Application of Translational Science to Clinical Development - Genomic Biomarkers for Pharmaceutical Development - page 6

to assess ALK fusion genes and was able to quickly translate published results into clinical
development.
The foregoing discussion has focused on cancer, but similar prospective approaches
have been applied to inflammatory diseases as well. As Arron and Harris describe in their
chapter on asthma (Chapter 4), gene expression analysis of lung epithelial tissue from treat-
ment-naïve asthma patients revealed that a subset of patients had significantly elevated
expression of genes that were regulated by the cytokine IL13. After substantial follow up,
a clinical trial demonstrated that this subset of patients, which could be identified with a
serum biomarker, derived significant benefit from a novel anti-IL13 therapeutic. This initial
observation needs to be confirmed in ongoing Phase III trials, but demonstrates the power
of this translational approach. An analogous translational approach to identify a subset of
patients with systemic lupus erythematosus is described in the chapter on autoimmune dis-
eases (Chapter 3).
1.2.1.1 Retrospective Analysis to Identify Responders
In contrast to the prospective approaches described above to identify patients who may
derive benefit from a therapeutic, we describe below successful examples to identify predic-
tive markers by comparing responders and non-responders, i.e., from retrospective analysis
of clinical trials.
1.2.1.2 Large Molecule Inhibitors of Epidermal Growth Factor Receptor (EGFR)
The monoclonal antibodies cetuximab and panitumumab which are targeted against the
EGFR have been approved for the treatment of metastatic colorectal cancer. Initial analysis
of a small number of responders and non-responders for mutations in genes in the EGFR
signaling pathway - KRAS, BRAF, PI3KCA - revealed that KRAS mutations were readily
detected in non-responders but not in responders [11] . Of the 11 patients who responded
to cetuximab, none was mutant for KRAS; in contrast 13 of 19 non-responders were KRAS
mutants. These significant results were confirmed in subsequent large trials of cetuximab
[12] and panitumumab [13] . Although the FDA guidance calls for prospective stratification
of clinical trials to provide an adequate test of a predictive marker (see Chapter 7), in this
case, KRAS mutation status as a predictor of response was approved as a companion diag-
nostic for cetuximab and panitumumab because of overwhelming evidence from multiple
retrospective analyses. Further details of KRAS and response to EGFR targeted therapies
can be found in Chapter 2.
1.2.1.3 Small Molecule Inhibitors of EGFR: Case of Gefitinib
The small molecule inhibitors of EGFR, gefitinib (IRESSA™, AstraZeneca) and erlotinib
(Tarceva®, Roche) were initially approved in all-comers based on standard registrational tri-
als [14,15] . It was several years post-approval that it was discovered that these inhibitors pro-
vide significant benefit to NSCLC patients carrying a particular tumor biomarker, a mutation
within the EGFR gene [16-18] . Encouraging anti-tumor activity was observed in NSCLC in
a Phase I trial [19] . In two subsequent Phase II trials (IDEAL 1 and IDEAL 2), promising and
well-tolerated drug activity was observed. In the same trials, EGFR protein expression levels
within the tumor were tested as a potential predictive biomarker for clinical response, but no
relationship was found between EGFR protein expression and response [20,21] .