TKIs in NSCLC: The down of a new era?
Oncology Unit, 3rd Dept of Medicine, University of Athens, Sotiria General Hospital, Athens, Greece
|
Cite this article as: Charpidou A, Syrigos KN. TKIs in
NSCLC: The down of a new era? Transl Lung Cancer Res
2012;1(2):147-148. DOI: 10.3978/j.issn.2218-6751.2012.04.02
Perspective
|
|
Submitted Apr 15, 2012. Accepted for publication May 02, 2012.
DOI: 10.3978/j.issn.2218-6751.2012.04.02 |
|
The understanding of the molecular pathology of
carcinogenesis in non-small cell lung cancer (NSCLC) has
led to the development of targeted agents. One of the most
profoundly investigated pathways is that of the epidermal
growth factor (EGF) and its receptor (EGFR). In our days
we have two types of inhibitors of EGFR, one being the
extra-membrane and the other, the intra-cellular tyrosine
kinase domain (EGFR-TKIs). The initial studies with
EGFR-TKIs, gefitib and erlotinib, had demonstrated that
a small proportion of unselected patients with NSCLC
showed a great response to these agents. It took more than
5 years to understand the reason for this response. A large
and confusing body of small or retrospective molecular
studies were published in order to evaluate if the EGFR
expression by immunohistochemistry (IHC) or the EGFR
copy number by in situ hymbidiazation (FISH) can predict
response to the new agents before actually concluding
that the EGFR gene mutation status is the predominate
predictive marker (1). This delay could underscore the need
for quick and total shift in the design of the lung cancer
trials.
The results of a prospective molecular markers analysis
from the randomized SATURN trial were published by
Brugger et al. (2). In SATURN study, it was evaluated the
use of erlotinib as a switch maintenance strategy in the
advanced, NSCLC patients who have responded in the
first line platinum based treatment (3). This study met its
primary end point of significantly prolonged progression
free survival (PFS) with erlotinib versus placebo. The fact
that the collection of tumor samples was mandatory allowed
the prospective analyses of prognostic and predictive
biomarkers.
In Brugger et al. study, EGFR protein expression by
IHC, EGFR copy number by FISH and the presence
of KRAS and EGFR mutations were evaluated for their
prognostic or predictive value. The authors concluded
that, although the study was underpowered for prognostic
tests, KRAS MUT+ status emerged as a significant negative
prognostic factor for PFS (HR, 1.50; 95%CI, 1.06 to 2.12;
P=0.020) and, on the other hand, EGFR MUT+ status
was a significant positive prognostic marker for OS (HR,
0.33; 95%CI, 0.19 to 0.59; P<0.001). As for the predictive
contribution of the examined biomarkers to the PFS by
the use of erlotinib, the interaction between treatment and
EGFR IHC status, EGFR FISH status and KRAS mutation
status was not significant, suggesting that there was no
differential effect of erlotinib on PFS between positive and
negative groups (P=0.63, P=0.35, P=0.95 respectively). On
the other hand, the interaction of treatment and EGFR
mutation status was significant (P=<0.001) indicating
that this marker has a predictive value for PFS benefit of
erlotinib switch maintenance strategy. As for the predictive
contribution of biomarkers to the overall survival by the use
of erlotinib, although in the ITT population of SATURN
the erlotinib significantly reduced the risk of death (HR,
0.81; 95% CI, 0.70 to 0.95; P=0.0088), the current study
of Brugger et al. was underpowed for such analysis within
subgroups. The lack of translating the PFS benefit into OS
benefit in patients with EGFR MUT+ status in Brugger’s
trial, can be first attributed to the fact that median OS had
not been reached by the time of the analysis (only 8 events
among the 22 EGFR MUT+ patients in erlotinib arm),
secondly to the small number of EGFR MUT+ patients
(49 among 889) and finally to the fact that OS is affected
by cross over and subsequent therapies in placebo arm. Studies that strengthen the use of EGFR TKIs in front line
treatment of advanced NSCLC have also failed to show
improvement in OS, with the new agents in EGFR mutated
patients mostly due to cross over (4). Considering also the
fact that more and effective subsequent lines of therapy are
now available, the question that rises is if this is the time for
us to compromise with PFS as primary end point in lung
cancer trials.
This extensive prospective molecular markers analysis
contributes greatly in selecting patients who can be
benefited from erlotinib maintenance strategy (5). It is also
pointing out the need for mandatory tissue sample collection
and biomarker analysis in early phase non randomized trials,
in order to use them for patients’ selection in phase III
trials. From 889 available tissue samples, EGFR mutation
status was able to be detected in only 437 because for many
patients only small amounts of tissue were available. Based
on the unclear previous knowledge for the predictive value
of EGFR expression, EGFR copy number and KRAS
and EGFR mutation status, the authors prioritized the
biomarkers analysis as follows: EGFR IHC, EGFR FISH,
KRAS mutation status and finally EGFR mutation status.
Thus, the most important biomarker was examined in only
49% of the study population. In IPASS study, which gave
the green light to the other EGFR TKI gefitinib for 1st
line treatment in EGFR mutant patients with NSCLC, out
of the 1,217 patients eligible for randomization only 683
(52%) provided tissue samples and EGFR mutation status
could be evaluated in only 437 (35.9%). This made more
emerging the need for a change in trial design paradigm
in lung cancer. A lateral aim should be the development of
new methods that can assay new and old markers in easier
collected samples like blood, bronchial washing and pleura
fluid or in cytological specimens.
If we want to improve the lives of our patients we must
close once and for all the era of unselected population
studies and try to enlighten the era of individualizing
medicine by detecting and using molecular markers in order
to give the right drug to the right patient, at the right time
and the right dose.
|
|
Acknowledgements
Disclosure: The authors declare no conflict of interest.
|
|
References
|
