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Dr Jarushka Naidoo is
an assistant professor
of oncology at the
Sidney Kimmel Cancer
Center at Johns
Hopkins, in Baltimore,
Maryland. Her research
interests include
immunotherapy, novel
immunotherapeutic
combinations, toxicities
of immunotherapy,
lung cancer, and
central nervous system
metastatic disease.
L
ung adenocarcinoma is the most common sub-
type of non-small cell lung cancer (NSCLC),
and it accounts for over one million new cases
each year worldwide.
1
Oncogenic driver mutations
can be found in up to 50% of advanced lung adeno-
carcinomas,
2,3
15% of which will harbour mutations
in the epidermal growth factor receptor (EGFR).
Since EGFR-mutant NSCLCs were first identified
in 2004, other driver oncogenic mutations have
been discovered in lung adenocarcinomas, such as
BRAF, KRAS, ERBB2, PTEN, AKT, and PIK3CA.
Targeted agents directed against these alterations
are currently under study in clinical trials. EGFR
exon 19 deletions and exon 21 L858R point muta-
tions are the main mutations that confer sensitivity
to EGFR tyrosine kinase inhibitors (TKIs).
4–6
Phase
III randomised studies have demonstrated that
patients whose lung cancers harbour sensitising
EGFR mutations benefit from first-line therapy
with EGFR TKIs rather than standard chemo-
therapy in terms of improved tolerability, quality
of life, progression-free survival, and overall survival
in selected studies.
7–10
Due to these impressive
results, there are currently three Food and Drug
Administration-approved EGFR TKIs licensed for
the treatment of EGFR-mutant NSCLC: erlotinib,
gefitinib, and afatinib.
Favourable objective response rates of up to 80%
have been described with some targeted therapies;
however, cancer cells that harbour oncogenic drier
mutations nearly universally “acquire resistance”
under the selective pressure of these agents. This
process is almost inevitable, and the emergence
of acquired resistance to targeted therapy is seen
after approximately 1 year of therapy on a targeted
agent.
6
Re-biopsy of new or growing lesions at the
time of acquired resistance has become a standard
approach aimed at revealing the mechanisms of
acquired resistance, which may in turn be thera-
peutically targeted. In the case of EGFR-mutant
NSCLC, mechanisms of acquired resistance to
EGFR TKIs include: the development of a second
gate-keeper mutation of the EGFR gene (T790M
mutation), ERBB2 gene amplification, PIK3CA
mutations, MET amplification, BRAFmuta-
tions, AXL activation, MAPK gene amplification,
and transformation to small-cell lung cancer
histology.
11–13
From here, two third-generation EGFR TKIs
mutant-specific for T790M were investigated in
patients with EGFR-mutant NSCLC harbouring
an EGFR T790M resistance mutation-rociletinib
(previously CO-1686) and osimertinib (previously
AZD9291). These agents were both studied in
clinical trials published in
The New England Jour-
nal of Medicine
in early in 2015, and demonstrated
promising overall response rates of up to 59% to
61% in patients with centrally confirmed T790M
mutations.
14,15
Further, osimertinib was FDA-ap-
proved for the treatment of patients with metastatic
EGFR T790Mmutation-positive NSCLC who had
progressed on prior systemic therapy including an
EGFR TKI, based on the results of two clinical
studies AURA andAURA2.
16,17
In the AURA study,
201 patients were treated with osimertinib and
demonstrated an overall response rate of 61%.16
In AURA2, 210 patients treated with this agent
demonstrated an overall response rate of 71%.
17
The duration of responses ranged from 1.1 to 5.6
months, with a median follow-up of 4.2 months
and 4 months, respectively.
Osimertinib is administered as a once-daily
pill, at a dose of 80 mg. Most commonly reported
adverse events (AEs) were mild in severity, and
consisted of diarrhoea, rash, dry skin, nail toxicity,
ocular toxicity, nausea, poor appetite, constipa-
tion, prolonged QTc, and neutropenia. The lat-
ter two AEs also led to dose interruptions. The
most common serious AEs included pulmonary
embolism and pneumonia, with treatment-related
pneumonitis and cerebrovascular accident leading
to treatment discontinuation.
Osimertinib is currently being compared with
standard platinum-doublet chemotherapy in a
phase III clinical trial in patients with T790M-
positive advanced NSCLC, in patients who have
received prior EGFR TKI therapy and progressed
(NCT02151981).
Targeted therapy for acquired resistance in lung
cancer is a truly practice-changing advancement
in the treatment of NSCLC that came to fruition
throughout 2015. The approval of osimertinib rein-
forces the importance for oncologists to understand
the concept of acquired resistance, need for re-
biopsy at the time of suspected acquired resistance,
and the potential choice of an appropriate further
targeted agent in the setting of identifying a resist-
ance mutation that is therapeutically targetable.
This article was first published on
PracticeUpdate.
com,
a site tailored to deliver the latest expert con-
tent based on the clinician’s area of practice, and is
optimised for viewing on any device. Access to Prac-
ticeUpdate, an Elsevier website, is free.
2015 practice changers in oncology:
FDA-approved EGFR TKIs for acquired
resistance to targeted therapy in lung cancer
BY DR JARUSHKA NAIDOO
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Abstract 1406.
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