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Edward Abrahams, Ph.D.,
President, Personalized
Medicine Coalition
“Variability is the law of life,
and as now no two bodies
are alike and behave alike
under abnormal conditions,
which we know as disease.”
- Sir William Osler
Challenges in Building a
Precision Medicine Program
Richard L. Schilsky, MD, FACP, FASCO
Chief Medical Officer
American Society of Clinical Oncology
Precision Medicine Impacts All Aspects
of Cancer Care
Meric-Bernstam F et al. JCO 2013;31:1849-1857
Hallmarks of Cancer: Therapeutic Implications
Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)
Targeted Therapy Superior to Chemotherapy
Gefitinib
Vemurafenib
In Biomarker Selected Populations
Crizotinib
Gefitinib
Schema of Personalized Medicine
MacConaill L E , Garraway L A JCO 2010;28:5219-5228
©2010 by American Society of Clinical Oncology
Schema of Personalized Medicine
Repeat each time a new clinical decision needs to be made.
MacConaill L E , Garraway L A JCO 2010;28:5219-5228
©2010 by American Society of Clinical Oncology
Implementing Personalized Cancer Care
Problem: Tissue Collection and Testing
• No established guidelines for tissue collection and
processing for molecular profiling
• Proliferation of testing facilities
• Few established standards for molecular work-up
of tumors, i.e., appropriate testing platforms,
standardized nomenclature and variant annotation,
description of the limitations of the test, reporting of
results
Problem: Increasing Complexity of Molecular
Testing
Li T et al. JCO 2013;31:1039-1049
Problem: Are You Confident in the Test You
Order?
• Analytic validity
– Sensitivity, specificity, NPV, PPV (relative to “gold standard”)
– Technical reproducibility
– Assay stability over time
• Clinical validity
– Does the assay identify a specific population?
• Clinical utility
– Does the use of the assay lead to better clinical outcome
(improved OS, less toxicity, less cost, improved PFS) ?
Febbo PG,, et al. NCCN task force report: evaluating the clinical utility of tumor
markers in oncology. J Natl Compr Canc Netw 2011; 9:S1–32
Parkinson DR, et al. Evidence of clinical utility: an unmet need in molecular
diagnostics for patients with cancer. Clin Cancer Res 2014; 20:1428–44.
Proposed Solution:
Guidelines and Certification
•
•
•
•
•
•
CLIA Certified
CAP Accredited
FDA approved (?)
Regular proficiency testing
Standard nomenclature for test reporting
Open access variant annotation for decision
support
• Record test used, test results, clinical
decisions and patient outcomes in national
registry
Genomic Landscape of 5000 Human Cancers
MacConaill, L, et. al., J Mol Diagn 2014, 16: 660-672
What is “Actionable”?
Van Allen E M et al. JCO 2013;31:1825-1833
Oncologist Confidence in Assessing
Genomic Test Results
Gray, S, et. al., JCO epub March 24, 2014.
Matching Drugs and Genomics
Meric-Bernstam, F., et. al. : JNCI 2015
How Useful Is It?
Kurzrock, Et. al., JNCCN 13:1337-46, 2015
How Useful Is It?
Nearly 60% of respondents said genomic
profiling informed clinical decisions less than
30% of the time!
Kurzrock, Et. al., JNCCN 13:1337-46, 2015
Why Wasn’t it Helpful?
Kurzrock, R. al., JNCCN 13:1337-46, 2015
Genomic-Driven Cancer Medicine
Opportunities and Challenges
Selected tumor molecular assays available/used in clinical practice
“…oncology has served as a
proving ground for the genomicsdriven framework that is unique
among medical specialties.”
“A well-recognized pitfall of
genomics-driven cancer medicine
centers on the risk that large-scale
genomic data generation could
emerge without an evidence-based
clinical approach to data analysis
and interpretation.”
Garraway L A JCO 2013;31:1806-1814
Parkinson DR et al Clin Cancer Res 2014;20:1428-1444
Health Systems Considerations
• Genome sequencing: use a commercial lab vs. build a CLIA
certified sequencing lab? NGS testing will likely soon be
regulated by FDA.
• More than the lab, building/curating the knowledge base is
essential but expensive.
• Do you have the necessary teams of clinicians,
bioinformaticians and molecular pathologists to
interpret/report results?
• If you build it, who will pay for it?
• Provider and patient education is key
• Investment in genetic counselors necessary
• Data storage (security) requirements are huge.
• The field is rapidly moving and requires continuous attention
and updating.
Implementing a Precision
Medicine Program
Jennifer Levin Carter
N-of-One Case Studies: Metastatic Lung Cancer
61 yo F non-smoker with
recurrent, metastatic non-small
cell lung cancer (NSCLC)
Tumors tested negative for
(EGFR, KRAS, ALK)
NGS testing pursued.
64 yo F non-smoker newly
diagnosed with non-small cell
lung cancer (NSCLC)
Activating mutations in the ERBB2 gene
- encodes the Her2 protein, a wellknown breast cancer biomarker
ERBB2YVMA
Clinical Impact – Case 1
Treated with Herceptin Off-Label
The patient has been progression
free for > 5 years
N-of-One all material confidential. Do not distribute.
