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Big Data and Smart Data in Oncology Prof. Dr. Christof von Kalle, Head of the Department of Translational Oncology

National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)

© HIMSS 2

THE PARADIGM SHIFT:

IMAGING EACH INDIVIDUAL PATIENT‘S CANCER AT THE MOLECULAR LEVEL

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© HIMSS 3

DKTK MASTER - WORKFLOW IMPLEMENTATION

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NCT/DKTK

MASTER

PI3K-AKT-mTOR

RAF-MEK-ERK

Tyrosine Kinases

Dev. Pathways

DNA Damage

Immune Evasion

Cell Cycle

Inte

rve

ntio

n B

aske

ts

Goal: 28 days

Joint DKTK activity since 03/16 Institutional Review Board approval

Internet-based clinical data repository

Access to sequencing data 8 Partner Sites (11 Comprehensive Cancer Centers)

DKTK MASTER Molecular Tumor Board Weekly videoconference

DKTK MASTER Scientific Board

DKTK MASTER Case by Case Monthly videoconference

© HIMSS 4

NCT RESEARCH PROGRAMS

MOLECULAR DIAGNOSTICS – NCT MASTER

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WES/WGS and RNA-S in young adults/patients with rare tumors • Treatment options for individual patients

• Basis for molecularly stratified clinical trials

• Fertile ground for translational research

Management recommendation: 83% (843/1017)

Genomics-guided management: 34% (282/843)

Clinical benefit rate (CR, PR, SD): 42%

PFS ratio > 1.3: 44%

Clinical trials: NCT PMO-1601 (NCT03110744): Palbociclib in

CDKN2A/B-deficient chordoma | NCT PMO-1601/TOP-ART

(NCT03127215): Trabectedin and olaparib in cancers with defective

homologous recombination DNA repair | NCT PMO-1604 (in prep.):

Afatinib in NRG1-rearranged cancers | SoraTram (in prep.): Sorafenib

and trametinib in cancers harboring BRAF mutations with impaired or

unknown kinase activity

Selected publications: Heining et al. Cancer Discov 2018 | Chudasama

et al. Nat Commun 2018 | Forschner et al. Clin Cancer Res 2017 |

Horak et al. Int J Cancer 2017 | Chudasama et al. Clin Cancer Res 2017

| Dieter et al. Ann Oncol 2017 | Kordes et al. Leukemia 2016

N = 1212 N = 1017 Unbiased

functional

testing

Focused

functional

testing

Validation

rate >

95%

Sarcoma

Neuroendocrine

Colorectal CUP Head and Neck

Pancreatic

Hepatobiliary

Hematologic

Dermatologic

Breast

Gynecologic

Urogenital

Gastric

Lung Other

© HIMSS 5

GENOMICS OF DRUG SENSITIVITY OF PRIMARY CANCER CELLS

PARALLEL MOLECULAR AND FUNCTIONAL CHARACTERIZATION

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Zenz et al.

© HIMSS 6

OUTCOME MEASURES - DESCRIPTIVE

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Median Age 45 years Range 17-76 years Male 145 Female 137 Median Survival after MTB 12 months

Implemented Therapies (N=282) O

S P

robabilt

y

Months after MTB

Sarcoma

Neuroendocrine

Colorectal CUP Head and Neck

Pancreatic

Hepatobiliary

Hematologic

Dermatologic

Breast

Gynecologic

Urogenital

Gastric

Lung Other

© HIMSS 7

COMPARISON OF PRECISION ONCOLOGY PROGRAMS

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May 2018 DKTK-MASTER MI-ONCOSEQ1 MOSCATO 012 ProfiLER3 MSK-IMPACT4

Institution NCT Heidelberg University of Michigan Institut Gustave Roussy Centre Léon Bérnard MSKCC

Enrollments 1883 556 1035 2676 5009

Tumor board decisions 1019 500 843 1944 -

Recommendation rate 83% (843) 72% (360) 49% (411) 35% (676) -

Method WGS(WES)+TS WES+TS Panel+CGH

(+TS+WES)* Panel+CGH Panel

Genomics-guided management 33% (282) 5-11% 48% (199) 21% (143) 11% (527)

