Fostering collaboration in the era of precision oncology: Pharmaceutical perspectiveForpath workshop: Working with BIG medical data in daily medical practice – 8 December 2018Rudy Hovelinck, Diagnostic Manager AstraZeneca

My presentation today

Who is AstraZeneca?

Why precision oncology matters?

How do we define big data at AstraZeneca?

Why do we visit pathologists? How do we handle any provided data?

Case examples:- Introducing a new test technology- Funding test cost- Supporting validation - Data collection for supporting decision making

AstraZenecaA global, science-led biopharmaceutical company

$23bn total revenue

$21.3bn product sales

$1.7bn externalisation revenue

As at 31 December 2016

$5.9bn invested in R&D with research across 5countries

138 projects in clinical development and 11NMEs in late-stage development

As a company built on delivering positive health outcomes, sustainability underpins everything AstraZeneca does

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3rd place on Dow Jones Sustainability Index: 100/100 in Environmental Reporting, Labour Practice Indicators, and Health Outcome Contribution reflects the increasing focus on our science-led sustainability strategy

Focus on three main therapy areas

Cardiovascular and

Metabolic

Respiratory, Inflammation and

AutoimmunityOncology

ASTHMA

affects 300 million

individuals worldwide(1)

DIABETES

422 million people affected

in 2014 (3)

COPD

3 million deaths in 2012 (2)

ONCO

8,2 million deaths in 2012 (5)

LUNG :

1,59 million deaths in 2012 (5)

CVD

n°1 cause of death

17 million deaths annually

(4)

(1) www.ginasthma.org/documents/1/Pocket-Guide-for-Asthma-Management-and-Prevention; (2) WHO Fact sheet COPD March 2015; (3) WHO factsheet Diabetes June 2016;(4) WHO factsheet CVD’s, September 2016;(5) Who factsheet n°297, feb 2015

AstraZeneca OncologyFour key platforms for Scientific Research in 4 indications

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*preclinical**combination with DNA Damage Repair

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The right medicine for the right patient ….

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Long history in diagnostic biomarkers

Nolvadex - also known as Tamoxifen

The success of personalized medicine in Oncology

10Schwaederle M,et al. Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials. J Clin Oncol. 2015; 33:3817–3825.

Companion diagnostic & medicine budget evolutionFactor 12,5 relation

Test specificity has a high impact factor on total budget

Caveat of this exercise!● This is only representing higher budget due to more drug

prescribed● Patient adverse events and their treatment not included● No inclusion of cost for loss of QUALIs

Pharmaceutical perspectiveFalse Positive● Loss of credibility of treatment effectiveness● Wrong treatment for patient can lead to serious adverse events

which are documented to the competent authorities who can decide to take actions including molecule being banned from human use.

False negative● Low test positivity rate leading to testing fatigue! Ex ALK● Patients miss optimal therapy● Drug benefit in patient group is suboptimal

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Crucial role of diagnostic labs for optimal cancer patient care and efficient use of healthcare resources

Big data approach for Genomics

Our genomics strategy will bring better medicines to patients, faster

A comprehensive approach

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Working with the best scientists to achieve our aims

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Genomics Big Data Considerations1: Genomic Data

Genomics Big Data Considerations2: Security and Access

Genomics Big Data Considerations3: Consent

Genomics Big Data Considerations4: Geography

Genomics Big Data Considerations5: Phenotypic data

Genomics Big Data Considerations6: Integration with other data Tissue P

henomics

Flow C

ytometry

Screening

Proteom

icsTranscriptom

ics

Genomics Big Data Considerations7: Global Collaboration Tissue P

henomics

Flow C

ytometry

Screening

Proteom

icsTranscriptom

ics

Genomics Big Data Considerations8: More integration Tissue P

henomics

Flow C

ytometry

Screening

Proteom

icsTranscriptom

ics

Rules around data handling

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Key themes of GDPR on one page

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1.1 Are we allowed to collect/process data (Lawful & fair)? Have

we been clear on purpose (Transparent)

1.2 Use it only for the specified and explicit

purpose it was collected for (purpose

limitation)

