2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

DRUG DEVELOPMENT AND PERSONALIZED ONCOLOGY
NSCLC and HER2-amplified breast tumors. Mesenchymal
epithelial transition (MET) amplification, mutations, or receptor
overexpression have been linked to responses with
MET inhibitors in different tumor types, such as gastric
adenocarcinomas, papillary renal cell carcinoma, and
NSCLC. The same approach is being implemented in phase
I trials evaluating fibroblast growth factor receptor (FGFR)
inhibitors in FGFR amplified tumors, such as breast cancer
and squamous NSCLC.
Challenges
Table 1. Response Rate of Successful Targeted Therapies in Selected Populations Evaluated in Early Clinical Trials
Many investigators have raised concerns over the use of
predictive biomarkers in early clinical trials, including inac-
KEY POINTS
Marker/Population Agent Mechanism of Action Response Reference
HER2-overexpressed/amplified breast cancer Trastuzumab Anti-HER2 antibody 12% 8
Trastuzumab-DM1 Anti-HER2 antibody � drug conjugate 44% 13
CD117-overexpressed GIST Imatinib c-KIT, PDGFR inhibitor 54% 14
BRCA1/2 mutant breast, ovarian and prostate cancer Olaparib PARP inhibitor 47% 9
BRAF V600E-mutant melanoma Vemurafenib BRAF inhibitor 75% 10
Dabrafenib* BRAF inhibitor 60% 15
ALK-rearranged NSCLC Crizotinib ALK, MET inhibitor 57% 11
Basal cell carcinomas (majority have inactivating
mutations in PTCH1 or activation of SMO)
Vismodegib SMO inhibitor (Hh pathway) 58% 12
Medullary thyroid cancer (known to have RET mutations,
MET expression and VEGF activation)
Cabozantinib MET, VEGFR2, RET inhibitor 29% 16
* GSK2118436.
Abbreviations: GIST, gastrointestinal stromal tumor; PDGFR, platelet-derived growth factor receptor; PARP, poly(ADP-ribose) polymerase; ALK, anaplastic lymphoma
kinase; NSCLC, non–small cell lung cancer; MET, mesenchymal epithelial transition; SMO, smoothened; Hh, hedgehog; VEGFR, vascular endothelial growth factor
receptor.
● The “one-size-fits-all” approach for drug development
of molecularly targeted agents in solid tumors has
shown disappointing results.
● With the switch from histology-driven to molecularly
driven therapy, phase I trials in clinical oncology are
providing an arena for clinical trial testing.
● Genomics-driven early clinical trial enrollment has
many possible advantages over an unselected
population-based approach, including clinical qualification
of predictive biomarkers, accelerated patient
benefit, and a positive impact on the drug development
process.
● Some concerns over the use of biomarkers in early
clinical trials have been raised, including the use of
assays that are not validated or certified, incorrect
patient selection, increased cost, logistical issues related
to the prescreening strategies, and ethical issues
regarding mandatory tumor biopsies.
● For the accelerated approach of drug development of
molecularly targeted agents to be possible, a cooperative
environment is necessary, with experienced
academic institutions, regulatory authorities, and
pharmaceutical and diagnostic companies working
together to promote data sharing, standardized procedures,
technology exchange, and avoidance of duplicative
efforts.
curate assays, high cost, and ethical issues regarding tumor
biopsies. Most importantly, the potential beneficial effects
of the MTA in a more broadly defined population could be
missed on the basis of incorrect patient selection. 6 Nevertheless,
unselected patient evaluation has a higher risk of
failure in late-stage trials because of the tumor’s molecular
heterogeneity, unless the prevalence of the predictive biomarker
is already known to be high in the disease overall. 5
It is clear that many technical, laboratory, and clinical
challenges still remain to be resolved before the widespread
implementation of molecular biomarker-based patient selection
in early clinical trials. At first, investigators need to be
aware of the possible reasons for failure of MTAs matched to
specific biomarkers of vulnerability in advanced disease.
The presence of the biomarker may not be representative of
the disease (tumor heterogeneity) or its biology (“driver” vs.
“passenger” genetic alteration). Analyzing the tumor sample
from disease diagnosis may not reflect the molecular alterations
that drive the metastatic disease as a result of further
molecular alterations (clonal evolution), selection pressure
from previous treatments, and tumor heterogeneity. 19
Driver mutations that promote growth and metastasis are
considered the primary targets for therapeutic intervention.
Nevertheless, ‘‘passenger’’ molecular dysregulations that
arise through the rapid growth and genetic instability of
tumor cells can confer resistance to specific therapies.
Secondly, the predictive test may not be accurate and the
subpopulation most likely to benefit from MTAs may not be
readily and reliably identified. Methodological problems,
including a threshold (cutoff point) for defining the status
of the potential biomarker, may still be missing. It is also
important to note that the strategy of matching a predictive
biomarker with MTAs will not always be applicable to all
novel therapies, for example, broad-spectrum inhibitors targeting
multiple signaling pathways and antiangiogenic
agents. In addition, some MTAs may have substantial activity
but no identifiable predictive marker, such as histone
deacetylase (HDAC) and proteasome inhibitors. Therefore,
a strong biologic hypothesis, solid preclinical data, and
tumor models that mimic the clinical disease accurately are
needed in order to assist in the drug development process. 5
Thirdly, rapid acquisition of resistance to single agents
is a problem. Complex interacting networks with adaptive
negative feedback and compensatory receptor tyrosinekinase
stimulation are imperative in cancer cells. In addition
to cross-pathways escape, there is always the possibility
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