Biomedical Engineering Reference
In-Depth Information
line setting patients with advanced NSCLC; a pre-planned subgroup
analysis showed a significant benefit only in patients of Asian origin
and non-smokers, the clinical profile identified in previous work.
29
Based on this preliminary work, the IPASS study was initiated to
see whether chemotherapy or gefitinib was the superior treatment
for this select population. As it was demonstrated that activating
EGFR
mutations occurred at a higher frequency among patients of
Asian heritage with adenocarcinoma histology with a never/light
smoking history, this clinical profile was required for participation in
the trial. The trial compared gefitinib with platinum chemotherapy
(carboplatin/paclitaxel) in the first-line setting with the objective
of demonstrating that gefitinib was non-inferior to platinum-
based doublet chemotherapy. In addition, the trial evaluated
EGFR
mutation status for the participants and was successful in
doing so in approximately a third of the trial participants. IPASS
demonstrated that the
mutation status of a patient's tumor
was a strong predictor of benefit from gefitinib. Pre-planned sub-
group analyses showed that PFS was significantly longer for gefitinib
in patients with
EGFR
mutation positive tumors. In contrast, doublet
chemotherapy was superior in patients with
EGFR
EGFR
mutation negative
20
In the trial's final analysis, IPASS failed to demonstrate an
overall survival advantage between the two arms in patients with
activating
tumors.
mutations, although this is believed to be due to the
use of subsequent lines of therapy, which would have included EGFR
TKIs in the group initially receiving cytotoxic chemotherapy.
EGFR
30
The
OPTIMAL trial randomized Asian patients with advanced NSLCLC
who were known to have activating
mutations to either
erlotinib or carboplatin/gemcitabine in the first-line setting. Patients
receiving erlotinib had a significantly improved PFS (13.1 months
vs. 4.6 months; HR = 0.16,
EGFR
31
p
= <0.0001).
This trial has confirmed
that activating
mutations are predictive for benefit from EGFR
TKIs in the first-line setting. The molecular profiling of patients with
advanced NSCLC for
EGFR
mutations to enable selection of first-line
therapy with either chemotherapy (
EGFR
EGFR
mutation negative) or
gefitinib (
mutation positive) has now become standard of care
in many jurisdictions.
The role of
EGFR
mutation status after first-line therapy is less
clear. In the second-line setting, the INTEREST study demonstrated
EGFR
