2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Drug Development in the Era of Personalized
Oncology: From Population-Based Trials to
Enrichment and Prescreening Strategies
By Rodrigo Dienstmann, MD, Jordi Rodon, MD, and Josep Tabernero, MD
Overview: Recent advances in tumor biology and human
genetics along with the development of drugs for specific
targets hold promise for an era of personalized oncology
treatment. Routine use of modern technologies, such as
large-scale genome sequencing, will help to unravel the specific
biology of each tumor. Adding a rigorous genomic view
could determine key genetic events, critical dependencies,
and stratification of patients in early clinical trials. Integrating
biomarker development into the early testing of novel agents
might provide clinically relevant therapeutic opportunities for
DRUG DEVELOPMENT in oncology remains a slow,
costly, and inefficient process. Taking advantage of
new science in the design and execution of clinical investigation,
with a switch from histology-driven therapy to molecularly
driven clinical oncology, is one way of addressing
the high failure rate of developing an innovative anticancer
agent. 1 Targeted therapeutics is optimal when applied in the
appropriate molecular context: it indicates a drug that
interferes with the function of a molecule readily identified
in cancer cells but not healthy tissues. This target plays a
critical role in the abnormal growth and/or invasiveness of
the tumor. A relative specificity of the drug exists, leading to
improvement in the therapeutic index over standard cancer
chemotherapy, higher efficacy, and decreased unnecessary
toxicity. Accomplishments of modern technologies in genomics
and biomarker detection are providing information that
enables clinical researchers to investigate selective therapies
for individual patients with cancer. Hundreds of new
experimental drugs and biologic agents target the products
of aberrant genes that are mutated or abnormally expressed
in human cancers. 2 Many of these approaches are based on
concepts such as oncogene addiction, non-oncogene addiction,
and synthetic lethality, which target distinctive and
complementary capabilities that enable tumor growth and
metastatic dissemination. 3,4
Given this perspective, phase I trials are providing an
arena for early hypothesis testing. 5 Molecular biomarkerbased
patient selection in early clinical trials has many
possible advantages over an unselected population-based
approach and include: (a) clinically qualify potential predictive
biomarkers for molecularly targeted agents (MTAs)
as early as possible; (b) generate valuable information regarding
cancer biology; (c) accelerate patient benefit; and
(d) affect the drug development process by assisting in the
“go–versus-no-go” decisions and changing drug approval
registration strategies of promising agents. 6,7 In this manuscript,
we describe a new trend in early drug development
with enrichment and prescreening strategies for personalized
oncology.
Success Stories
The success of several targeted agents has shown that
personalized cancer treatments can have an enormous effect.
Development of trastuzumab in HER2-amplified breast
cancers, with conversion of a biomarker for negative prog-
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patients with advanced-stage cancer and also accelerate the
drug-approval process. After recent success stories of therapies
targeting driver molecular aberrations in genetically
defined tumor subtypes, innovative clinical trials based on a
strong biologic hypothesis are expected to bring further
excitement to the field. In this article, we describe a new trend
in biomarker-driven early drug development using enrichment
and prescreening strategies. Technical and logistical obstacles
that may hinder progress of this approach will be discussed,
along with ethical and economic concerns.
nosis into one that was predictive of benefit from the drug,
was a major advance in the field. 8 More recently, patients
with advanced gastric and gastroesophageal junction adenocarcinomas
overexpressing HER2 have also been shown to
achieve improved survival when trastuzumab is combined
with chemotherapy. Another example is the PARP inhibitor
olaparib, developed for patients with BRCA1/2-mutant cancers,
with antitumor activity observed in different malignancies,
including breast, ovarian, and prostate. 9 Further
excitement for this approach came with the recent regulatory
approvals of vemurafenib for advanced melanoma that
harbors BRAF V600E mutation and crizotinib for non–small
cell lung cancer (NSCLC) with EML4-anaplastic lymphoma
kinase (ALK) translocation. 10,11 Interestingly, responses
with selective BRAF inhibitors were seen in other tumor
types carrying BRAF V600E mutations, such as thyroid
cancer. The same is true for crizotinib in inflammatory
myofibroblastic tumor and anaplastic large-cell lymphomas
harboring ALK translocation. The hedgehog inhibitor vismodegib
has also been developed with enrichment for specific
target patient populations in early clinical trials. Clear signs
of activity were seen both in basal cell carcinomas and
medulloblastomas known to have activating mutations in
the pathway components Patched or Smoothened. 12 This
highlights that cancers should likely be treated with targeted
agents based on their specific molecular alterations
rather than organ of origin.
The impressive response rate in the selected population of
patients included in the particular trials listed in Table 1 8-16
is in contrast with the approximate 5% response observed
in early-phase trials conducted in unselected patient populations.
17,18 Based on preclinical data, potential enrichment
biomarkers already under investigation include PIK3CAactivating
mutations and PTEN loss of expression in early
trials with PI3K pathway inhibitors, with focus on breast
and gynecologic tumors. Clinical development of chaperone
(HSP90) inhibitors is now focused on ALK-rearranged
From the Molecular Therapeutics Research Unit, Vall d’Hebron University Hospital,
Barcelona, Spain.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Josep Tabernero, P. Vall d’Hebron 119-129, Barcelona, Spain
08035; email: jtabernero@vhebron.net.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10