Oncology Drug Development
Advantages and challenges of using stratified clinical studies

Simon J Hollingsworth
The 18th Anti-Tumour Drug Development Forum

21 February
Japan

Stratified Medicine In The Clinic
Targeted therapeutics are improving survival…
Example: NSCLC is an evolving landscape

Where we’re going

30

Overall 20Survival(months)
100

1970

1980

1980

2000

2010

2020

1965
1970
1975
1980
1985
1990
1995
2000
2005
2010
2015
2020

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IMED Biotech Unit – Oncology

1998

2004

2009

2011

2012

2013

Stratified Medicine Requires Portfolio Approach
AZ/MedImmune are uniquely placed…
Lung – adenocarcinoma– squamous

Selumetinib (AZD6244)
AZD5363
Caprelsa (vandetanib)
Selumetinib (AZD6244)
AZD9291

Medi-4736

AZD5363

AZD2014
AZD8186

IressaAZD9291

AZD4547

Selumetinib (AZD6244)

AZD4547

Volitinib
Medi-4736

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IMED Biotech Unit – Oncology

FGFR 2/3 mutation
FGFR1 amplification
FGFR translocations
Met expression
Met amplification
PDL-1 expression
PDL-1 amplification

Medi-4736

Reality Of Drug Development
Current trial paradigm isn’t working…?
Screening approaches don’t work – for patients, physicians or Pharma• Low frequency events are difficult to find

• Diagnostic sample quality/quantity compromises multiple analyses• Poor patient and physician experience with cycles of repeat diagnostics• Current regulatory requirements to validate companion diagnostics
We need…
• Innovative trial designs suited for development of highly targeted molecules• Diagnostic standards and methods standardisation• Regulators to engage with new types of (different) datasets• Improved patient access (NGS-based companion diagnostic)

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IMED Biotech Unit – OncologyReality Of Drug Development
Delivering stratified medicine requires innovation…
Reality of conventional screening
AZ Sponsored Study

1Ph.1 expansion –molecular subgroup

Screening / patient recruited(assay, processing, logistics, reporting)

Patients screened / recruited

522% prevalence
IHC / DNA ($1,125)

3

15% test fail75% patient conversion= patient recruited

Hollingsworth

For 20 patient study
Operational delivery$88,235
78 (77 discarded)$1.8 million
1,560 patients screened
very complex

Physician’s experience

Limited options –keep screening if tumourmaterial allows

Patient experienceCycle of Disappointment
Up – potential trial
Down – not eligible
Repeat biopsies
Limited drug options

IMED Biotech Unit – Oncology

Stratified Medicine In Drug Development
Basket studies offer a practical solution…
Choosing the patient for the trial“Baskets” – choose the trial for the patient

Trial 1

Trial 2

Trial 3“basket” – portfolio, multidrug, umbrella, etc...

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IMED Biotech Unit – Oncology

Basket Studies By Tumour Type And Region
Global level of innovation…

LungSolids
Lymphoma
Cholangiocarcinoma
Endometrial

Lung Master Protocol
NCI MATCHNCI MPACT

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IMED Biotech Unit – Oncology

LungBreast
Colorectal
Solids (epithelial)
SarcomaOvarian
PancreaticLung
Gastric

SAFIR
MATRIX, SMP2
AURORA – BIGWIN Consortium
SPECTA-Lung

VIKTORYSCRUM-JapanBasket Studies In Lung Cancer
Are being done at a National level…
MATRIX National Lung Cancer Trial –Cancer Research UK

Lung Master Protocol –Friends of Cancer Research USA‘Master protocol’ aims torevamp cancer trials (2013).
Pilot project will bring drug
companies together to test
targeted lung-cancer therapies

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IMED Biotech Unit – Oncology

The key things we have learnt…

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Basket Studies – Success Requires
Innovation in clinical diagnostics…

Clinicallyactionable
alterations inpatient samples

Unprecedented
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IMED Biotech Unit – Oncology

Basket Studies – Success Requires
Innovation in clinical diagnostics…
Detail and accuracy are essential –We want to select patientswith PIK3CA mutations• What mutations, specifically• What regions of the gene
• What evidence supports they are clinically actionable• What about mutations with little or no evidence
Tier 1 – clinically actionable (prospective selection)
Tier 2 – research interest (retrospective analysis)
Tier 3 – do not use

Which next-generationsequencing (NGS) platform

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IMED Biotech Unit – Oncology• Do they select the same patients• How can we cross-validate

Basket Studies – Success Requires
Innovation in clinical trial design…
Complex designs need flexible protocols –MATRIXNational Lung Cancer Trial

Adenocarcinoma

Starting line-up...