Reevaluation of clinical diagnosis ≈5% - - - -

Pathogenic germline variants 11% 12% - - - 1Nature 2017 Aug 17;548(7667):297-303 2Cancer Discov. 2017 Jun;7(6):586-595 3ASCO 2017 4Nat Med. 2017 Jun;23(6):703-713

WGS: Whole-Genome-Sequencing; WES: Whole-Exome-Sequencing;

TS: Transkriptome-Sequencing ; CGH: Comparative Genomic Hybridization

*TS and WES in 472 and 166 patients, respectively

© HIMSS 8

“BRCANESS” AS ACTIONABLE FEATURE OF LEIOMYOSARCOMA

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Newly diagnosed, locally recurrent, metastatic (n=49) Extra-uterine and uterine Whole-exome and RNA sequencing • Mutational heterogeneity • Near-universal inactivation of TP53 and RB1 • Widespread DNA copy number alterations • Chromothripsis (35%) • Whole-genome duplication (55%) • Alternative telomere lengthening (78%) • Defective homologous recombination DNA repair (>90%)

• Gene mutations

• Pattern of DNA copy number alterations

• Alexandrov-COSMIC mutational signature AC3

Chudasama et al. Nat Commun 2018

© HIMSS 9

GENOMICS-GUIDED BASKET STUDIES WITHIN DKTK

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NCT/DKTK

MASTER

PI3K-AKT-mTOR

RAF-MEK-ERK

Tyrosine Kinases

Dev. Pathways

DNA Damage

Immune Evasion

Cell Cycle

Eligibility

• Advanced-stage cancer

• Prior standard treatment

• Actionable molecular alteration, as determined by analysis within NCT/DKTK MASTER

SoraTram (N. von Bubnoff [Freiburg],

H. Glimm, S. Fröhling)

Sorafenib/trametinib in patients with

non-V600 BRAF mutations

NCT PMO-1601 (S. Fröhling, C.

Heilig, R. Schlenk)

Palbociclib in patients with

CDKN2A/B-deficient chordoma

NCT PMO-1603 (S. Fröhling, S.

Gröschel, R. Schlenk)

Trabectedin/olaparib in patients with

DNA repair-deficient cancers

© HIMSS 10

INFORM = INDIVIDUALIZED THERAPY FOR RELAPSED MALIGNANCIES

IN CHILDHOOD

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Phase I/II Enrollment

Standard of Care: Backbone

Chemotherapy Backbone

Targeted

Drug 1

Targeted

Drug 2

ALL AML

HGG (incl. DIPG) Medullo/Ependym.

Ewing Sarcoma Neuroblastoma

NHL Osteosarcoma

Rhabdomyosarcoma Rhabdoid Tumors

Feasibility-Registry Study (Year 1+2) Clinical Trial (Year 3-5)

Angelika Eggert Stefan Pfister Olaf Witt Peter Lichter

© HIMSS 11

Clinical

development

Preclinical

evaluation using

explant models

(fully human, fully

immunocompetent)

Integrated data analysis

Pathway analysis

Regulatory networks Statistical

analysis

Generation of therapeutic

monoclonals, bispecifics and

CAR constructs

NCT RESEARCH PROGRAMS - IMMUNOTHERAPY

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Interrogating mechanisms of response and resistance in individual patients identifies

novel target structures (tumor and stromal antigens)

Example:

Identification of CCL5/CCR5

pathway as novel mediator of

an immunosuppressive

environment

Clinical testing of CCR5

antagonists in metastatic

colorectal cancer patients

Clinical development of

combination strategies, e.g.

