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Efforts to expedite and streamline the development of effective cancer therapies as well as to reduce the overall costs associated with conducting clinical trials, have led drug developers to increase their investment in clinical biomarker research. In response to recommendations from the International Conference on Harmonization (ICH), the United States Food and Drug Administration (FDA) issued guidance in April 2008, which provided definitions for genomic biomarkers as well as how to code the collected data1. The guidance followed the publication by FDA staff of a “Process map proposal for the validation of genomic biomarkers”, suggesting that the key to the increased usage of biomarkers in clinical trials could be found in assisting drug developers in reaching a consensus on how to best interpret the data resulting from the incorporation of biomarkers2.

To further encourage the use of biomarkers in clinical trials, the United States FDA issued additional biomarker guidance in August 2011 designed in part to help promote and harmonize biomarker development among regulatory agencies in the United States, European Union and Japan, and was developed within the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)3. The recognition by the FDA and other regulatory agencies of the need to work together on the use of biomarkers in clinical trials underscores the increasing importance of collaborative efforts between clinical trial sponsors in various countries during the drug development process.

1. ICH E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories

2. Goodsaid F. and Fruch F. Process Map Proposal for the Validation of Genomic Biomarkers (2006) Pharmacogenomics 7(5):773-782.

3. ICH E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure, and Format of Qualification Submissions, U.S. Department of Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), August 2011 ICH

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4. Helwick C. I-SPY Trial Characterizes Tumor Biology and Response to Neoadjuvant Chemotherapy, December 17, 2007 http://www.cancernetwork.com/articles/i-spy-trial-characterizes-tumor-biology-and-response-neoadjuvant-chemotherapy#sthash.4kldq2Xx.dpuf

5. Barker A.D., Sigman C.C., Kelloff G.J., Hylton N.M., Berry D.A. and Esserman L.J. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy (2009) Clin Pharmacol Ther 86(1):97-100

Since 2002, there has been a steady increase in the number of oncology clinical trials identifying, testing

or using pharmacogenomic (PGX) biomarkers to either select or stratify patients. Among biomarker trials,

there has been a shift in the proportion using PGX selection or stratification, from 19% in 2002 to 43% in

2013 (Figure 1). Interestingly, the use of biomarkers in oncology clinical trials peaked in 2010, approximately

two years after the FDA issued guidance on biomarker definitions and coding of data collected from these

trials. The steady increase in the proportion of biomarker trials using PGX biomarkers to select/stratify

patients is indicative of many successes in validating biomarkers in the context of clinical trial testing.

During this time period, PGX biomarkers were used most often in Phase II trials compared to other phases,

and over the period from 2009 through 2013, there was a slight increase in the proportion of Phase III

trials, from 9 to 13%, utilizing PGX biomarkers (data not shown).

Examples of progression in the utilization of biomarkers in oncology clinical trials are the I-SPY (Investigation

of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular analysis) program,

designed to correlate responses to therapy with the presence of particular receptors in women with breast

cancer and the BATTLE (Biomarker-integrated Approaches of Targeted Therapy of Lung cancer Elimination)

program in non-small cell lung cancer (NSCLC). Both of these trial programs employed an adaptive design

strategy. The primary objective of the I-SPY-1 trial, initiated in 2002, was to identify surrogate markers of

response to neo-adjuvant therapies in stages II and III breast cancer, using magnetic resonance imaging4.

While I-SPY-1 tested neo-adjuvant chemotherapy regimens, the subsequent Phase II I-SPY-2 trial tested

and correlated responses to targeted drug combinations to hone in on the best treatment strategies for

the various breast cancer receptor subpopulations5. This trial program was one of the protocols that set

the stage for later translational research studies and was a model for collaborative efforts, in that the study

allowed for data sharing, via a portal, among the large number of trial investigators in the immediate

sponsoring group, SPORES (Specialized Programs of Research Excellence).

