2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

that the core pathway is not completely blocked with the
selected MTA. Furthermore, in tumors that have similar
molecular aberrations, variability in patient outcomes has
been observed, such as selective BRAF inhibitors in BRAFmutant
melanoma and colorectal cancer. Single genomic
markers are often found to be unsuitable as biomarkers in
clinical studies, and probably a biomarker signature will
eventually be required to predict a response. 20 This points
toward a broader approach when analyzing tumor samples
to include molecular profiling of several cancer genes, such
as mutations, rearrangements, and somatic copy-number
alterations. In addition, for true personalized medicine, one
should also take into consideration not only characteristics
of the tumor but also the relationship host-tumor (tumor
microenvironment and immune response) and host-drug
(metabolism genes and pharmacogenomics). 19
Additional Issues to Consider for Genomics-Driven
Early Clinical Trial Enrollment
Do We Need Certified and Validated Biomarkers?
An increasingly large number of putative biomarkers
using innovative sophisticated technologies are being used
in phase I trials. The lack of fully validated and reproducible
assays that can be conducted in appropriately certified
laboratories operating according to Clinical Laboratory Improvement
Amendments (CLIA) or Good Clinical Laboratory
Practice (GCLP) standards is a major concern. In order to
deal with this obstacle, De Bono and colleagues propose a
parallel and simultaneous predictive biomarker/clinical
anticancer drug development process: in early clinical trials,
when patient selection is many times based on the best
guess, pharmacodynamic biomarkers must follow very rigorous
criteria in order to define “proof-of-mechanism.” Conversely,
predictive biomarkers for selecting patients could
be explored according to less strict standards. 21 Successfully
enriching phase I trials with patients whose tumors harbor
specific molecular aberrations that may predict response
can demonstrate “proof-of-concept” and encourage further
research with a given drug or target. Lack of anticancer
effect in the best-case scenario, provided that sufficient
target inhibition is achieved, may ultimately redefine drug
development strategies. Importantly, delineating a selected
patient population does not restrict the late development of
a specific drug to that subpopulation. If predictive biomarkers
are proven robust and potentially useful in early clinical
trials, they can be further clinically qualified through prospective
evaluation in large randomized controlled trials
before regulatory approval. In other cases in which the
predictive value is not very high, and, therefore, the clinical
utility of the biomarker is not obvious, a randomized and
stratified phase II trial is needed to assess both the new drug
and the corresponding biomarker. 20
How Can We Identify Suitable Candidates?
Targeted agents are developed to treat small subsets of
patient populations, and the operations to perform trials
with the old methods become inefficient. Many difficulties in
recruiting suitable patients have to be addressed. The most
evident is the time to perform molecular analysis to identify
targetable aberrations in the context of an early drug development
program.
The traditional approach is to prescreen patients by send-
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DIENSTMANN, RODON, AND TABERNERO
ing their tumor tissue to a central laboratory for analysis
(either the sponsor of the trial or a vendor) just before
considering the enrollment of the patient in a trial with an
MTA. This strategy usually demands availability of large
amounts of tumor tissue, which may be a limitation when
scarce material was used for diagnostic purposes, patients
were enrolled in previous trials, or there is competing
in-house academic research. In addition, because of the
delay during the prescreening process and clinical deterioration
at the time of recruitment, patients may miss the
opportunity to receive a promising agent.
The alternative strategy calls for local prescreening at
academic institutions and analyzing tumor samples of patients
who are still receiving standard treatment for advanced
disease. Molecular selection can be performed at any
time during the disease course. Advantages include the
requirement of only one consent form (based on a protocol
approved by the local institutional review board) and the
reduction in the time from disease progression with standard
treatment until enrollment in a clinical trial with an
MTA. Nevertheless, upfront tumor analysis has one big
hurdle: its cost is usually not covered by health care providers,
neither national health systems nor private insurance
companies. Building the cost of a broad molecular analysis
into the budget of a specific trial is not feasible because it
precedes inclusion in any given trial. Finally, there is always
the possibility of not having a slot at the time of progression
or the patient not being eligible for a particular trial
with matched MTA as a result of inclusion/exclusion criteria
being too strict.
Another important dilemma is the magnitude and type of
molecular analysis that is likely to be informative for definition
of tumor vulnerability and corresponding targeted
therapy. Usually, targetable molecular aberrations are examined,
including specific mutations, common gene amplifications/translocations,
and selected protein-expression
levels. Screening for single mutations has now been replaced
by multiassay platforms, and several are now available both
commercially and at academic centers that evaluate simultaneously
for mutations in 40 to 200 genes (Sequenom,
SNaP shot, among others). Such platforms require very little
tissue, can be performed quickly, and are less expensive.
Academic institutions are already starting to run pilot
projects, including comparative genomic hybridization,
microarray-based profiling of gene expression, massively
parallel sequencing, exome, and whole-genome sequencing.
22,23 In this regard, there is the issue of whether crossvalidation
of molecular profiling results should be performed
at each single institution or at a centralized laboratory
serving many institutions in the same region. In addition,
translating high-throughput sequencing for biomarkerdriven
clinical trials for personalized oncology presents
unique logistical challenges, including the development of
an informed-consent process that addresses how to handle
incidental findings, the selection of the results that should
be disclosed to patients, and the implementation of efficient
and integrative computational pipelines for data analysis. 22
Should Tumor Biopsies Be Mandatory?
Tissue that is collected as part of a research protocol (at
baseline, during treatment, or at the time of tumor progression)
has great potential to advance scientific knowledge
by determining how well a drug is affecting the target tissue,