Journal of Thoracic Oncology  •  Volume 7, Number 12, Supplement 5, December 2012
Targeting MEK for the Treatment of Non–Small-Cell
Lung Cancer
Jonathan W. Goldman, MD, and Edward B. Garon, MD
I nhibition of the RAS/RAF/mitogen-activated protein kinase
kinase (MEK)/extracellular signal-regulated kinase (ERK)
pathway has been the focus of drug development for many
years. The pathway is dysregulated in a significant percent-
age of solid tumors, including approximately 20% to 35% of
non–small-cell lung cancers (NSCLC).1 Nevertheless, suc-
cessful targeting of this pathway has been difficult to achieve.2
Inhibitors of RAS, the most commonly mutated gene in this
pathway, have not generated successful results in clinical tri-
als. Therefore, inhibition at other points along the pathway has
been evaluated.
MEK1 and MEK2 are threonine/tyrosine protein
kinases that are phosphorylated by activated RAF and in
turn, phosphorylate ERK1 and ERK2, leading to proliferation
and migration. Mutations in RAS or RAF lead to a sustained
oncogenic signal and predict response to MEK inhibition in
laboratory models.3,4 Three MEK inhibitors and an Akt inhibi-
tor were presented in this session at the 12th Annual Targeted
Therapies of the Treatment of Lung Cancer and will be
reviewed here.
SUMMARY OF PRESENTATIONS
Selumetinib (AZD6244 or ARRY-142886) is an oral,
uncompetitive, potent inhibitor of MEK 1/2 (IC50 14 nM for
MEK1). Selumetinib has high specificity for MEK1/2, with
little activity against a panel of more than 40 other kinases.
Although a gene-expression profile associated with response
to selumetinib among cell lines has been demonstrated,5 the
strongest association was arguably the association with RAS
mutations.4 When evaluating a large panel of human NSCLC
cell lines, a significant association was found between sensi-
tivity to the compound and RAS mutational status. Preclinical
combinations have been an active area of investigation and
studies have been reported with concomitant VEGF or mTOR
inhibition.
Clinical development of selumetinib began with a phase
I trial demonstrating tolerability and preliminary efficacy of
selumetinib at 100 mg twice daily.6 An acneiform rash was
the most frequently reported and dose-limiting toxicity. In a
UCLA Medical Center, Los Angeles, California.
Disclosure: Edward B. Garon received funding from 1K23CA149079-01A1.
The authors declare no conflicts of interest.
Address for correspondence: Jonathan W. Goldman, MD, David Geffen
School of Medicine, UCLA, 2020 Santa Monica Blvd., Suite 600, Santa
Monica, CA 90404. E-mail: JWGoldman@mednet.ucla.edu
Copyright © 2012 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/12/0712-0377
Copyright © 2012 by the International Association for the Study of Lung Cancer
Santa Monica Supplement
randomized, open-label, phase II trial of selumetinib versus
pemetrexed in pretreated NSCLC, selumetinib showed no
advantage in an unselected population.7 On the basis of the
preclinical data discussed above, further study specifically in
RAS or RAF mutated tumors was suggested.
A randomized trial of selumetinib with docetaxel ver-
sus docetaxel alone in patients with RAS-mutated NSCLC has
completed accrual. At the time of this meeting, data regarding
this trial had not been formally presented, and the only data
with respect to the outcome of the trial came from a press
release. The press release described that the study was pow-
ered for a benefit in overall survival, and although survival
was numerically superior, the result did not reach statistical
significance. However, a statistically significant improvement
in response rate and progression-free survival with the com-
bination of docetaxel and selumetinib was seen in this small
phase II trial, generating some enthusiasm.
Several selumetinib trials are currently enrolling
patients, including a phase II study (NCT01229150) in previ-
ously treated NSCLC stratified by KRAS status; mutated KRAS
patients are randomized to receive selumetinib and erlotinib or
selumetinib alone, and wild-type KRAS patients are random-
ized to receive selumetinib and erlotinib or erlotinib alone.
In addition, the drug is being evaluated with thoracic radia-
tion in one trial (NCT01146756) and in two multiarm trials
(NCT01306045 and NCT01248247) that assign treatment by
molecular tumor characteristics. Other combinations in vari-
ous tumor types are also under study.
