Precision Medicine: Shifting from One Drug for All Trials ... · Precision Medicine: Shifting from One Drug for All Trials to Targeted Therapy Trials October 28, 2015 Patrice Hugo,
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McDermott et al, N Engl J Med. 2011 Jan 27;364(4):340-50
• 22% of the pipeline agents
currently in pivotal trials are
being developed in a
biomarker-defined patient
population.
• of the 189 oncology
therapies currently under
development in the period of
2012-2015, 56% have an
associated biomarker.
• By 2017, 34 of these
pipeline therapies are
expected to launch, and 20
of these will be targeted to
biomarkers.
‘According to recent data from McKesson Specialty Health/US Oncology Network (MSH) http://www.nxtbook.com/nxtbooks/pharmcomm/20130910/?utm_source=Campaigner&utm_campaign=SeptOct_Digital_Edition_eBlast_8-28-13&campaigner=1&utm_medium=HTMLEmail#/0
A properly designed genomic panel + associated
bioinformatics can address both sides of the graph…
Matching patients to studies based on prospective genomic testing
Genomic testing registry
Genomic testing at
Q2 Solutions Labs
Clinical Report
Site staff activities of treatment
decisions and study initiation < 3 weeks
14 COMPANY CONFIDENTIAL
• Shifting from single-analyte to multiple increases risk
– Each variant has it own error and is compounded when
you interrogate 1.34M positions
• Validation showed variants < 10% of cells
• High sequencing depth is needed (which increases noise)
• In same assay we also want to look at breakpoints and
other complex indels
• Variant reporting should account for risks with sequencer error
Accuracy is Critical Search for low frequency variants & complex changes has risk
Ris
k
# loci assayed
Co
lin P
ritc
ha
rd (
Wa
sh
U)
Indels
Rare
Alleles
Breakpoints
15 COMPANY CONFIDENTIAL
• Having a pharmaceutical company be able to leverage the same assay in
different countries opens the door to multiple protocol delivery options
• No need to chase down labs to run the assay you are looking for an hoping the
results are similar across testing sites
• Can use vendor to help store and mine rapidly growing biomarker for indications
data across global network
Leveraging Global Laboratory Footprint Single panel can power multiple protocols across the world
Cancer patients in pre-profiling
network with alterations identified Protocols with specific genomic
alteration entry criteria
Pre-profiled cancer patients matched
to right protocol just-in-time
16 COMPANY CONFIDENTIAL
• Higher actionability increases patient and physician interest
– One test, one biopsy with quick turn times (2-3 weeks)
– General oncology assay can identify many pan-cancer biomarkers
– Increases chance for rare positive biomarkers to be found for various trials
– Patients can be matched with approved drug as first line Rx
• Enhanced Trial enrollment
– Large sample study shows that 11% (of 2000) went onto genotype-matched trials
– Many Groups facilitate this matching • Molecular Match
• Caris
• IBM (Watson)
• New Protocols are leveraging this power! – TAPUR (ASCO) M-PACT (NCI)
– Lung-MAP (NCI) IMPACT-2 (MD Anderson)
– FOCUS-4 (UK)
Increasing the Adoption of Genomic Pre-Profiling Good for the patient, good for Pharma
Meric-Bernstam F. et al JCO, May 2015
17 COMPANY CONFIDENTIAL
Genomics Powering
Immuno-Oncology Landscape
18 COMPANY CONFIDENTIAL
Current Landscape in Oncology Turning a fatal disease into a chronic treatable disorder
Over 800 cancer drugs in clinical trials - almost all are targeted at particular gene products
Some Fundamental Problems in Cancer Treatment
• Cancer is rarely detected early
• Cancer develops resistance rapidly to targeted therapies and chemotherapies due to the development/expansion of resistance mutations.
• Many patients do not respond to immunotherapies. Immunotherapies are changing the approach to treating cancer by treating the immune system rather than the cancer but not all patients respond.
Therapy Response
Rate
Toxicity Long term
Survival
Chemotherapy /
Radiation
Low High Poor
Targeted
Therapy
High Lower Poor
Immunotherapy Mid Lower Good
Source: Sharma, Allison: Cell, April 2015
19 COMPANY CONFIDENTIAL
Number of Products in Development for Selected Targets*
Source: BioMedTracker, copyright 2015
*as of May 2015
20 COMPANY CONFIDENTIAL
20
Routinely collected clinical samples
Data can be mined for molecular immune-oncology characterization
Immuno-Oncology Innovation New opportunities for molecular characterization
Samples Molecular Services Benefits
These characterizations can be used in drug studies
Saliva
Blood
Biopsy
Slides
Self-recognition HLA alleles
Immune activation B and T-cell
Tumor
characterization DNA and RNA
Stimulate T-cell response
• Cell therapies
Block immuno-suppression
• CTLA4
• PD1/PDL1
• IDO1
• OX40
Develop cancer-specific
vaccines (neoantigens)
• NY-ESO-1
• MAGE-3
• gp100
Through Immuno-oncology:
• Gain a deeper understanding of drug safety and PK/PD
• More precise tumor characterization
• More effective, personalized therapies
21 COMPANY CONFIDENTIAL
Situation:
– Patients in trial selected for receipt of Immunotherapy but does not respond
Solution:
– High Depth Exome Sequencing can identify new mutations in antigen coding genes
• Can identify allele-specific expression (ASE) of mutations with supplemental RNA-Seq
– Build associations of mutations across cohorts to highlight specific genes / mutations.
Result:
– Reduction in target identification through bypassing of screening of tumor-infiltrating
lymphocytes1
– Patients now have method to identify mutations in tumor for other biomarker identification,
along with neoantigens to facilitate biomarker discovery pipeline
– Collection of large-scale mutation information across indications allows for identification of
pan-cancer biomarkers that could extend existing immunotherapies to new indications
Case Study: Identification of Tumor-Specific Antigens Facilitating Drug Development by Identifying Novel Biomarker Classes
Source: 1. Yadev et al. Nature 2014
22 COMPANY CONFIDENTIAL
Situation:
– Targeted therapy has been selected for patient
– After treatment, certain patients develop hepatotoxicity to treatment, causing Drug
Induced Liver Injury (DILI) and potential post marketing withdrawal of drug.
Solution:
– Human Leukocyte Antigen (HLA) allele calling showcases toxicogenomics and
identifies
type that is associated to adverse reaction in affected population • ~30% of patients develop Colitis
– HLA gene association analysis will identify risk alleles
Result:
– Patients in trial with the risk allele can be more closely monitored / have treatment
amended
– Pharmacogenomics (PGx) data also generated for all trial participants
Case Study: Forecast Toxicity Risk HLA alleles have proven associations with toxicity
23 COMPANY CONFIDENTIAL
Immuno-oncology is Genomics Solutions Oriented
Technology
Service Need
Somatic Mutation Analysis DNA deep Sequencing, Breakpoint