Precision Medicine: Opportunities and Challenges for Clinical Trials

Physician Led | Therapeutically Focused
© 2015 Medpace, Inc. All Rights Reserved
1

What Is Precision Medicine?
o National Research Council (2011)
 “Tailoring of disease prevention and treatment
based on the characteristics of each individual”
 Old idea, but new implications due to new
technology that allows for the analysis of large
scale genomic data

What Is Precision Medicine?
3 Physician Led | Therapeutically Focused
o President Obama’s Precision Medicine Initiative
(2015)
 “……an innovative approach to disease prevention
and treatment that takes into account individual
differences in people’s genes, environments and
lifestyles.”

Precision Medicine Initiative
o President’s 2016 budget
 $216 million
o Goals:
 Develop more and better treatments for cancer
 Create a national voluntary research cohort
 Protect privacy
 Modernize regulation
 Develop public-private partnerships

Precision Medicine: Core Premise
o “The application of evidence-based medicine can
improve quality and control cost in a healthcare
system”
Aronson N, Annals NY Acad of Sci 2015
5

o Simplistic impression
 Do a test (e.g., sequence the genome of a tumor)
 Identify “actionable” target(s)
 Pick a drug (approved or experimental) for the
identified target(s)
6

o Likely more complex than this
 Diagnostic test performance
 Test interpretation
 Multiple targets
 Prioritization of targets (e.g., which are drivers)
 Number of targets that are “actionable”
 Availability of approved or experimental drugs
• Drugs need to be tested in patients with specific
abnormalities and proven to be effective
• Drug needs to be proven safe and effective if used in
combination
 Clinical decision making and management
 Healthcare delivery variables
 Measuring treatment outcomes
7

Precision Medicine: Goals
o Determine:
 How do we better target driver (central oncogenic
event)abnormalities?
 Who will respond to treatment?
 Who will not respond to treatment?
 How can we reduce harm associated with
treatment, especially if the treatment does not
work?
 How can we make treatments more cost effective
 How can we improve access to better treatments?
 Will molecular testing improve outcomes?

What Is Personalized Medicine?
o “Although the term personalized medicine is
repeated like a mantra in scientific papers,
meetings, media and even the Internet, its exact
definition is vague and remains almost unclear to
many.”
Giuseppe Lippi and Mario Plebani, Clin Chem Lab Med 2015
9

Are Personalized Medicine and Precision
Medicine the Same?
o Not clear
o Terms are often used interchangeably
o Clinical care versus clinical research
 Physicians always personalize care
 Clinical research requires “lumping of patients” to
some degree
• Results of clinical research are based on the mean
of the study population
• Relevance to an individual?
o Clinical care is increasing precise as knowledge
and technology advances

Are Personalized Medicine and Precision
Medicine New?
o New terminology?
o Fad?
o Politics?
o Marketing?
o Media?

Strategy Is Not New!
o These concepts and strategies have guided
cancer therapeutics for more than 60 years
o Example:
 One of the greatest success stories in the history of
medicine: ALL in children

Childhood ALL: 10-Year Survival Estimates by
Year of Treatment
0
10
20
30
40
50
60
70
80
90
100
1968-
1970
1972-
1975
1978-
1983
1989-
1995
EstimatedSurvivalPercentage

How Did We Achieve These
Remarkable Improvements in
Outcome For Children With ALL?
o Clinical trials have been increasingly precise and
personalized since the 1950’s
 Biology!
 Risk group identification
 Risk group directed therapy

Frequency of cytogenetic subtypes of pediatric ALL.
Charles G. Mullighan Hematology 2012;2012:389-396
©2012 by American Society of Hematology

Does Improvement in Outcome Require
New and Expensive Approaches?