1.3 Do we really need it? Limit to what is necessary (data

minimization)

1.4 Keep it up to date (Accuracy)

1.5 Keep no longer than necessary

(storage limitation)1.6 Handle and

manage securely

6 principles Data subject rights

1.Right to Refuse: consent

1.Right of Transparency:

notice

1.Right to Access Copy, Correct, Transfer, Limit

1.Right to Be Forgotten (deletion)

Requirements 1.1. Hold an

inventory of all processes and

systems that process personal data

1.2. Perform a Privacy Impact

Assessment upon new process

1.3. Report any Data breach notification

within 72 hours:

With an overarching principle of Accountability

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What to do when an HCP wants to exercise rights

AZ has a global website and process in place. Why:• It tracks and documents the process to be able to complete within the 30 days.• It checks the identify of requester, especially in case of copy of data, as anyone can

connect to this website and submit a request• Website available externally at:

• Via www.astrazenecapersonaldataretention.com• Via www.astrazeneca.com, at the bottom, Privacy Notice

If the HCP does not want to complete the form to request access, we can complete on their behalf.

• To withdraw e-mail consent: send a mail to the Helpdesk • For all other questions refer to global website below

1.Right to Refuse or Withdraw consent

1.Right of Transparency

1.Right to Access, Copy,

Correct, Transfer, Limit

1.Right to Be Forgotten (deletion)

Transparency for all financial contributions to HCOs, HCPs and Patient Organisations‘Sunshine act’

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Ethical clearance of an activity by MdeonAll events ≥ 2 consecutive days benefiting to BE HCPs

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Interactions with pathologists

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Diagnostic focus of AstraZeneca Belgium Get it right for the right patient….

the right people

the right science

the right quality

the right communication

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the right people• Dedicated team that are end

responsible for diagnostic strategy and actions

• Diagnostic Manager leading 2 Diagnostic Liaisons

• X-functional working in brand team• Molecular biology or biomedical

sciences• Hands-on lab experience and/or

experience in diagnostic company• True experts in their field

the right science• Solid companion diagnostic

data generated during AZ clinicaltrials

• Adapt to local situation eg instrument resources available

• Keep track of the fast diagnostictechnology evolution = challenge

the right quality• Most important • How do we know for certain ?• Benchmark is the clinical trial test,

ideally it is a CE-IVD test• Lab developed tests are uncharted

terrain• Organise a Ring Trial with unknown

samples• Preceptorship training program• Set up reference labs• Biggest challenge

the right communication• Always based on scientific facts • Individualize but synchronise

messages for clinical and diagnosticstakeholders

• Gather all stakeholders from the MOC/COM in a round table meeting to sort out practical aspects

• Channels: face to face visits by DLs, digital newsletter, congress attendance, satellite symposia

Diagnostic focus of AstraZeneca Belgium Get it right for the right patient….

Case 1: Developing new test technology somatic BRCA testing

PARPi

● Approved for use in Belgium in 2016● second line maintenance therapy for Ovarian Cancer patients with germline or somatic BRCA mutation

The BRCA genes and BRCA mutationsGermline and somatic BRCA mutations

1. National Cancer Institute. http://www.cancer.gov/dictionary?cdrid=46384; 2.. Pennington KP, et al. Clin Cancer Res 2014;20:764–75; 3.National Cancer Institute. http://www.cancer.gov/dictionary?CdrID=46586;

Germline mutations1

Mutations described as germline are replicated in every cell of the body. This reflects their origin in the DNA within germinal cells (eggs or sperm) and the resulting transmission to progeny at conception. Inherited (germline) BRCA mutations account for the majority of familial ovarian cancer.2

Somatic mutations3

Somatic mutations can arise in any cell other than a germinal cell.BRCA mutations described as somatic are those that occur in the BRCAgenes within tumour cells. Somatic mutations are non-heritable.

