EDITORIAL
Sequence, Treat, Repeat: Addressing Resistance in
EGFR-Mutant NSCLC
Samuel J. Klempner, MD,a,b,* Aaron N. Hata, MD, PhDa,b
Lather, rinse, repeat are the instructions on most
shampoo bottles, and if followed literally, they would
lead to an iterative cycle until no shampoo remains.
The management of oncogene-driven NSCLC, especially
EGFR-, ALK receptor tyrosine kinase gene (ALK)-, and
ROS1-positive tumors, now parallels this old idiom.
The spectrum of resistance mutations in EGFR-mutant
NSCLC is influenced by the therapeutic agent chosen
and the line of therapy in which the patient receives it.
With an increase in approved EGFR-directed agents,
there are now numerous treatment sequences that can
be considered. Key factors in later lines of therapy are
the mechanism(s) by which the tumor escaped the
prior EGFR inhibitor and the resistance mutation
coverage of alternate agents. In patients progressing
while taking first- or second-generation EGFR
tyrosine kinase inhibitors (TKIs), the dominant resis-
tance mutation is EGFR T790M, which occurs in
50% to 60% of patients. When these patients are
subsequently treated with the third-generation
inhibitor osimertinib, a number of additional muta-
tions conferring resistance to osimertinib can arise,
typically in exon 20. In some cases, these mutations
occur in cis with EGFR T790M, whereas in others, they
occur independently with “loss” of T790M. In the brief
report in the current issue of the Journal of Thoracic
Oncology, Castellano et al. expand the growing list
of osimertinib acquired resistance mutations and
preclinically characterize a novel EGFR M766Q exon
20 mutation.1
Briefly, Castellano et al.1 identify a patient with
recurrent EGFR L858R–mutant NSCLC who was treated
with frontline erlotinib for nearly 5 years. At progression,
an EGFR T790M mutation was found and the patient was
briefly exposed to rociletinib followed by transition to
osimertinib at a dose reduction of 40 mg. After 11
months, she experienced development of radiographic
progression and a cell-free DNA assay identified the
original EGFR L858R mutation, no EGFR T790M mutation,
and two additional EGFR alterations (S306L and M766Q).
The patient did not receive any further therapy and ulti-
mately died of progressive disease.
To explore the role of EGFR M766Q, Castellano et al.1
generated Ba/F3 cells with EGFR L858R and M766Q in
cis and confirmed in vitro resistance to osimertinib (a
concentration that inhibits 50% of 50.6 nM versus 4.2
nM for EGFR L858R). The compound mutant was not
sensitive to “rechallenge” with erlotinib or afatinib but
remained sensitive to the smaller EGFR TKIs neratinib
and poziotinib. This posited explanation as to why the
irreversible agent poziotinib is effective but the irre-
versible agent osimertinib is not highlights the important
structure and/or size–function relationship that is also
seen in newer ALK inhibitors such as repotrectinib.2
Although the clinical and preclinical stories are com-
plementary and we believe that the resistance mecha-
nism is real, the brief report by Castellano et al.1 exposes
issues with TKI resistance studies, the main one being
the chronologic timing of sample collection affecting the
ability to fully evaluate the genomic evolution time line.3
As is all too common, we do not have complete charac-
terization from the original pretreatment lung resection
or the tumor biopsy specimen obtained before admin-
istration of osimertinib. Ideally, tissue-based compre-
hensive genomic profiling from the tumor before
osimertinib and contemporary cell-free DNA assay
would aid in understanding whether the EGFR M766Q
mutation existed before osimertinib treatment or
emerged under pressure of osimertinib. On the basis of
the nearly 5-year response to erlotinib and the preclin-
*Corresponding author.
a
Massachusetts General Hospital Cancer Center, Boston, Massachusetts,
and bHarvard Medical School, Boston, Massachusetts.
Disclosure: Dr. Klempner has received consulting advisory fees from Eli
Lilly, Astellas, Foundation Medicine, and Bristol-Myers Squibb and
holds stock/equity in Turning Point Therapeutics. Dr. Hata has
received commercial research funding from Pfizer, Amgen, Relay
Therapeutics, Roche/Genentech, and Novartis.