Figure 1. Percent Oncology Trials Selecting or Stratifying by PGX Biomarkers

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Source: Citeline’s Trialtrove®, data accessed January 2014

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Figure 2. Oncology Indications Representing at Least 10% of PGX Selection/Stratification Trials

0 10 20 30 40

Breast

NSCLC

Melanoma

Colorectal

Gastric

NHL

Percent Trials

2013

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The BATTLE program was the first to address personalized medicine in lung cancer using molecular

signatures obtained from real-time biopsies to determine the course of targeted therapy. Patients meeting

the eligibility criteria of advanced NSCLC and who have received at least one prior chemotherapy regimen

are first enrolled in an “umbrella” or screening trial to undergo an analysis of biomarkers obtained from

tumor biopsies. Upon completion of the analysis and depending upon the outcome, eligible patients were

enrolled into one of four phase II trials, treating with one of four targeted drugs either as monotherapy or in

combination with chemotherapy regimens. Investigators reported at the American Association for Cancer

Research meeting in 2010 that statistical modeling of the data from these trials matched four different

molecular signatures in biopsies from stage IV non-small cell lung cancer patients to specific drugs which

led to additional studies within this program6. BATTLE-2, was initiated in June 2011 and is recruiting

advanced, second-line or greater NSCLC patients, in order to investigate whether particular targeted

drugs given alone or in combination with other targeted drugs are effective, and to identify prognostic

and predictive markers for four proposed regimens. The BATTLE-FL trial, initiated in May 2011, is enrolling

patients with previously untreated advanced NSCLC to identify targeted therapy regimens effective for this

patient population. Finally, the BATTLE-XRT trial, while not yet open to recruitment, takes the program a

step further from the identification of biomarkers to the use of biomarkers in patient stratification.

which oncology indications most frequently include PgX selection/stratification biomarkers?Among the trials initiating in 2013, breast cancer was the largest indication, and was included in 35% of

these trials (Figure 2). From 2009 through 2013, breast cancer was being studied in an average of 34% of

the PGX trials, a not too surprising observation given the amount of research in this area and the numbers

of approvals of drugs including targeted therapies for breast cancer over the years. Non-small cell lung

cancer (NSCLC) and colorectal cancer comprise the next largest diseases. Interestingly, from 2004 through

2008, breast cancer was being studied in an average of 52% of the PGX trials per year (data not shown).

The decrease in later years can be partly explained by an increase in PGX biomarker utilization in other

indications such as gastric cancer, melanoma and non-Hodgkin’s Lymphoma (NHL).

6. Kim E.S., Herbst, R.S., Lee J.J., Blumenschein Jr G.R., Tsao Al, Alden C.M. Tang X., Liu S., Stewart D.J., Heymach J.V., Tran H.T., Hicks M.E., Erasmus Jr J., Gupta S., Powis G., Lippman S.M., Wistuba I.I., Hong W.K. (2010) The BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination): personalizing therapy for lung cancer, In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; 2010. Abstract No. LB-1

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where are PgX biomarker selection/stratification oncology trials being conducted?As of January 2014, Trialtrove lists 2,402 currently planned or ongoing trials, where ongoing is defined as

open, closed or temporarily closed to recruitment. Many of these trials are being conducted globally, so

there is a great degree of overlap in the numbers of trials represented by the various countries. The majority

of these trials are being conducted in the US (1102), while Japan is second highest with 545 trials (Figure 3).

In addition to the availability of clear guidance and support from the FDA on the role of pharmacogenomics

in the drug approval process, another factor contributing to the US lead in PGX trials may be the

establishment of the Cancer Genome Atlas (TCGA) program, by the National Cancer Institute (NCI) in

2006 to promote the use of genomics technologies in research on the prevention, diagnosis and treatment

of cancer. France, Germany, Italy, Spain and the UK are among the next top locations for PGX selection/

stratification trials. The European Medicines Agency (EMA) has been providing guidance since November

2002 on the use of pharmacogenetics/pharmacogenomics in various clinical trial related settings as well as

promoting the use of the ICH E15 guidance issued by the US FDA. In addition, the European Commission

held a workshop in June 2010, “Stratification Biomarkers in Personalised Medicine” in order to discuss the

scope of PGX stratification biomarkers, barriers to their use in clinical trials and with the purpose of building

a road map or vision for the year 20207. Finally, China is the only other Asian location among the top 10

locations for ongoing or planned PGX biomarker selection/stratification trials.

