976HansenLung ca7SCLC, adeno 2002SchillerNSCLC7.9Platinum dblts 2006SandlerNon-squamous NSCLC12.3Bevacizumab 2009MokE Asian never light smoker/adenoca18.6Gefitinib arm 2009RosellSpanish EGFR mutant NSCLC27Erlotinib 2009MitsudomiJapanese EGFR mutant NSCLC30+Gefitinib 2010MaemondoJapanese EGFR mutant NSCLC30.5Gefitinib 2010JanneUS EGFR mutant NSCLC27.6Erlotinib Melanoma 1999ChapmanMelanoma7Dacarbazine 2011SosmanBRAF mutant melanoma16Vemurafenib

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Goals of the VICC PCMI - 2009 To establish reflex testing of common clinically relevant genetic alterations in lung cancers and melanomas To develop a clinically-applicable high- throughput molecular genotyping facility for rarer genetic variants To develop bioinformatic algorithms to report genetic results in the electronic medical record in ways that are clinically useful for practicing oncologists Collaboration among Depts of Medicine, Pathology, BioInformatics, and VICC

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Vanderbilt-Ingram Cancer Center What Test? What Should Be in the Test? Which platform? SNaPshot (ABI 3730) vs new technology (Sequenom) Ease of calls High sensitivity One panel for all cancers? Or tumor-specific panels? Feasibility vs. wide-applicability How often does one really find an actionable mutation (e.g. EGFR kinase domain mutation in a melanoma)? Which mutations? Occurs in the cancer Occurs with frequency >1% Has relevance to existing or emerging targeted therapy

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Vanderbilt-Ingram Cancer Center How to Implement? Molecular diagnostics Assays developed in Pao Lab as collaboration with CLIA-lab Assays transferred to/re-validated by CLIA-lab Bioinformatics Monthly meetings among Bioinformatics, Pathology Input from practicing clinicians Pathology workflow Re-organization/tissue librarian Education Consent Lung reflex Melanoma consent form

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Vanderbilt-Ingram Cancer Center One Size Does Not Fit All: Melanoma/Lung Ca Molecular Profiling Results Melanoma Panel: 538 Samples Lung Panel: 451 Samples 7/1/10-12/31/11 Cindy Vnencak-Jones

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First 150 Patients: 20% of BRAF V600 Mutations Would Be Missed by Allele-Specific PCR Lovly, Dahlman, Fohn, Su et al 12 First 150 Patients: 20% of BRAF V600 Mutations Would Be Missed by Allele-Specific PCR

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Vanderbilt-Ingram Cancer Center Lovly, Dahlman, Fohn, Su et al 12 First 150 Patients: 40% of Pts with Mutant Metastatic Disease Genotype-Driven Treatment Gene# of metastatic cases# patents placed on a genotype- driven clinical trial (%) BRAF3212 (38%) CTNNB11*1 (100%) GNAQIGNA1163 (50%) KIT11 (100%) NRAS154 (27%) No mutation detected28N/A Total cases8221/54 (39%) *This CTNNB1 mutation (CTNNB1 S45P) occurred concurrently with an NRAS Q61L mutation.

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Vanderbilt-Ingram Cancer Center # amino acids to fusion Kinase Fusions in Human Cancers JAK2 ALK ROS1 ABL1 PDGFR 43-350GXGXXG PDGFR FGFR1 48-79 GXGXXG 70-201 GXGXXG 56GXGXXG 15-33GXGXXG 44-64 GXGXXG 222GXGXXG NTRK1 117 GXGXXG BRAF 83 GXGXXG RET 18-62 GXGXXG NTRK3 15GXGXXG Chmielecki et al 10; Chmielecki et al 11 Exon (-1)Exon*Exon (-2) intron (-3)intron (-2)intron (-1) *encodes GXGXXG motif

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Vanderbilt-Ingram Cancer Center Using NGS to Detect Kinase Fusions Systematically Chmielecki et al 10; Chmielecki et al 11

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Vanderbilt-Ingram Cancer Center Novel C6orf204-PDGFRbeta Fusion in Pt with Recurrent T-ALL and MPN Chmielecki et al 10; Chmielecki et al 11

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Summary Building a Sustainable Model Impact in the clinic Prioritize treatment options for existing targeted therapies Impact on clinical trials Accelerate accrual to trials with emerging targeted therapies Enrich for cohorts of pts likely to benefit Impact on translational science Create opportunities from the bedside to bench and back Initiate new projects

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Goals of the VICC PCMI - 2009 To establish reflex testing of common clinically relevant genetic alterations in lung cancers and melanomas To develop a clinically-applicable high- throughput molecular genotyping facility for rarer genetic variants To develop bioinformatic algorithms to report genetic results in the electronic medical record in ways that are clinically useful for practicing oncologists Collaboration among Depts of Medicine, Pathology, BioInformatics, and VICC

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Vanderbilt-Ingram Cancer Center Knowledge Gap 94% of community oncologists responded that they discuss genetic mutation testing with their patient 17% of lung cancer patients were aware of genetic mutation testing 44% of oncology nurses did not discuss genetic mutation testing with patients, because they felt they lacked knowledge to discuss it

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Vanderbilt-Ingram Cancer Center Old Method for Reporting Mutation Results in the Electronic Medical Record Old Method: Report Template Scanned into Electronic Health Record as image file (not computable) Challenges: How to report > 40 mutations in 8 genes? Whose role to curate knowledge regarding clinical significance? Lack clinical trial information