PI3K/AKT
deregulation

AKT1
mutation

FGFR
mutation

LKB1
mutation

TSC1/2mutation

CDK4amplification

CCND1
amplification

KRAS
mutation

MET
amplification

ROS1
gene
fusions

EGFRm+&T790M+

NF1
mutation

NRAS
mutationNoactionablechange

A3

A6

B1

C1

C2

D2

D3

D4

E1

E2

F1

G2

G3

H1

AZD5363

AZD4547

AZD2014

Palbociclib

Crizotinib

AZD9291

Selumetinib+ Docetaxel

MEDI4376

Squamous cell carcinoma

PIK3CA
mutation

A1

PIK3CAamplification

A2

PTEN
mutation

A4

PTEN
loss

A5

AKT1

FGFR

LKB1

TSC1/2mutationmutationmutationmutation

A6

AZD5363

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IMED Biotech Unit – Oncology

B2

AZD4547

C1C2

AZD2014

Rb-wildtype
andhomozygous
p16 loss

D1

CDK4

CCND1

MET

ROS1

EGFRm+

amplification

amplification

amplification

gene& T790M+

NF1
mutation

NRASmutationNoactionablechange

F1

G1

G3

H1fusions

D2

Palbociclib

D3

E1

E2

Crizotinib

AZD9291

Selumetinib+ Docetaxel

MEDI4376

Basket Studies – Success Requires
Innovation in clinical trial design…
Differing flexibility – differing needs...

Single protocol
Requires amendment

Screening protocol
Core inc-/exclusion criteria
Core trial design
Supplement 1Supplement 2
Supplement 3
Supplement 4
Supplement 5

Individual, flexible
Regulatory friendly

Modular, flexible
Requires amendment

Screening protocol

Screening protocol

Protocol 1

Core inc-/exclusion criteria
Core trial design

Protocol 2

Sub-protocol 1

Protocol 3

Sub-protocol 2

Protocol 4

Sub-protocol 3
Sub-protocol 4

Protocol 5

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IMED Biotech Unit – Oncology

Sub-protocol 5

Basket Studies – Success Requires
New models for implementation…
MATRIX National Lung Cancer Trial –Cancer Research UK

LC-SCRUM-Japan –National screening programme
National programmes –Centralised Pharmacy is needed
for cost-effective drug delivery

ECMC Network• UK-wide National network• +28 feeder hospitals in “hub-and-spoke” model

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IMED Biotech Unit – Oncology

147 Institutes in 46 Prefectures participating(as of November 2013)

Basket Studies – Success Requires
Innovation across trial design and implementation…
1 Diagnostic System• Platform• Screening/selection algorithm• Broad patient profiling• Sample efficient• Robust data generation• Cost-effective• Transferable, widely deployable• Works to agreed standards• Viable development route• Support regulatory interactions• Support for markets

2 Protocol• Single or aligned protocol• Aligned and efficient review –centralised Regulatory/Ethics• Flexible• Modular• Rolling – open ended• Adaptable to emerging science• Allows different datasets• Allows regulatory interactions• Hub-and-spoke models• Must accommodate – diverse
groups and geographical areas• Centralised Pharmacy – toenable cost-effective delivery ofmultiple drugs to multiple sites• Highly collaborative working –across many different groups• Good partners

Flexible protocol
with central review

Centralised
Pharmacy andcollaborative working

Broad and robust
tumour profiling forpatient selection

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3 Operational Delivery

IMED Biotech Unit – Oncology

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IMED Biotech Unit – Oncology