Figure 3. Top Country Involvement in Ongoing Oncology PGX Trials

United States

Japan

France

Germany

Italy

Spain

United Kingdom

Canada

Belgium

China

1,102

545

323 313

284

278

253

220

193 177


7. Biomarkers for Patient Stratification: Workshop to clarify the scope for stratification biomarkers and to identify bottlenecks in the discovery and the use of such biomarkers. Brussels, 10-11 June 2010, http://ec.europa.eu/research/health/pdf/biomarkers-for-patient-stratification_en.pdf

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the cast of characters: Drugs and mechanisms of action involved in PgX biomarker selection/stratification trialsAmong the 2402 ongoing or planned trials, 42% or 1024 of these trials involve novel drugs not yet approved

in any indication. For early phase development, thirteen novel drugs involved in four or more ongoing PGX

trials are listed in Table 1: 10 in Phase II and 3 drugs in Phase I. Four of the drugs in Phase II, dovitinib,

entinostat, pictilisib, and RG-7446 each are being developed in conjunction with a companion diagnostic test.

To date, none of the three Phase I drugs have a disclosed companion diagnostic in development. Phase II

candidate, luminespib, a heat shock protein 90 antagonist, developed by Vernalis and licensed to Roche,

is currently in testing in 13 planned or ongoing trials selecting or stratifying patients with PGX biomarkers.

The remainder of the unapproved drugs with a global development status of Phase I or Phase II are

generally kinase inhibitors of various types (see Table 1), with the exception of entinostat, which is a

histone deacetylase inhibitor and RG-7446, a CD274 (PD-L1) antagonist.

Source: Citeline’s Trialtrove® and Pharmaprojects®, data accessed January 2014

table 1. investigational Drugs in early Phase Development in Planned or ongoing oncology trials using PgX Biomarkers to select or stratify Patients

DrUg originator licenseehighest

DeveloPMent statUs

MechanisM oF action# trials

PgX selection

coMPanion Diagnostic

luminespib Vernalis Novartis Phase II Heat shock protein 90 antagonist 13 No

MK-2206 Merck & Co N/A Phase II Protein kinase B inhibitor 12 No

BYL-719 Novartis N/A Phase II PI3 kinase inhibitor 11 No

dovitinib Novartis N/A Phase II Multi-kinase inhibitor 9 Yes

AZD-4547 AstraZeneca N/A Phase II Pan-FGFR kinase inhibitor 8 No

GSK-2141795

GlaxoSmith-Kline

N/A Phase I Protein kinase B inhibitor 7 No

dactolosib Novartis N/A Phase IIPI3 kinase inhibitor, mTORC1 and mTORC2 kinase inhibitor

6 No

pictilisib Roche N/A Phase II PI3 kinase inhibitor 5 Yes

INCB-028060

Incyte Novartis Phase II MET tyrosine kinase inhibitor 5 No

BGJ-398 Novartis N/A Phase I Pan-FGFR kinase inhibitor 5 No

entinostat Bayer Syndex Phase II Histone deacetylase inhibitor 4 Yes

RG-7446 Roche N/A Phase II CD274 antagonist 4 Yes

ARRY-380Array BioPharma

Oncothyreon Phase I ErbB-2 tyrosine kinase inhibitor 4 No

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emerging trend: epigeneticsIn addition to patient selection and stratification by genomic mutations in clinical trials, another area of research

that is starting to gain traction is the use of epigenetics, which includes the acquisition of alterations that, instead

of involving gene mutations, result from changes in chromatin structure — usually environmentally induced.

Epigenetic modifications, which include acetylation, methylation, phosphorylation, and ubiquitination affect

interactions between DNA and the transcriptional machinery, thereby incorporating environmental changes at

the cellular and molecular level. With the recognition that epigenetic modifications play a role in disease etiology,

drug developers are beginning to investigate aspects of the epigenetic machinery as potential oncology targets.

As of January 2014, there were 681 ongoing or planned oncology trials testing drugs with known epigenetic

mechanisms of action (MoA) in Trialtrove. Of these, 126 studies involve PGX biomarkers to either select

or stratify patients, and 334 trials have endpoints for identifying or testing efficacy biomarkers (data not

shown). The overlap between these two populations of trials is 57% (388 of 681). Use of PGX biomarkers in

trials testing epigenetic drugs has increased over time. In completed or terminated trials testing drugs with

epigenetic MoAs, 43% (458 of 1070 trials) were using these epigenetics to select or stratify patients, while

57% of currently ongoing or planned trials are using epigenetic biomarkers in this way -- a 1.3 fold increase

(57% vs. 43%, data not shown). Table 2 lists the top 10 drugs with epigenetic MoAs most frequently tested

in oncology PGX trials. The highest development status of these drugs varies from Phase I through

Launched. Four of these drugs are already launched or in pre-registration for certain cancer indications,

but each is being pursued for registration in additional indications. In addition, five of these drugs,

including olaparib, which is in Pre-registration for ovarian cancer, are being co-developed with companion

diagnostic reagents. The other four drugs with companion diagnostics in development currently have a

highest development status of either Phase I or Phase III.