Address for correspondence: Samuel J. Klempner, MD, Massachusetts
General Hospital Cancer Center, Harvard Medical School, 55 Fruit St.,
Yawkey 7-E, Boston, MA 02114. E-mail: sklempner@partners.org
ª 2019 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
ISSN: 1556-0864
https://doi.org/10.1016/j.jtho.2019.07.014
Journal of Thoracic Oncology Vol. 14 No. 11: 1875-1877
1876 Klempner and Hata
ical erlotinib insensitivity of the EGFR M766Q mutation,
it is possible that both the T790M and M766Q clones
evolved de novo from erlotinib-tolerant EGFR L858R
cells, a mechanism that was previously modeled.4
Admittedly, the clinical management may not have
been affected if the M766Q mutation was known to be
present, even at low frequency, at the onset of osi-
mertinib treatment, and whether “fast-fail” or early
switch approaches improve outcomes is not well known.
At the time of this publication there have been
several series and cases describing osimertinib resis-
tance mechanisms, but the EGFR M766Q exon 20 mu-
tation has not been observed.5-10 Why would this tumor
“choose” the M766Q mutation versus one of the more
common mechanisms? Perhaps this rare variant is just
that—a rare variant. There are computational data to
suggest that profiling of 600 to 800 samples (osi-
mertinib-resistant samples in this case) is needed
to adequately capture rare variants, and well-
characterized osimertinib resistance data sets of this
size do not exist. We also note that this patient received
a reduced dose of osimertinib at 40 mg, and whether
this would influence the resistance spectrum is not well
known. Similarly, the influence of the rociletinib cannot
be ruled out, as there was not an intervening sample. It
is interesting to note that the patient experienced
radiographic progression in August 2017 but continued
taking osimertinib until January 2019, at which time
she died of progressive disease. Details of any dose
interruption or adjustment during this time period are
not presented, making it difficult to differentiate be-
tween continued partial activity of osimertinib and
indolent disease.
Tumor cells often incur a fitness cost for acquiring
therapeutic resistance, and adaptive dosing strategies
can aid in preserving the sensitive clones and delaying
dominance of the most resistant cells, although whether
the dose reduction in the presented case would factor in
is unknown.11
Although lacking some scientifically interesting data
points, the article by Castellano et al.1 reflects real-world
NSCLC management and raises the question of how to
incorporate our accumulating knowledge of osimertinib
resistance mechanisms into clinical practice. Although
we await the development of fourth-generation EGFR
inhibitors, this study adds to previous preclinical data
suggesting that some osimertinib resistance mutations
may be sensitive to earlier-generation TKIs.7,12 However,
the heterogeneity of the observed osimertinib resistance
mutations, compounded by the presence or absence of
co-occurring T790M mutation and influenced by the
original activating mutation (L858R versus exon 19
deletion), paints a complicated picture. The recent report
that adenosine triphosphate–competitive irreversible
Journal of Thoracic Oncology Vol. 14 No. 11
EGFR inhibitors (osimertinib) combined with the novel
EGFR L858R allosteric inhibitor (JBJ-04-125-02) that
binds adjacent to the adenosine triphosphate binding
pocket can delay or overcome osimertinib resistance in
preclinical models adds perhaps another emerging op-
tion, though exon 20 mutations other than C797S were
not studied.13 Modeling from the evolutionary dynamics
of mass extinctions (e.g., extinction of the dinosaurs) has
hinted that perhaps sequencing with single-agent or
combination strategies may be the preferred method for
long-term control in a heterogeneous tumor popula-
tion.14 Ultimately, prospective trials of agents such as
poziotinib (which is currently being investigated for
EGFR exon 20 insertion mutations) are needed to inform
clinical guidelines. However, we would like to express
support for the Journal of Thoracic Oncology and authors
in publishing single-patient cases, particularly those
describing novel resistance alterations. Although not
held to the same level of evidence as large prospective
trials, articles disseminating the description of rare
resistance variants are important to the thoracic
oncology community. N-of-1 data can provide pilot
clinical support for future studies in rare EGFR muta-
tions and support the mission to learn from every
patient.
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