Application of Translational Science to Clinical Development - Genomic Biomarkers for Pharmaceutical Development - page 7

In 2004, two independent investigators published retrospective analyses demonstrating that
patients with encouraging responses to gefitinib harbored activating mutations in the EGFR
gene [16,17] . AstraZeneca had already initiated two Phase III trials, ISEL and INTEREST, for
gefitinib in unselected NSCLC in 2003 and 2004, respectively. The ISEL study showed some
improvement in survival for NSCLC patients treated with gefitinib compared to placebo, but
this difference did not reach statistical significance in the overall population. A planned sub-
group analysis showed that patients who were female, Asian, non-smokers, or who had ade-
nocarcinomas had better responses [22,23] , and demonstrated a trend for increased EGFR
gene copy number to be predictive of survival benefit versus placebo [24] . In the INTEREST
study, gefitinib demonstrated non-inferiority relative to docetaxel in terms of overall survival
with a more favorable tolerability profile and better quality of life. However, there was no evi-
dence from the co-primary analysis to support the hypothesis that patients with high EGFR
gene copy number had superior overall survival on gefitinib compared with docetaxel. EGFR
mutation-positive patients had longer progression-free survival and higher objective response
rate and patients with high EGFR copy number had higher response rates with gefitinib versus
docetaxel, but no biomarkers were predictive of differential survival [21,22,25-27] .
As part of the testing of patients who had been shown to have a better response to gefi-
tinib versus standard of care chemotherapy, AstraZeneca then conducted a clinical study in
an Asian population of non-smokers or light ex-smokers with adenocarcinoma (the IPASS
study). IPASS was a randomized, large-scale, double-blind study which compared gefi-
tinib vs. carboplatin / paclitaxel as a first line treatment in advanced NSCLC. IPASS studied
1217 patients, and samples were analyzed for several biomarkers related to the mechanism
of action of the drug including EGFR copy number, EGFR expression and EGFR-activating
mutations. A pre-planned subgroup analyses showed that progression-free survival (PFS)
was significantly longer for gefitinib than chemotherapy in patients with EGFR mutation-
positive tumors, and significantly longer for chemotherapy than gefitinib in patients with
EGFR mutation negative tumors [ 28 ; Fig. 1.5 ]. Although the IPASS study was not designed
specifically to test this biomarker hypothesis, this was the first study that was powered to
do so; in total, 437 patients in IPASS provided evaluable samples and approximately 60% of
these patients carried the EGFR-activating mutations [29] .
Thus, in 2009, a targeted monotherapy was able to demonstrate significantly longer PFS
than doublet chemotherapy, and the European Commission granted marketing authorization
for the treatment with gefitinib of adults with locally advanced or metastatic NSCLC with
activating mutations of EGFR-TK, across all lines of therapy [30] . The role of EGFR mutations
as a predictive biomarker for response to EGFR TKI therapies has also been demonstrated in
other Phase III, randomized clinical trials [31-34] .
This validation of biomarkers predictive of response to gefitinib in NSCLC highlights the
clinical benefit of identifying patients who are most likely to respond. It also emphasizes the
importance of generating robust biomarker hypotheses early in the drug development pro-
cess. In the absence of strong preclinical and clinical evidence, scientists may explore multi-
ple hypotheses in late stage clinical trials, without the power to test any one biomarker in a
rigorous manner.
The development of advanced genome analysis tools, including high throughput next-
generation sequencing (NGS), which allows the sequencing of many individual molecules,
as opposed to the most prevalent ones in a heterogeneous mixture, has resulted in an