Precision Medicine: Opportunities and Challenges for Clinical Trials

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

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What Is Precision Medicine?

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

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.”

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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

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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


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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)



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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



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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?

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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


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Are Personalized Medicine and Precision Medicine the Same?


o Not clearo Terms are often used interchangeablyo 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

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Are Personalized Medicine and Precision Medicine New?


o New terminology?o Fad?o Politics?o Marketing?o Media?

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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

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Childhood ALL: 10-Year Survival Estimates by Year of Treatment


0102030405060708090

100

1968-1970

1972-1975

1978-1983

1989-1995

Estim

ated

Sur

viva

l Per

cent

age

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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?

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FDA Approval of Drugs Used To Treat ALL


o Methotrexate 1953o Mercaptopurine 1953o Dexamethasone 1958o Vincristine 1963o Thioguanine 1966o Cytarabine 1969o Daunomycin 1979o Etoposide 1983o Asparaginase 1994

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Smith M A et al. JCO 2010;28:2625-2634

Mortality Rates for Childhood Cancer


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What Next?


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

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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

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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, 2004o Currently, only a relatively small subset of these

abnormalities are “actionable” (e.g., serve as drug targets)

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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

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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

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Central Question For Precision Medicine


o Is this same approach effective regardless of the patient’s conventionally defined diagnosis?

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Current Landscape

o Adult interventional cancer trials registered on clinicaltrials.gov

o September 2005-May 2013o 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


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Precision Medicine Studies

o 18,797 trials identified 9094 (48%) were eligible for inclusion 684 (8%) were classified as “precision cancer

medicine” trialso Increase from 3% of trials in 2006 to 16% in 2013o Most often involved breast, colorectal and skin

cancero Required 38 unique genomic alterations for

enrollment

Roper N et al Cancer Treatment Rev 2015


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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


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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


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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 diseaseo Adaptive Trials

Match treatment to patients during the conduct of the study based on responses

Schork NJ Nature 2015


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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


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Are Basket Designs Feasible?

o 647 patients with advanced thoracic malignancieso 88% had tumors assessed for at least 1 geneo EGFR mutation frequency was 22.1% in NSCLC

with 60% response rate to erlotinibo 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


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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

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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

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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

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Challenges


o Limited number of pathways identifiedo Limited number of geneso Limited number of “actionable” geneso Focus on the genome is likely overly simplistico Ability to analyze data across multiple platforms

New models of disease

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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

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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

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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”

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Challenges


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

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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?

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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

studyo Physician-led

Medical and scientific knowledge and expertise CRO’s that have recruited disease-specific KOL’s to

work for themo Biostatistics and data management

Novel study designso IT infrastructures

Big datao Regulatory experts

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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

[email protected]

Precision Medicine: Opportunities and Challenges for Clinical Trials

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