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on nucleic acid detection
[123,124]
. The majority of IVDs used for oncology indications are
for breast cancer (36%) and prostate cancer (31%), and oncology IVDs are the only ones cur-
rently approved to yield data supporting specific treatment selection
[123-125]
. Companion
diagnostics are likely to become increasingly important as researchers continue to dissect
particular patient subsets within various cancer indications that respond to specific therapies.
Additionally, it has become clear that a validated companion diagnostic provides tremen-
dous support and can often accelerate FDA approval of new therapeutics.
Successful recent examples of companion diagnostics utilized in oncology include those
that accompany the FDA approval of two relatively new therapies, crizotinib (Pfizer) and
vemurafenib (Roche) in advanced or metastatic NSCLC and metastatic melanoma, respec-
tively. Approvals for both drugs were dependent on simultaneous companion diagnostic test
approvals - the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) with crizo-
tinib
[55,56,61]
and the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems) with
vemurafenib
[66,67]
. Crizotinib received accelerated FDA approval based on Phase II data
due to the existence of a prospective genomic biomarker and parallel companion diagnostic
development. It is the first drug approval that occurred within four years of identifying its
role in disease. These new approvals join the growing list of other drug
/
diagnostic combina-
tions used in clinical practice, such as anti-EGFR antibodies
/
K-ras mutations, geitinib
/
EGFR
mutations, trastuzumab
/
HER2 levels and tamoxifen
/
ER expression. Approvals of crizotinib
and vemurafenib may represent a new paradigm for the next generation of targeted thera-
pies in oncology, in that large changes in patient outcomes are possible when molecularly
defined sub-populations are identified appropriately. Additionally, the development of both
drugs illustrates the benefit of incorporating hypothesis testing into early clinical trials when
possible because it permits the collection of appropriate samples to evaluate multiple bio-
marker strategies.
The concept of testing multiple biomarker strategies is beginning to be incorporated crea-
tively into clinical trial design to address the absolute need for predictive biomarkers to guide
treatment selection for patients with various diseases. One specific example where this con-
cept is particularly relevant is in NSCLC, where only two drugs that target signaling path-
ways have been approved by the FDA in unselected NSCLC patients: erlotinib (EFGR TKI)
and bevacizumab (mAb targeting vascular endothelial growth factor). In contrast, nine drugs
in 13 Phase III trials of unselected patients with NSCLC have failed recently
[126,127]
, due, in
part, to a lack of predictive markers. To address this, a novel Phase II Biomarker-integrated
Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial was designed,
in which NSCLC tumors are prospectively biopsied and assigned to the treatment with great-
est potential benefit using adaptive randomization (see
Fig. 2.5
for overall trial schema).
Agents were selected due to high scientific and clinical interest at the time (2005) and included
EGFR (erlotinib), KRAS
/
BRAF (sorafenib), retinoid-EGFR signaling (bexarotene and erlotinib),
and vascular endothelial growth factor receptor (vandetanib)
[126]
. Patients were enrolled in
the BATTLE study with equally random assignments for the first 97 patients and adaptive
randomization for the remaining 158. Biomarker analysis was done in real time, with a large
panel of mutation, gene copy number, and IHC analyses performed on each sample. Patients
were grouped into predefined biomarker signature groups, which were used to evaluate
treatment-biomarker interactions. After equal randomization of the initial 97 patients, the
eight week disease control rate (DCR) was evaluated and compared with the biomarker status
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