Tumor specific somatic mutations

Germline wild type Mutation in tumor cells only

● Prevalence of BRCA mutation in High Grade Epithelial Ovarian Cancer patients - 18% germline- 7% somatic only

Outcomes advisory board

● Provided update on available technology● Clarity on who performs the test (Gen – Path)● Insight on current status of BRCA tumour test per centre● Agreement on sharing experience with BRCA tumour test with other centres● Most common named barriers to overcome are:

- Access to reference material for validation- Differentiate between what is a real mutation – what is an artefact?- How deep to sequence- detection of large genomic rearrangements

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Common validation approach

Phase 1● AZ provides external reference material aquired from Horizon Discovery● AZ collaborates with Horizon Discovery to provide BRCA mutation list● CME test dilution series of samples with own method to confirm sensitivity threshold of 10% is reached

Phase 2● CME + Path provide a pool of well characterised patient FFPE samples with known BRCA mutations● CME all test these samples● All results are compared and recommendations are shaped (Ring trial) Slide kit with Tumour testing recommendations

Phase 1 - 2● In the start up phase (50 first patients tbd.) germline and tumour BRCA are tested simultaneously This completes the validation file

Phase 3● AZ sponsors participation to a tumour BRCA External Quality Assesment

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Phase 2: Samples in Ring Trial represent diagnostic reality

● 9 samples submitted by Belgian labs● UZ Gent, Erasme, IPG, UZA and CHU de Liege● 6 selected together with expert BRCA● Blinded and distributed

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Blinded ID Sample ID Pathogenic mutations (germline) Comments Difficulty level

B PB2378 BRCA1: deletion exons 8 to 13 5 year old block hardest to assay

PB2379 BRCA2: c.6405_6409del 5 year old block easy

A UZG 14B13795 B11 BRCA1 c.5155dupG, p.(Val1719Glyfs*6) 30 slides 10µ easy

C A_UZA (B293082) BRCA1: c.2197_2201del; p.Glu733Thrfs*5 4µ easy

B_UZA (B293553) BRCA2: c.5263G>T; p.Glu1755Ter 24 slides, 4µ easy

D 15H15953 BRCA1:c.5062‐5064delGTT (p.Val1688del) hardest to classify

E 13H13630 BRCA1:c.4327C>T (p.Arg1443X) easy

F 12H08210 BRCA2:c.8053delA (p.Thr2685Hisfsx9) easy

ULG‐BRCA1 BRCA1 c.5137delG (p.Val1713*)DNA extracted from FFPE HGSOC

Phase 2 results

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Correct resultTechnical limitation of methodincorrect result

Participant identification 1 2 3 4 5 6 7

Method description

extraction QiagenQIAamp DNA FFPE Tissue Kit (Qiagen) Maxwell Qiamp DNA FFPE Tissue

Qiagen QIAamp DNA FFPE Tissue kit QiaAmp FFPE kit Maxwell DNA extraction

library preparationBRCA Tumor MASTR Plus assay

BRCA Tumor MASTR Plus Dx (Multiplicom)

BRCA tumor MASTR ASSAY  Multiplicom

Multiplex PCR (Multiplicom kit)

Multiplicom BRCA Tumor MASTR Plus Multiplicom Multiplicom 

sequencing platform MiSeq (Illumina) Miseq Miseq Miseq MiSeq Miseq (2X250) BRCA Tumor MASTR Plus

secquencing coverage or read depth 17822

median coverage: 6000x; minimum coverage of >90% target: 2000x around 1000X 5000x

* our targets for all samples were 100% at 100x, 65% at 500x and 25% at 1000x

min 300X for each nucleotide Min 100x

databases consulted for variant calling

Alamut (BIC, LOVD, Lindor, ClinVar, Polyphen, SIFT,…)

HGMDProf, LOVD3.0, UMD, BIC, Cosmic seqnext, Alamut BIC, LOVD

Sophia Genetics (No CNV analysis yet)

BRCA1: NM_007294.3; BRCA2: NM_00059.3

SeqNext module (JSI Medical Systems), AF min 10% for variant calling

ResultsPathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Pathogenic variants detected