Trametinib (GSK 1120212 or JTP-74057) is a revers-
ible, allosteric MEK1/MEK2 inhibitor with an IC50 of 0.7 nM
for MEK1, and a high specificity as demonstrated by limited
activity against a panel of 180 other kinases.8 In vitro and in
vivo models reveal significant activity against tumors harbor-
ing mutant RAF or RAS. A phase I trial using trametinib dem-
onstrated acneiform rash, diarrhea, and rare left ventricular
cardiac dysfunction as the primary toxicities.9 A reversible
serous retinopathy was observed at higher doses and seemed
to be a potential class effect of MEK inhibitors. The recom-
mended phase II dose was 2 mg daily. The half-life was 4.5
days and sustained target inhibition was seen in pharmacody-
namic studies. Preliminary evidence of activity was demon-
strated in melanoma and pancreatic cancer.
Combination treatment with trametinib is under study
with agents including gemcitabine, everolimus, pazopanib,
the BRAF inhibitor GSK 2118436, the Akt inhibitor GSK
2141795, and the PI3K inhibitors GSK 2126458 and BKM120.
A multiarm phase I/Ib trial (NCT01192165) is assessing many
treatment combinations—docetaxel, erlotinib, pemetrexed,
carboplatin, cisplatin, and nab-paclitaxel—specifically with a
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Santa Monica Supplement Journal of Thoracic Oncology  •  Volume 7, Number 12, Supplement 5, December 2012
goal of identifying appropriate regimens for lung and pancre-
atic cancer treatment. An open-label, randomized phase II trial
(NCT01362296) in second-line NSCLC that harbors a muta-
tion in KRAS, NRAS, BRAF, or MEK1 is currently recruiting
patients.
PD-0325901 is a derivative of the first-generation MEK
inhibitor CI-1040. A maximum tolerated dose of 15 mg twice
daily was identified in a phase I trial, but late adverse events
included retinal vein occlusion and neurotoxicity.10 The same
schedule in a single-arm phase II trial in previously treated
NSCLC demonstrated significant toxicities whereas an inter-
mittent dosing schedule revealed insufficient anticancer
activity to warrant future single-agent study in an unselected
population.11
MK-2206 is an oral pan-Akt inhibitor. The PI3K/Akt
pathway is frequently activated in cancer. In NSCLC and
small-cell lung cancer, activity of this pathway has been seen
with PIK3CA mutations and amplification, AKT mutations,
and loss of the PTEN tumor-suppressor as well as in tumors
that do not demonstrate these genetic alterations. MK-2206
binds Akt in its inactive configuration. Preclinical activity
has been seen in a panel of NSCLC lines, with the greatest
activity in a PIK3CA-mutated model.12 Synergy is seen with
docetaxel, carboplatin, gemcitabine, and erlotinib. Of note,
combination therapy with selumetinib demonstrated synergy
and is being evaluated clinically (NCT01021748).13 A phase
I trial of MK-2206 revealed good tolerance with common
adverse events of rash, nausea, fatigue, and hyperglycemia.
The maximum tolerated dose is 75 mg every other day and
weekly doses up to 300 mg are being evaluated.
In addition to concurrent treatment with selumetinib,
other MK-2206 combinations are being clinically evaluated.
MET (also known as HGF) up-regulation has been shown to
mediate resistance to EGFR inhibition, and preclinical studies
reported at the meeting reveal that this resistance to EGFR
inhibition is overcome with the addition of MK-2206. A phase
II trial (NCT01294306) of MK-2206 with erlotinib in patients
who benefited from and then progressed on erlotinib is cur-
rently accruing subjects. In relapsed small-cell lung cancer
patients, a trial of topotecan versus topotecan with MK-2206
is under development.
FUTURE DIRECTIONS
The RAS/RAF/MEK/Erk pathway underlies carcino-
genesis in multiple tumor types but has been a difficult target
for drug therapy. Successful MEK-directed treatment of lung
cancer potentially depends on two factors: identification of
biomarkers to predict sensitivity and the selection of optimally
S378 Copyright © 2012 by the International Association for the Study of Lung Cancer
beneficial drug combinations. At this time, RAS mutation may
be the most reliable predictor of a cancer cell’s dependence
on this pathway but other techniques have been evaluated to
refine selection further. Concurrent treatment with cytotoxic
agents has shown early promise in phase II trials. Dual target-
ing of MEK with inhibition of other kinases in the same path-
way (such as EGFR) or with inhibition of a parallel pathway
(such as the PI3K/Akt pathway) are also promising directions
for ongoing trials.
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