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Vanderbilt-Ingram Cancer Center Mia Levy New Method for Reporting Mutation Results in the EMR

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome

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Vanderbilt-Ingram Cancer Center My cancer genome 7 Cancers Lung Melanoma Breast Colon Thymic GIST Thyroid 22 Genes 203 Disease- Gene-Variant Relationships 7 Cancers Lung Melanoma Breast Colon Thymic GIST Thyroid 22 Genes 203 Disease- Gene-Variant Relationships ~50,000 visits/>170,000 pageviews/ 119 countries/52 US territories in 1 year (only 8500 oncologists in US) Now ~1000 visits/week

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Vanderbilt-Ingram Cancer Center My cancer genome Clinical trial search 36,167 Cancer Trials (PDQ) 135 Cancer Diagnoses 437 Cancer Genes (COSMIC) Clinical trial search 36,167 Cancer Trials (PDQ) 135 Cancer Diagnoses 437 Cancer Genes (COSMIC)

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Vanderbilt-Ingram Cancer Center My cancer genome Trial search results can be filtered by geographic location or trial phase

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Vanderbilt-Ingram Cancer Center Consortium Science Contributors: 30 Informatics: 11 Knowledge Management Experts: 3

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Vanderbilt-Ingram Cancer Center DIRECT A Mutation Knowledgebase DNA-mutation Inventory to Refine and Enhance Cancer Treatment COSMIC for clinicians Horn et al PASCO 11

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Vanderbilt-Ingram Cancer Center >100 Reported EGFR Mutations: How Does One Find Clinical Relevance of a Specific One? Riely et al 06

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Vanderbilt-Ingram Cancer Center www.mycancergenome.org/DIRECT 1022 pts with EGFR mutation/ EGFR TKI- response data; 180 different GFR mutns Horn et al PASCO 11

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Table 2: EGFR Mutations associated with disease control Paul Yeh, Leora Horn

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Vanderbilt-Ingram Cancer Center Future Directions DETECT DNA Evaluation of Tumors for Enhanced Cancer Treatment Breast ca, colon ca using SNaPshot NGS on pan-negative cases Develop in-house next-gen panels Partner with Foundation Medicine, MolecularMD MyCancerGenome.org Web-based decision support Expand content; monthly updates DIRECT DNA-mutation Inventory to Refine and Enhance Cancer Treatment We need a national effort: COSMIC for clinicians MCG Drug Compendium

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Vanderbilt-Ingram Cancer Center Sanford Guide to AntiMicrobrial Therapy

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Vanderbilt-Ingram Cancer Center MCG Guide to Anticancer Therapy

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Vanderbilt-Ingram Cancer Center 2 Issues DIRECT Journals and/or the NCI should mandate that for genotype-directed clinical trials, ALL individual level patient data, including genotypes, MUST be reported in a public fashion! FDA-mandated companion diagnostics vs multiplexed assays Tissue $ Time Lung cancer: EGFR, HER2, PIK3CA, ALK, ROS, RET, etc.

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Vanderbilt-Ingram Cancer Center Acknowledgements Vanderbilt Ingram Cancer Center Jennifer Pietenpol Ashley Lamb Kim Dahlman Molecular Diagnostics Laboratory Cindy Vnencak-Jones Medical Oncology Christine Lovly Jeff Sosman Leora Horn Carlos Arteaga Pathology Sam Santoro Cheryl Coffin Bioinformatics Junfeng Xia Peilin Jia Zhongming Zhao Knowledge Management Christine Micheel Paul Yeh Pao Lab Katie Hutchinson Clinical Informatics Mia Levy Scott Sobecki Jim Tibbetts Stacy Cooreman Mik Cantrell Dario Giuse Jonathan Grande RuAnn Schleicher UCLA Toni Ribas MGH Dora Dias-Santagata John Iafrate Grant Support Kleberg Foundation Martell Foundation Anonymous Foundation NCI/SU2C-AACR

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Vanderbilt-Ingram Cancer Center Co-Editor-in-Chief: Mia Levy Deputy Editor: Christine Lovly Executive Editor: Christine Micheel Editorial/Business: Paul Yeh, Ashley Lamb Contributors: Rick Abramson, Carlos Arteaga, Alberto Bardelli, Justin M. Balko, Paul Bunn, Emily Chan, Haiquan Chen, Christopher Corless, Dan Costa, Allan Espinosa, Jim Fagin, Jill Gilbert, Nicolas Girard, Leora Horn, Vicki Keedy, Marc Ladanyi, Mia Levy, Roger Lo, Christine Lovly, Robert Maki, Ingrid Mayer, Geoff Oxnard, Paul Paik, William Pao, Gregory Riely, David Solit, Ben Solomon, Martin Sos, Jeff Sosman, Roman Thomas Informatics: Mik Cantrell, Stacy Cooreman, Daniel Carbone, Vincent Gould, Nathan Johnson, Anna Belle Leiserson, Riyad Naser, Ross Oreto, Scott Sobecki, Jim Tibbetts, Mikhail Zemmel Funding: Kleberg/Martell/Anonymous Foundations; BMS; GE Awards/Grants: HHS/Office for the National Coordinator for HIT (ONC) public data and cancer challenge to create health IT applications that use public data and existing technology to help patients and health care professionals prevent, detect, diagnose and treat cancer (Health 2.0) GE HealthyImagination We welcome academic/industry/govt partnerships! Acknowledgements