The top industry sponsors (originators and licensees) developing epigenetic targeted drugs with PGX trials

are Abbvie, AstraZeneca, Celgene, Clovis Oncology, Genesis, Incyte, Nippon Shinyaku, Novartis and Pfizer.

Interestingly, of these sponsors, only AstraZeneca, Novartis and Incyte are also among top developers of

novel drugs of any MoA in PGX trials (see Table 1). Clearly, some drug developers are pursuing different

MoA strategies (targeting mutations versus epigenetic machinery) in their trial programs with respect to

using PGX and companion diagnostic development, or are working in stealth mode at a late stage.

table 2. top ten Primary Drugs with epigenetic Mechanisms in ongoing and Planned oncology trials using PgX Markers to select or stratify Patients

DrUg originator licensee(s)highest

DeveloPMent statUs

Moa# trials

PgX selection

coMPanion Diagnosis

veliparib Abbott Abbvie Phase IIIADP ribose polymerase 1,2 inhibitor DNA repair enzyme inhibitor

26 No

olaparib AstraZeneca N/APre- registration

ADP ribose polymerase 1,2 inhibitor DNA repair enzyme inhibitor

18 Yes

azacitidine Celgene

Nippon Shinyaku Genesis Pharma

LaunchedRNA, DNA synthesis inhibitor DNA methylase inhibitor

12 No

ruxolitinib Incyte Novartis Launched Janus kinase 1, 2 inhibitor 8 No

rucaparib PfizerClovis Oncology

Phase III ADP ribose polymerase 1,2 inhibitor 7 Yes

vorinostat Merck & Co Taiho Launched Histone deacetylase inhibitor 6 No

BMN-673 BioMarin N/A Phase III ADP ribose polymerase 1,2 inhibitor 4 Yes

entinostat Bayer Syndax Phase III Histone deacetylase inhibitor 4 Yes

panobinostat Novartis N/A Phase III “Histone deacetylase inhibitor 3 No

Source: Citeline’s Trialtrove® and Pharmaprojects®, data accessed January 2014

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Just as important as the successes in clinical trials outcomes, are the failures, or the instances where trials

are terminated prematurely for negative reasons. On January 30, 2014, AVEO and Astellas announced the

discontinuation of the Phase II BATON (Biomarker Assessment of Tivozanib in ONcology) breast cancer

clinical trial due to insufficient patient enrollment. This was a global trial with a low target patient enrollment

of just 147 patients, and was being conducted at 54 sites in 14 countries. Efforts to compensate for slow

recruitment rates by adding sites did not have the desired effect. This is not surprising, since tumors

lacking expression of all three receptors, estrogen receptor, progesterone receptor and HER-2/ERBB2

receptor, comprise only 10-20% of all breast cancers and coupled with the requirement for metastatic

cancer, is a fairly small subset of breast cancer patients. The BATON trial started recruiting patients in

December 2012 and was terminated 14 months later, which may not have allowed sufficient recruitment

Unexpected advantages and potential pitfalls of using PgX selection/stratification biomarkersThe drive towards the molecular characterization of tumors, characterized by high profile trial programs

such as I-SPY-2 and BATTLE, with the eventual goal of providing the knowledge to select or stratify patients

into the trials and treatment arms in which they are most likely to benefit, may already be bearing fruit.

An analysis of outcome assessments, measuring the degree of a trial’s success, was undertaken in order

to determine if trials selecting and stratifying patients using PGX biomarkers differed to the outcomes

obtained in a set of internally controlled trials: those that were identifying and testing biomarkers but not

using them for selection or stratification. In other words, among trials utilizing biomarkers, was there any

advantage to using PGX biomarkers to select or stratify patients in the trial?