Sample ABRCA1: c.5155dupG/ p.Val1719Glyfs*6

BRCA1 (NM_007294) c.5155dupG, p.Trp1718Glyfs*7 (VAF 64%)

c.5155dup (p.Val1719Glyfs*6)

BRCA1: c.5155dup (p.Val1719Glyfs*6) c.5155dupG

BRCA1 c.5155_5156insG, p.(Val1719Glyfs*6) VAF: 63% (coverage: 2220)

BRCA2 c.5703_5704delGG, p.(Asp1902Tyrfs*4) VAF: 31% (coverage: 6214)

BRCA1 c.5155dup (g.41215388dup, p.Val1719Glyfs*6)

Sample B NoneBRCA1 (NM_007294) deletion (exon 8 to 13)

probable deletion exon 8-13 BRCA1 (decreased coverage)

BRCA1: deletion exons 8 to 13 None

BRCA1 c.442-?_4357+?del

no mutation found

Sample C

BRCA1: c.2197_2201del/ p.Glu733Thrfs*5

BRCA1 (NM_007294) c.2197_2201delGAGAA, p.Glu733Thrfs*5 (VAF80%)

c.2197_2201del (p.Glu733Thrfs*5)

BRCA1: c.2197_2201del (p.Glu733Thrfs*5) c.2197_2201delGAGAA

BRCA1 c.2197_2201delGAGAA, p.(Glu733Thrfs*5)

BRCA1 c.2197_2201del (g.41245347_41245351del, p.Glu733Thrfs*5)

Sample D Calling error - VUS

BRCA1 (NM_007294) c.5062_5064delGTT, p.Val1688del (VAF 53%)

c.5062_5064del (p.Val1688del)

BRCA1: c.5062_5064del (p.Val1688del) Extraction failed, retest

BRCA1 c.5062_5064delGTT, p.(Val1688del)

BRCA1 c.5062_5064del (g.41219635_41219637del, p.Val1688del)

Sample EBRCA1: c.4327C>T/ p.Arg1443*

BRCA1 (NM_007294) c.4327C>T, p.Arg1443* (VAF 49%)

not done yet due to delay in extraction. 

BRCA1: c.4327C>T (p.Arg1443*) c.4327C>T

BRCA1 c.4327C>T, p.Arg1443*

BRCA1 c.4327C>T (g.41234451G>A, p.Arg1443*)

Sample FBRCA2: c.8053delA/ p.Thr268Hisfs*9

BRCA2 (NM_000059) c.8053delA,p.Thr2685Hisfs*9 (VAF 66%)

c.8053del (p.Thr2685Hisfs*9)

BRCA2: c.8053del (p.Thr2685Hisfs*9) c.8053delA

BRCA2 c.8053delA, p.(Thr2685Hisfs*9)

BRCA2 c.8053del (g.32937392del, p.Thr2685Hisfs*9)

Blood DNAtest

TumourDNA test

Counselling by clinical geneticist for hereditary risks and

prevention

Mutation frequency based on Pennington et al Clin Cancer Research 2014

HGSOC cancer patients(regardless of age or family history)

Consensus on algorithm for new HGSOC patients

• BRCA 1 & 2 + 24 genesinvolved in homologousrecombination repair (HRR)

• hereditary mutations only

18% BRCA pathogenic mutation

• BRCA 1 & 2 genes• hereditary and acquired

mutations

25% BRCA pathogenic mutation(7% somatic + 18% germline)

Eligible for PARPi therapy

NEW*

Case 2: Test quality – EGFR T790M test on plasma

• 2017 third generation EGFR TKI• For NSCLC patients progressing on

first line tki therapy• Overcomes T790M resistance

mutation• Many progressing patients are not

eligible for biopsy

Liquid biopsy• But only used in research and no

data on clinical performance• Ring trial with artificial samples

Ring Trial – T790M ctDNA liquid biopsy

Ring trial liquid biopsy – report and interpretation

• Participants asked to write a report for 3 patients with nominative test result

• Found differences in reporting• Some reports were wrong

• Considerable opportunity for errors

• Now looking into clinician understanding of a report

Polling at scientific meetings: BWP, Respiratory Oncology Update, Forpath meeting