FDA Approval of Drugs Used To Treat ALL
o Methotrexate 1953
o Mercaptopurine 1953
o Dexamethasone 1958
o Vincristine 1963
o Thioguanine 1966
o Cytarabine 1969
o Daunomycin 1979
o Etoposide 1983
o Asparaginase 1994

Smith M A et al. JCO 2010;28:2625-2634
Mortality Rates for Childhood Cancer

What Next?
o Progress is slowing
o After almost 60 years, have
o we optimized therapy with
o current treatment?
o If so, what do we do next?

Effective Cancer Treatment
o What has gotten us to this point?
 Surgery
 Radiation
 Chemotherapy
 Blood and marrow transplantation
o To make further improvements, we need to add
something new
 These new treatments will be based on the biology
of the cancer and the patient
• For example, sequencing the genome

How Many Genes Are Involved In Cancer?
o Current data suggest about 1% of genes have
mutations that are involved in cancer (less than
300)
 Futreal PA, et al. “ A census of human cancer
genes”. Nature Rev Cancer 4:177-183, 2004
o Currently, only a relatively small subset of these
abnormalities are “actionable” (e.g., serve as drug
targets)

Excitement About Precision Medicine
o BCR-ABL CML
 Kantarjian H et al. “Hematologic and cytogenetic
responses to imatinib mesylate in chronic
myelogenous leukemia”. N Engl J Med 346:645-
656, 2002
o EGFR-mutant lung cancer
 Paez JG et al. “EGFR mutations in lung cancer:
Correlation with clinical response to gefitinib
therapy”. Science 304: 1497-1500, 2004
o ERBB2+ breast cancer
 Romond EH et al. “Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast
cancer”. N Engl J Med 353: 1673-1684, 2005

Process-To-Date
o Identification of genomic alterations in patients
with a specific diagnosis
o The genomic alteration is a driver (central) of the
oncogenic event
o Activity of the targeted drug has been tested
against the target in pre-clinical and early phase
human clinical trials

Central Question For Precision Medicine
o Is this same approach effective regardless of the
patient’s conventionally defined diagnosis?

Current Landscape
o Adult interventional cancer trials registered on
clinicaltrials.gov
o September 2005-May 2013
o Trial is classified as “precision cancer medicine” if
a genomic alteration in a predefined set of 88
genes was required for enrollment
Roper N et al Cancer Treatment Rev 2015
25

Precision Medicine Studies
o 18,797 trials identified
 9094 (48%) were eligible for inclusion
 684 (8%) were classified as “precision cancer
medicine” trials
o Increase from 3% of trials in 2006 to 16% in 2013
o Most often involved breast, colorectal and skin
cancer
o Required 38 unique genomic alterations for
enrollment
Roper N et al Cancer Treatment Rev 2015
26

New Actionable Targets: Example
o “Comprehensive Genomic Profiling of Carcinoma
of Unknown Primary (CUP) Site: New Routes to
Targeted Therapy”
 Objective
• “To discover opportunities for targeted therapies in
patients with CUP not currently searched for in
routine practice
 200 patients with CUP
 Results
• Abnormalities found in 217 genes
» 30 clinically relevant
• Almost all CUP samples had a least 1 clinically
relevant genomic alteration (mean=4.1)
Ross JS et al JAMA Oncol 2015
27

Is This Approach Feasible?
o “Feasibility of Large-Scale Genomic Testing to
Facilitate Enrollment Onto Genomically Matched
Clinical Trials”
 2000 patients with advanced cancer
 Broad-based genomic testing
 Results
• 35 genes were “actionable”
• 39% of patients had at least 1 mutation in one of
these genes
• 11% of patients enrolled in a genotype-matched trial
targeting these alterations
Meric-Bernstam et al J Clin Oncol, Epub ahead of print 2015
28

Novel Study Designs
o Basket Trials
 Test treatments based on mechanism of action (as
opposed to histology)
o Umbrella Trials
 Test multiple drugs for a single disease
o Adaptive Trials
 Match treatment to patients during the conduct of
the study based on responses
Schork NJ Nature 2015
29