In a subset of Phase I/II through Phase IV oncology trials, conducted by industry and/or large cooperative

groups, and completed after January 1, 2008, trial outcome assessment was found to be more positive in

those trials using biomarkers to select or stratify patients versus those that were identifying or testing

biomarkers only (Figure 4). Trials using biomarkers for selection were four times as likely to have a positive

outcome for the primary endpoint compared to a negative outcome (61% versus 15%), whereas those trials

identifying or testing biomarkers were only twice as likely to have a positive outcome compared to a negative

outcome for the primary endpoint (51% versus 22%). This suggests an increased tendency for positive

outcome in trials where patients are more appropriately matched for therapy based on PGX biomarkers.

Figure 4. Effect on Completed Trial Outcomes of using PGX Biomarkers to Select or Stratify Patients

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Trials selecting/stratifying using PGX biomarkers

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Completed, Positive outcome/primary endpoint(s) met Completed, Negative outcome/primary endpoint(s) not met Completed, Outcome unknown/indeterminate


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time for this population of patients. Trial sponsors may need to factor in lower recruitment numbers when

planning to conduct trials enrolling specialized populations of patients based on genomic/epigenetic

biomarkers, because of the reduced numbers of eligible patients. In addition, recruitment period estimates

may need to be lengthened to allow necessary time for the appropriate screening of patients. Further

development of companion diagnostic reagents targeting the appropriate populations should contribute

to the success of future trial programs.

In the subset of Phase I/II through Phase IV oncology clinical trials terminated on or after January 1, 2008,

a few trends are noted in Figure 5. Not surprisingly, as was the case in the BATON trial, trials selecting or

stratifying patients using both known and novel PGX biomarkers had a slightly greater tendency to

terminate due to poor enrollment (48%) compared to those trials identifying or testing biomarkers only

(39%). Interestingly, the trend is reversed in trials terminated for lack of efficacy, whereas the trials using

PGX biomarkers had a slightly lower termination rate for this reason (32%) versus those trials identifying or

testing biomarkers only (42%). Both types of trials had similar rates of termination for safety reasons (14%

for PGX, 16% for Biomarker testing trials). While trial termination for positive reasons, such as early positive

outcome, was much less frequent, there were twice as many trials utilizing PGX biomarkers for selection/

stratification terminated for this reason (6%) than trials identifying or testing biomarkers only (3%).

Figure 5. Effect on Terminated Trial Outcomes of using PGX Selection/Stratification Biomarkers

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Perc

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Trials testing biomarkers Trials selecting/stratifying using PGX biomarkers

Terminated, Earlypositive outcome

Terminated, Safety/adverse effects

Terminated,Lack of efficacy

Terminated, Poor enrollment

36

16 14

42

32

39

48


who’s who in PgX biomarker selection/ stratification trials?As shown in Figure 6, an analysis of the top 20 sponsors of PGX trials yields a mix of industry, academic and

government groups. Both the US National Cancer Institute (NCI) and Roche are currently conducting the most

PGX selection/stratification trials. NCI PGX trials account for 21% of all ongoing trials by this sponsor and

Roche PGX trials comprise 40% of all of their ongoing trials. PGX trials comprise 53% and 41% of all ongoing

trials sponsored by the Japanese Ministry of Education, Science and Culture and GlaxoSmithKline (GSK),

respectively. This indicates a very large investment by both industry and government sponsors in utilizing

PGX markers to select patients into trials. In addition to the investment by Roche and GSK, Merck KGaA and

Novartis are other industry sponsors at the forefront of personalized medicine. As seen previously in Table 1,

both Roche and Novartis are developing drugs in conjunction with companion diagnostic reagents for use in

Phase II PGX trials. Other industry sponsors with moderately high proportions of ongoing PGX biomarker

selection/stratification studies include Bristol-Myers Squibb at 30%, AstraZeneca at 29% and Pfizer at 28%.

10

Industry sponsored PGX trials by company and trial phase are shown in Figure 7. Pharma companies, on the

whole, currently have a large investment in Phase II trials. However, among top industry sponsors of these

trials, there were some differences in the proportions of the various phases. Bristol-Myers Squibb has a

proportionately high number of ongoing Phase I/II trials (24%), followed by Novartis with 23%, Pfizer with

20% and GSK with 14%. Roche, however has the greatest numbers of PGX biomarker selection/stratification

trials (226) with only 6% in Phase I/II. Furthermore, certain companies, such as Roche, Novartis, GSK,

AstraZeneca and Takeda are using PGX biomarkers to select or stratify patients in Phase IV post-marketing

trials, with at least 3 trials being conducted by each of these sponsors and 24 trials in the case of Roche.