Case 3: test funding

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AstraZeneca covers the cost of EGFR tests outside reimbursement to relieve patients from additional financial burden and assure access for stage 4 Lung Cancer patients to optimal therapy

Lung cancer stages

1 2 3 4

Out of the 350 EGFRm patients who progress on a first‐generation EGFR 

TKI…

…only ~100 will have the cost oftheir diagnostic testing fully

reimbursed by the RIZIV/INAMI For the remaining 250 AZ provided a 

solution

48% of all lung cancers are diagnosed in stage IV

For stage IV therapy options are limited to either chemo or targeted 

therapy 

a tumour biopsy needs to be analysed for molecular biomarkers selecting eligibility for targeted 

therapy

One such example is the EGFR testit needs to be performed at 

diagnosis and potentially multiple times at progression

On 1 August 2017 a new RIZIV/INAMI code specific for EGFR was introduced

The new reimbursment code 589831 589842 in article 33bis allows for reimbursment of 340,67 EUR tolabs for performing the EGFR test This is restricted to

. Pathology, genetics or clinical chemistry labs

. that meet a minimal set of quality criteria proven by BELAC accreditation for the EGFR testThe reimbursment allows for

. tissue or plasma samples to be used

. Testing activating mutations at diagnosis

. Testing resistance mutations (T790M) at progressionThe reimbursment is restricted to

. NSCLC patients with non Squamous Histology

. Once per year per individual patient

These restrictions lead to a lack of test reimbursment for a part of the patient population eligeablefor an EGFR tki

1. the NSCLC label of the EGFR tki is broader then non-squamous histology2. the average time to progression on first line EGFR tki is shorter then 1 year3. Many patients need repeated attempts to identify T790M if a plasma sample is used

AZ has entered in to an agreement with your test lab to cover all the EGFR testing cost for the patients for which you needto take a therapeutic decision

RIZIV Test reimbursement changes

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Article 33TER expected in February ‘Good’ news for Molecular testing

- All companion tests included- Fixed technology based codes- Faster approval new tests

NGS convention expected in March

Nothing yet for IHC….

Data collection on biomarkers – PD-L1

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2018 Belgian Guidelines

How is the situation in Belgium today? PD-L1 survey!

What specific indications/histology/stage is a PD-L1 test performed?

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0

5

10

15

20

25

30

All NSCLC irrespective of stage Survey gap At request clinician

Which samples are tested?

What antibody should the lab use?

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PD-L1 positivity rate with TPS 1% cut-off:

• 70% in AZ clinical trials (SP263)

• 55-60% in real world publications1,2

What is the situation in Belgium?

1) Evans et al https://doi.org/10.1371/journal.pone.02063702) Velchetti et al https://doi.org/10.1007/s12253-018-0469-6

LDTs versus approved IVDs: HER2 exampleHigher healthcare system costs & worse patient outcomes

“Every $1 saved by laboratories by using cheaper reagents could potentially result in approximately $6 in additional costs to the healthcare system.”

Vyberg et al. BMC Health Services Research (2015) 15:352. DOI 10.1186/s12913-015-1018-6

$1

$6

Approved Laboratory

1. Decreased life expectancy

2. Decreased quality-adjusted life years

3. More recurrences and progressions

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• Depending on platform available in the lab (Dako/Ventana)• 22C3 and SP263 mostly used • CE-IVD versus LDT)

0123456789

101112

22C3 DakoAutostainer

(IVD)

SP263Ventana (IVD)

22C3 Ventana(LDT)

22C3 Omnis(LDT)

28.8 Omnis(LDT)

Survey gap

Which PD-L1 assay do you use at the moment?

Participated in EQA rounds?

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Key messages

● Diagnostic labs play a central role to provide patients with the correct targeted therapy● Data generation is not limited to clinical trials and continues in the real world setting● AstraZeneca strives that

- All patients have access to testing- Tests performed are accurate- Test results are in time for therapeutic decision making

● Diagnostic labs and industry are true partners

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Thank you!

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