CCR5 and PD1/CTLA4

blockade

Selected publications: Halama et al. Cancer Cell 2016 | Zoernig et al. Int J Cancer 2015 | Weber et al. J Immunol Res 2015

© HIMSS 12

NCT DataThereHouse

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Display Data from

Various Sources for

a Comprehensive

Overview of

Information

Relevant for

Personalized

Treatment INDIVIDUALIZED TREATMENT PLAN

SEQUENCING DATA

ARRAY DATA

CLINICAL PATHWAYS

UNSTRUCTURED DATA

DOCTOR’S LETTER

STRUCTURED DATA

PHYSICIAN

SCIENTIST

TUMOR BOARD

CASE MANAGER

STUDY NURSE

DOCUMENTALIST

© HIMSS 13

NCT DataThereHouse: Current scenario

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ARZT FORSCHER CASE MANAGER

REPORTER

DOKUMENTAR

PHYSICIAN

SCIENTIST

=

NEUE STUDIE

EINSCHLUSS &

AUSSCHLUSS

KRITERIEN

BOARD

SPRECH-

STUNDE/

AMBULANZ SOP*

BEGLEITEN

DE DIENSTE

KIS, PACS,

REGISTER

KIS, PUBMED, UPTODATE, BIOBANK,

INTRANET, REGISTER

PATIENT

HYPOT

HESE

STUDIEN

PROTOKOLL

AUFKLÄ

RUN/SC

REENIN

G

STUDY NURSE

REPORT

EINBINDUNG

THERAPIE

AM NCT ODER

EXTERN

LOI*

THERAPIE

POP*

ARZTBRIEF

PATIENTEN

AKTE

ABLAUF

DATENFLU

SS

PATIENTEN

PFAD

DATENBAN

K

ARTEFAKT

E

KONFEREN

Z

BEGLEITEN

DE

DIENSTE

© HIMSS 14

NCT DataThereHouse: NCT Clinical Development Strategy

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PATIENT

THERAPIE

AM NCT

KLINISCH

E

STUDIEN

DIAGNOS

E

IS-H, PUBMED, UPTODATE, BIOBANK,

INTRANET, IS-H, PACS

MONITORING

DOKUMENTAR

ARZT FORSCHER

PUBLIKATION

IS-H, PUBMED, UPTODATE, BIOBANK, INTRANET, IS-H, PACS

FORSCHER

ARZT

DOKUMENTAR

Organized in

SAP HANA

DOKUMENTAR DOKUMENTAR

NCT CANCER

REGISTRY

© HIMSS 15

INNOVATIVE DIAGNOSTICS AND THERAPIES

DataThereHouse

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Data

Integration

Suite

Big Data

Analytics

Suite

Researcher

Physician

Optimize

patient

treatment

Generate

new

insights

DKFZ

HIPO

HD

HIS

PACS

LIMS

NCT

Cancer

Registry

Medical

Reports

NCT

Biobank

Te

xt

An

aly

sis

Radiomics

Genomics

Diagnoses

Stratification

Therapies

Findings

Follow-up Data

Doctors‘ Letters

Interfaces to

Networks (e.g.

DKTK)

Patient

Working copy of all patient-related records from UKHD

computer sources, coupled with steadily expanding scientific

data sets, as intuitive tool for clinical decision making and

translational research

© HIMSS 16

DataBox: The IDEA

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Management of complex health datasets

• patient-centered platform

• Data derived from different sources

• Integration of innovative big-data

analysis concepts

• Machine Learning

• Artificial Intelligence approaches

© HIMSS 17

DataBox: The Challenge

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The patient is confronted with

• a clutter of data distributed over several clinical systems

• actively request copies of his data from health service providers

Patient

Clinic Health insurance

General practitioner

© HIMSS 18

DataBox

Clinical studies

Information

Analysis

Services

DataBox: Added Value for Patient and Society

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• Pseudonymized basic datasets can

be queried by certified institutions,

in order to e.g. search for study

candidates

• Information to patients about e.g.

clinical and scientific trials (after

consent)

© HIMSS 19

SMART DATA IN ONCOLOGY…

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Personalized medicine…

• needs to RETHINK the old & the new

• needs SMART Data

• is a TEAM Effort

© HIMSS 20

NCT PARTNERSHIPS

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Academic Collaboration

DKTK

EMBL DKFZ-ZMBH

ALLIANCE

Joint Industry-Academia Collaboration

Cancer Core Europe Consortium Centers

© HIMSS 21

NATIONAL CENTER FOR TUMOR DISEASES NCT HEIDELBERG

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THANK YOU