Figure 6. Top Sponsors of Ongoing or Planned Oncology Trials Using PGX Biomarkers to Select or Stratify Patients

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# PGX biomarker selection/stratification trials

% all ongoing trials by sponsor


Source: Citeline’s Trialtrove®, data accessed March 2014

Figure 7. Top Industry Sponsors of Ongoing Oncology PGX Selection/Stratification Trials

0 10 20 30 40 50 60 70 80 90 100

Merck KGaA

Celgene

Sanofi

Amgen

BMS

AstraZeneca

Pfizer

GSK

Novartis

Roche

# of Trials

IV III II/III II I/II I

11

what’s on the horizon for pharmacogenomics and epigenetics in drug development?Clearly, the use of biomarkers in clinical trials is a strategy being undertaken by many different types of industry,

cooperative group, government and academic sponsors in order to help increase the success of drug dev-

elopment programs. The availability of targeted therapies for a variety of tumor types has led to the increasing

use of protocols that utilize molecular profiling of patients to determine the best treatment strategies. Clinical

trial programs such as I-SPY and BATTLE employed an adaptive design strategy that allowed investigators

to modify protocols in response to the data, albeit within certain parameters which insured the validity of

the outcome. The success of high profile trials like these in investigating and validating predictive biomarkers

of response to molecularly targeted therapies has led to the more frequent use of genomic biomarkers to

preselect patients into trials and/or to stratify them into particular treatment arms once enrolled.

In addition, sponsors are looking towards epigenetic targets as a promising avenue for drug development.

Ultimately, drugs that target the cellular epigenetic machinery may have more far-reaching effects in terms

of degree of effectiveness in populations of patients compared to drugs that target patients harboring

particular mutations. The top drugs in clinical development in trials selecting or stratifying patients using

PGX biomarkers are specific for the enzymes involved in epigenetic processes (see Table 2), and fall into

one of two classes termed epigenetic writers or erasers8. However, a third class exists, the epigenetic

readers, consisting primarily of proteins that bind to chromatin either as part of their structure (architec-

tural proteins) or as modifiers or these proteins and interact with chromatin to modify and remodel its

structure, allowing for changes in gene expression.

Furthermore, going beyond the use of genomic and protein biomarkers, US pharmaceutical company Berg

plans to focus on the metabolic aspects of cancer. Their proprietary discovery platform will be used to

build metabolic as well as molecular fingerprints for each patient and correlate these data with responses

to drugs. As a result of continuing reductions in the costs of sequencing individual genomes and advances

in large scale data processing and analyses as well as increased support and guidance from regulatory

agencies, gathering these types of data will soon become a routine part of the protocol in research studies

designed to optimize drug treatment regimens.

conclusionsRecently completed oncology biomarker trials tended to analyze enrolled patients for one, two or perhaps

a handful of genomic mutations or polymorphisms. However, increasing recognition of the need for

molecular profiling in tailoring oncology therapies has led some sponsors to undertake large, multiple arm,

PGX biomarker trial programs. The NCI has recently initiated or is planning several programs, such as

ALCHEMIST, Master Lung Protocol, M-PACT, and MATCH to accommodate the need to quickly identify

patient populations best suited to respond to current therapies in development as well as to identify novel

biomarkers9. With these programs, NCI has set out to meet the goal of successfully transitioning the use of

molecular profiling to the clinic and translating genotype to phenotype, ultimately matching the molecular

characteristics of each tumor with the optimal treatment regimen. Coordinated genomic screening efforts

are being undertaken in these trial programs, which will serve as useful models for other groups attempt-

ing similar programs. Finally, NCI is working on creating a publicly accessible results database linking

clinical outcomes to molecular characteristics of tumors, which will certainly demonstrate the value of

translational medicine approaches in treating disease and help advance the use of genomic and epigenetic

approaches in drug development10.

8. Arrowsmith C.H., Bountra C., Fish P.V., Lee K., Schapira M. Epigenetic protein families: a new frontier for drug discovery (2013) Nature Rev Drug Discov 11(5):384-400

9. The Cancer Letter, Vol. 39 No. 43, Nov 15, 2013

10. Genomic Clinical Trials: NCI Initiatives, National Cancer Advisory Board, Washington DC, December 10, 2013, http://deainfo.nci.nih.gov/advisory/ncab/164_1213/Doroshow.pdf

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