Treating acquired resistance to EGFR-tyrosine kinase inhibitors:
Still a work in progress
Assistant Professor, Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave., R-35, Cleveland, OH 44195, USA
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Cite this article as: Pennell NA. Treating acquired resistance
to EGFR-tyrosine kinase inhibitors: Still a work in progress.
Transl Lung Cancer Res 2012;1(2):149-151. DOI: 10.3978/
j.issn.2218-6751.2012.05.01
Perspective
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Abstract
While most patients with metastatic non-small cell lung cancer (NSCLC) containing sensitizing
mutations in the epidermal growth factor receptor (EGFR) gene will achieve an objective response to EGFR
tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, patients inevitably develop resistance to
these agents. One of the strategies being tested to overcome acquired resistance to EGFR TKIs is the use of
irreversible EGFR inhibitors such as afatinib. In the randomized phase 2b/3 LUX-Lung 1 trial in advanced
NSCLC patients who progressed after at least 12 weeks of benefit from EGFR TKIs, afatinib failed to
improve overall survival compared to placebo. Although the liberal entry criteria likely allowed the inclusion
of some patients without true acquired resistance, the failure of this study calls into question the viability of
irreversible EGFR inhibitors in this patient population.
Key words
EGFR; acquired resistance; tyrosine kinase inhibitors
Submitted Apr 25, 2012. Accepted for publication May 28, 2012.
DOI: 10.3978/j.issn.2218-6751.2012.05.01
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The last decade has seen major progress in the
understanding of non-small cell lung cancer (NSCLC), with
the growing recognition that NSCLC is not a single disease
but rather a collection of many different subgroups with
identifiable and potentially targetable genetic lesions. The
first targetable driver mutations were sensitizing mutations
in the tyrosine kinase domain of the epidermal growth factor
receptor (EGFR) gene (1,2), now known to be present in
about 10% of NSCLC in Caucasian patients and conferring
a high degree of responsiveness to the oral tyrosine kinase
inhibitors (TKIs) erlotinib and gefitinib (3). A number of
prospective clinical trials have now established that EGFR
TKIs induce objective responses in about 70% of patients
whose tumors harbor mutations, with a significantly
increased median progression free survival (PFS) compared
to cytotoxic chemotherapy (4). Nonetheless, most of these
patients will eventually progress despite TKI therapy, a
phenomenon termed acquired resistance (AR).
Acquired resistance to EGFR TKIs can be achieved
through a number of different mechanisms. The most
common mechanism (50%) is the development of a
secondary T790M mutation in exon 20 of the EGFR gene (5).
Other less common mechanisms include increased signaling
through parallel receptor tyrosine kinases such as the
MET (6) and transformation into a small cell phenotype (7).
Presumably this heterogeneity of mechanisms would make a
single approach unlikely to be successful at overcoming AR,
but nonetheless a number of strategies have been proposed
and are being tested in randomized trials. One such strategy
is the use of second-generation EGFR inhibitors such as XL
647 (Exelixis Inc., San Francisco, CA) and irreversible pan-
HER inhibitors such as neratinib (HKI-272; Wyeth/Pfizer,
New London, CT), PF00299804 (Pfizer), and afatinib
(BIBW 2,992; Boehringer Ingelheim Pharma GmbH,
Ingelheim, Germany). Although these agents have shown
some ability to inhibit T790M mutant NSCLC in vitro (8,9),
evidence of clinical activity of these agents in patients with
AR is lacking (10,11).
The LUX-Lung 1 trial was a randomized, double-blind,
international phase 2b/3 trial of single agent afatinib versus placebo in 585 patients with advanced lung adenocarcinoma
who had not progressed after at least 12 weeks of treatment
with either erlotinib or gefitinib. This study population
was intended to represent a clinically defined group with
AR to EGFR TKIs, and the primary endpoint was overall
survival. Although the response rate (7% versus 0.5%)
and PFS (3.3 vs. 1.1 months; P<0.0001) were improved
in the afatinib group compared to placebo, there was no
difference in median overall survival (OS) between the
arms (10.8 months for afatinib vs. 12 months for placebo;
P=0.74) (12). Of note, tissue was not required for entry in
the study, and as a result only 141 of the 585 pts (24%) had
tissue available for analysis. Of those, 68% were found to
have EGFR mutations, evenly split between the treatment
and control arms. Only 8 patients (4 in the afatinib arm)
had identifiable T790M mutations, and no other known
mechanisms of AR were tested.
The intent of the study investigators was to test the
efficacy of afatinib in patients with EGFR mutant lung
cancer who had developed AR, but the way they went about
it was problematic. For one thing, they did not require
testing for EGFR mutations prior to enrollment, which
diluted the study sample with patients with wild-type
EGFR who would perhaps be less likely to benefit from an
irreversible EGFR TKI. Second, efforts have been made
to rigorously define clinical acquired resistance to EGFR
TKIs, to allow maximum enrichment of patients in trials
such as the LUX-Lung study. The most widely accepted
definition is the Jackman definition: prior treatment
with a single-agent EGFR TKI and either or both of the
following: a tumor that harbors an EGFR mutation or
objective clinical benefit from treatment with an EGFR
TKI (PR/CR or stable disease for ≥6 months); systemic
progression of disease while on continuous treatment
with the TKI within the last 30 days; and no intervening
systemic therapy between cessation of the TKI and
initiation of new therapy (13). By this strict definition
only 34% of patients in the afatinib arm (vs. 42% in the
placebo arm) would have had true AR, and the magnitude
of benefit was indeed numerically higher in this group
with a PFS of 4.5 vs. 1 month although not statistically
significant.
So are we able to draw any conclusions at all from
this trial? The liberal definition of AR, the lack of tissue
testing to determine mutational status and mechanisms of
resistance, and the high degree of subsequent treatment
(68% and 79% in the afatinib and placebo arms) combined
to muddy the waters. However, if we extrapolate from
the minority of patients with available tissue, then we can
assume that most patients had tumors with EGFR mutations
and that most had AR of one mechanism or another. If
that is the case then this study, along with the prior failure
of neratinib to show benefit in this population (11), casts
doubt on the strategy of using irreversible EGFR TKIs as
monotherapy in patients with AR.
Interestingly, there is preliminary evidence that afatinib
has activity in AR, including T790M, when combined with
the anti-EGFR antibody cetuximab (Imclone, owned by
Eli Lilly and Company, New York, NY and Bristol-Myers
Squibb Company, Princeton, NJ) (14). We know that
cetuximab combined with erlotinib has no activity in the AR
population (15/a>), raising the intriguing idea that irreversible
EGFR inhibitors may have promise in AR when combined
with other agents. More mature, peer reviewed results from
this trial are anxiously awaited. The indisputable lessons
from LUX-Lung 1, however, are that future trials in the
EGFR TKI acquired resistance population must be rigorous
in defining their target population, and that every patient
enrolled must have tissue available for molecular testing so
that clear conclusions can be made from the results.
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Acknowledgements
Disclosure: This manuscript is my original work and not
submitted for publication elsewhere. I have served as a
consultant for Oncogenex and for Teva Pharmaceuticals in
the past year. I have served as a consultant for Boehringer
Ingelheim which is relevant to this manuscript, but not in
the past 2 years.
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References
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