WINTHER Study

Jean-Charles Soria,

Razelle Kurzrock, Josep

Tabernero, Apostolia

Tsimberidou, Jordi Rodon,

Raanan Berger, Amir Onn,

Gerald Batist, Eitan Rubin,

Yohann Loriot, Catherine

Bresson, Vladimir Lazar

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WINTHER:

A study to select rational therapeutics

based on the analysis of tumor and

matched normal tissue biopsies in

subjects with advanced malignancies

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Position of the problem

and clinical challenges

to be addressed

Tumor Biopsy

Match with

targeted therapies

Personalized

Medicine

Today

Relevant DNA

structural

changes

30 to 40% of pts Standard

Protocols

DNA

investigations

Standard

Pathology

How can we improve

cancer care

for 60 to 70% of pts ?

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State of the Art

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State of the Art Patient with metastatic cancer

TUMOR BIOPSY

MOLECULAR PROFILING

Histology Control

CGH

% of cancer

cells

Mutational aberrations

TREATMENT BASED ON DNA BIOLOGICAL INVESTIGATIONS OF THE TUMOR

Deep sequencing

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WINTHER

concept

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Patient with metastatic cancer

TUMOR BIOPSY

MOLECULAR PROFILING

Histology Control

CGH Transcriptomic

Aberrations

% of cancer

and normal

cells

Mutational aberrations

& MATCHED NORMAL TISSUE BIOPSY

WINTHER concept

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Patient with metastatic cancer

TUMOR BIOPSY

MOLECULAR PROFILING

Histology Control

CGH Transcriptomic

Aberrations

% of cancer

and normal

cells

Mutational aberrations

& MATCHED NORMAL TISSUE BIOPSY

WINTHER concept

1. Novelty: use of matched normal

and tumoral biopsies from strictly

the same patient.

2. Goal is to assess the

genetic distance between

tumor and normal by profiling

of mRNAs

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2

Individual

Drug efficacy

Scoring

Statement

Doctor’s

decision

3. Genetic distance converted into

drugs scoring

Computational

tools – Algorithm

and genes_drugs

database

WINTHER concept

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2

Individual

Drug efficacy

Scoring

Statement

Doctor’s

decision

3. Genetic distance converted into

drugs scoring

Computational

tools – Algorithm

and genes_drugs

database

WINTHER concept

RATIONAL TREATMENT BASED ON HOLISTIC BIOLOGICAL INVESTIGATIONS

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Example of WINTHER predictive scoring , that ranks drugs depending on

estimated efficacy

4

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WINTHER Study

Main components

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WINTHER Participants

Gustave Roussy [France]

Jean-Charles Soria, Coordinating PI

MD Anderson Cancer Center [USA]

Lia Tsimberidou, PI

VHIO [Spain]

Jordi Rodon, PI

Chaim Sheba Medical Center [Israel]

Rannan Berger, PI

McGill Segal Cancer Center [Canada]

Wilson Miller

UCSD Moores Cancer Center [USA]

Razelle Kurzrock

Cancer Centers Technology Partners

Foundation Medicine

Gary Palmer

NGS

Ben Gurion University

Eitan Rubin

WINTHER Data Analysis

Agilent Technologies

V Lazar

Gene Expression, miRNA

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Actionable DNA aberrations

Est. 30-40% of patients

NO Actionable DNA aberration

Est. 60-70% of patients

Enroll 200 patients with metastatic cancer

Tumor and matched normal tissue biopsies from each patient

Histology Control

Next Generation Sequencing

(mutational and CNV aberrations)

WINTHER ARM A:

Patient matched with

existing targeted

therapies or included in

Phase 1 trials

WINTHER ARM B:

Choice of therapy guided by WINTHER

drug efficacy predictive scoring derived

from

tumor vs. normal RNA investigations

Recruitment goals

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Estimated repartition of patients

200 patients

Arm A :

80 patients

Labeled Targeted Therapies:

20 patients

Targeted Therapies in Clinical Trials:

60 patients

Arm B :

120 patients

Standard of care:

20 patients

Off label drugs (non clinical

trials):

100 patients

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WINTHER study main objectives

Better identification of

actionable DNA

aberrations in patients

(today limited to 30%),

by using NGS

PFS2/PFS1 > 1.5 in 50%

of patients

WINTHER ARM B:

Offer a solution guided by each

patient’s individual biology to the

vast majority of patients without

actionable DNA aberrations

Prove the efficacy of using

alternative investigations based on

functional genomics of the RNA on

a dual biopsy of tumor and

matched normal tissue to identify

relevant aberrations in patients

PFS2/PFS1 > 1.5 in 40% of patients

WINTHER Arm A:

RATIONAL TREATMENT BASED ON HOLISTIC BIOLOGICAL INVESTIGATIONS

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Statistical design of the study