Novel Study Designs
o Registries/Databases
 Precision Medicine Initiative
 “In silico” research
o N-of-1clinical trials
 Require massive amounts of data on the individual
patient
Schork NJ Nature 2015
30

Are Basket Designs Feasible?
o 647 patients with advanced thoracic malignancies
o 88% had tumors assessed for at least 1 gene
o EGFR mutation frequency was 22.1% in NSCLC
with 60% response rate to erlotinib
o KRAS mutation frequency 24.9% in NSCLC with
selumetinib failed to reach its primary endpoint
with a response rate of 11%
o Completion of accrual to all other arms was not
feasible
Lopez-Chavez a et al. J Clin Oncol 33:1000-1007, 2015

Ongoing: National Cancer Institute-Sponsored
Precision Medicine Clinical Trials
o NCI-Match
 ECOG-ACRIN
 3000 patients with solid tumors and lymphoma
 200 genes will be analyzed
 40 drugs from 20 pharmaceutical companies
pledged

Ongoing: National Cancer Institute-Sponsored
Precision Medicine Clinical Trials
o Lung-MAP
 Phase II/III clinical trial
 Patients with advanced squamous cell lung cancer
 Genomic analysis
 Pairs patients to targeted agents based on results

What is Fueling Recent Progress in
Precision Medicine?
o Biology
 Genomics
• High-throughput deep sequencing
• Just a few years ago, 1 genome sequenced in 2
weeks
• Now, >100 genomes per day
o Ability to store massive amounts of data
inexpensively (DeGennaro, L Personal
communication)
 Storage of 1 gigabyte of data
• 1985: $71,000
• 2015: $0.03
o Ability to analyze large data sets

Challenges
o Limited number of pathways identified
o Limited number of genes
o Limited number of “actionable” genes
o Focus on the genome is likely overly simplistic
o Ability to analyze data across multiple platforms
 New models of disease

Challenges
o Profound number of potential targets
 Which targets are important?
 How many targets are “actionable”?
 Can targets be made actionable?
 How many targets do you need to hit?
 Will the targeted therapy kill only the susceptible
clones?
 Prioritization of targets and drugs
 Availability of clinical trials

Challenges
o Targeted agents are highly unlikely to work as
single agents in cancer
o Use in combination with other targeted agents or
conventional therapies is highly likely
o Safe and effective use of targeted drugs in
combination is still predicated upon Phase I, II
and III safety and efficacy studies

Challenges
o Will precision medicine reduce healthcare costs?
 Spending on genetic and molecular testing
• $15-25 billion by 2021
» United Health Center for Health Reform &
Modernization, 2012
o Equity
 Will it be available to only the “rich”

Challenges
o Implications of knowing a person’s genome
sequence
 Ethical
 Legal
 Financial
 Social

Challenges
o While medicine will continue to be increasingly
precise, what are the limits on truly “personalized”
treatment?
 Are N-of-1 trials realistic, safe, effective and
informative?

What Kind of CRO’s Will Be Important In the
Development and Execution of
These Complex Studies?
o Full service
 Ability to integrate all required elements of a
complex study
o Physician-led
 Medical and scientific knowledge and expertise
 CRO’s that have recruited disease-specific KOL’s to
work for them
o Biostatistics and data management
 Novel study designs
o IT infrastructures
 Big data
o Regulatory experts

Summary
o Biologic understanding of disease is advancing at a
remarkable pace
o Improvements in the outcome of patients is
undoubtedly going to follow
o The “precision medicine approach” is more complex
than most understand
 Feasibility still being assess
o It is still highly experimental and in the end will still
require Phase I, II and III studies to establish safety
and efficacy
o “Don’t try this at home” (e.g., outside the context of a
clinical trial) if the safety and efficacy of the approach
has not yet been proven

Q& A
Franklin O. Smith, III, M.D., FAAP, FACP,
Medpace Vice President, Medical Affairs,
Hematology and Oncology
f.smith@Medpace.com

Precision Medicine: Opportunities and Challenges for Clinical Trials

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