Clinical Relevance
- FDA Approved Therapy: None approved
to target ERBB2/HER2 for NSCLC
- Drugs targeting ERBB2/Her2 are
approved for treatment of breast cancer
and are being tested in clinical trials.
- Drug targeting both Egfr and Her2
approved in EGFR-mutant NSCLC
ERBB2YVMA
Clinical Impact – Case 2
-Treated with radiation and SOC.
- Progressive disease with development of
CNS metastases
-Switched to afatinib
-Stable disease for approximately 6 months
then passed away
Why a Cancer Center wants a Precision Medicine
Program?
• Many IDNs are implementing or
exploring precision medicine
programs
– Growing competition for patients
– With growing reimbursement clarity,
pathology labs can offer NGS testing
profitably
– Many institutions bringing molecular
testing in house to drive revenues
• Molecular Testing is becoming
Standard of Care
N-of-One all material confidential. Do not distribute.
What is required to Launch a Precision Medicine
Program? The Diagnostic Lab
Lab
Bioinformatics
Clinical
Interpretation
Pathologist
Data
Filtering,
Variant
Calling
Delivery of
Relevant
Evidence
and
Therapeuti
c Options
Analysis
and
Sign Out
Sequencing
Validation
CLIA/CAP
Molecular Tumor Board Access
N-of-One all material confidential. Do not distribute.
Clinical Trial Access
What are the Challenges to Launching a Program? Trends in
Molecular Testing Driving Complexity in Interpretation
• Even small NGS panels can be complex
• Understanding the full molecular profile to identify drug resistance and
sensitivity requires multi-variant analysis
• Access to relevant Clinical Trials
• NGS is not the only important molecular test
• Benefit of incorporating additional clinical information such as prior drugs,
relevant labs, co-morbidities etc…
To launch and scale their programs, organizations are struggling with the
translation of the molecular data such that it can be delivered to the
oncologist at the point of care in a high quality, scalable way.
N-of-One all material confidential. Do not distribute.
Patient-Specific Analysis is Required
to Find the Most Relevant Therapeutic Options
Patient 1
Disease: Melanoma
Gene: BRAF
Variant: V600E Mutation
Potential Therapeutic Strategy:
vemurafenib + cobimetinib
or
dabrafenib + trametinib
Patient 2
Disease: Colorectal
Cancer
Gene: BRAF
Variant: V600E Mutation
Patient 3
Disease: Colorectal Cancer
Gene: BRAF
Variant: D594G Mutation
Potential Therapeutic Strategy:
vemurafenib + cetuximab
or
trametinib or cobimetinib
Potential Therapeutic Strategy:
trametinib or cobimetinib
or
sorafenib or regorafenib
Conclusion: Gene and Variant Analysis in context of each Patient’s Disease
N-of-One all material confidential. Do not distribute.
How are Health Systems Addressing these Challenges?
•
•
•
•
Some are attempting do everything in-house
Some are buying tools
Many are working with N-of-One
Some send out to another lab or Community Hospitals for
comprehensive testing
N-of-One all material confidential. Do not distribute.
Partnering for Success in the Community:
Intermountain Healthcare
Partnering for success: Intermountain provides NGS Lab services to other
Community Hospitals. N-of-One supports this effort by providing Intermountain with
Clinical Interpretation and Clinical Trial Matching
Intermountain Healthcare conducted two studies:
•Treatment changed to targeted therapy in 62% of cases where
molecular testing and N-of-One interpretation were available
•Outcomes progression free survival of 22.9 weeks for precision
therapy approach compared to 12.0 weeks for traditional
chemotherapy
•Cost was essentially the same
Nadauld et al., J. Clin. Oncol. 33, 2015 (ASCO Abstract e17647, e17641)
N-of-One all material confidential. Do not distribute.
What Lies Ahead for 2016: Even More Complexity
Liquid Biopsies
Integrated Molecular Tests
Novel and Combination
Therapies
EMR Clinical Data
More Novel Clinical Trials
N-of-One all material confidential. Do not distribute.
How Does N-of-One Support Precision Medicine
Programs?
Additional Supporting Services Available
Major
Hospital
Systems
Pathology Lab
Support
Diagnostic
Labs
Globally
Clinical Trial PreEnrollment
Services
Cancer
Treatment
Centers
N-of-One
Clinical
Interpretation
And Clinical Trial
Matching
Molecular Tumor
Board Support
Collaboration on
Research
leveraging N-ofOne’s database
N-of-One all material confidential. Do not distribute.
THANK YOU!
QUESTIONS?
Jennifer Levin Carter MD, MPH
617 947-1631
[email protected]
Michael Kolodziej, M.D.,
National Medical Director
Oncology Solutions, Aetna
Moderators:
Amy Abernethy, M.D., Ph.D., Senior Vice
President and Chief Medical Officer,
Flatiron Health
Edward Abrahams, Ph.D., President,
Personalized Medicine Coalition
Panelists:
Jennifer Levin Carter, M.D., MPH, Chief
Medical Officer and Founder, N-of-One
Michael Kolodziej, M.D., National Medical
Director Oncology Solutions, Aetna
Richard L. Schilsky, M.D., FACP, FASCO,
Chief Medical Officer, American Society of
Clinical Oncology®