Objective of WINTHER:

achieve 1.5 ratio in 50% of patients in arm A

achieve 1.5 ratio in 40% of patients in arm B

30 % being the average oncologist threshold

PFS 1 PFS 2

PFS1

PFS 2 > 1,5 Relevant Molecular Targeted Agent

(WINTHER) Standard Therapy

Tumor

Progression

Tumor

Progression

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MOLECULAR SCREENING

NGS-CNV-CGH-gene expression

CLINICAL

DECISION

Max 6 working weeks

FRESH TUMOR

BIOPSY PATHOLOGICAL

CONTROL

TREATMENT

• Multi-disciplinary trial

WINTHER Workflow

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WINTHER Study

Initial achievments

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Recruitment

Rapid Accrual

Currently 2-3 pts / week

July April June May

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WINTHER

From April 16 to July 2, 2013

32

Consents

5 Screening

Fails

1 pt included in another therapeutic

clinical study

1 pt with rapid worsening condition

1 pt withdraw consent

2 pts with normal tissue not

obtainable

8 biopsies yet to

be performed

19 Biopsies

3 biopsies July 2, 2013

9 Analyzed

7 Logistical Failures

1 inappropiate choice of normal

tissue

6 Tumor tissues < 60% of T cells

IGR-1011 Breast cancer

IGR-1012 Oral squamous cell carcinoma

IGR-1013 Colon cancer

IGR-1016 Lung ADK

IGR-1019 Kidney cancer

IGR-1027 Oral squamous cell carcinoma

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Patients characteristics

0

1

2

3

4

5

6

7

8

head andneck

breast lung sarcoma kidney colon/rectum

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0%

10%

30%

50%

100%

70%

90%

80%

20%

60%

40%

Not reliable

NGS + CGH

Pe

rcen

tage o

f C

ells

WINTHER

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WINTHER

9 sent

DNA structural alterations

N=5

Transcriptomic

alterations

N=3

8 reports

ARM A ARM B

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Target characteristics

DNA alterations

0

1

2

3

4

5

6

Mutation

Deletion

Amplification

Gene fusion

0

1

2

MET VEGFA HER3

Transcriptome-based targets

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WINTHER

9 sent

DNA structural alterations

N=5 transcriptomic alterations

N=3

8 reports

ARM A ARM B

HER2 amp Still on 1st line chemo

FGFR1 amp Included in EOS-3810 study

MET amp On screening (MET inhibitor)

TSC1 mut On everolimus therapy

RET gene fus On sorafenib therapy

Target MET

Target VEGF-A

Target HER-3

On screening

On screening

Still on treatment

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IGR-1004 Head & Neck SCC FM: MDM2 ampl, P53 mut BGU: MET

ARM B 1/ SAR125844 (Met inhibitor)

2/ cabozantinib

IGR-1007 Lung ADK FM: KRAS G12D BGU: HER3, HER2

ARM B 1/ MM-141 phase I

2/ capecitabine + trastuzumab

IGR-1006 uterine Leiomyosarcoma FM: TSC1 mut

ARM A: Everolimus

IGR-1010 Lung Carcinosarcoma FM: RET transl, MYC ampl

ARM A 1/ sorafenib

2/ switch to another RET TKI with better IC50

TC 20130625

IGR-1004

IGR-1007

IGR-1006

IGR-1010

WINTHER - Pr SORIA

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IGR-1005 Lung ADK FM: EGFR and MET amp ARM A: SAR-MET trial

IGR-1014 Kidney cancer FM: VHL mut BGU: VEGFA ARM B: bevacizumab

IGR-1001 Breast carcinoma FM: FGFR1 ampl, FGF3 ampl, FGF4ampl ARM A: lucitanib phase I

IGR-1002 Head & Neck SCC FM: HER2 and EGFR ampl ARM A: Paclitaxel + Trastuzumab

TC 20130521

TC 20130702

IGR-1001

IGR-1002

IGR-1005

IGR-1014

WINTHER - Pr SORIA

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Summary: Why is WINTHER different?

• Includes all patients, with or without actionable genetic aberrations

• Investigates both DNA and RNA

• Includes a variety of different technologies: Next Generation Sequencing,

Copy Number Variations, gene expression, Comparative Genomic

Hybridization

• Based on a dual biopsy of tumor and matched normal tissue of same

histology, which enables:

• Evaluating the genetic distance between tumor and normal

• Disregarding variability factors between individuals

• Limiting the number of irrelevant aberrations and noise

• Increasing the statistical factor of the study by 16

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Thank you Gustave Roussy:

- Fabienne Dufour, Maud Ngo Camus

- Aurélie Abou Lauverne

- Catherine Richon

- Nathalie Auger, Valerie Kouby, Ludovic Lacroix

- Philippe Vielh

- Thierry De Baere

- Gilles Vassal