VOLUME 31 䡠 NUMBER 20 䡠 JULY 10 2013
JOURNAL OF CLINICAL ONCOLOGY
Dramatic Response Induced by
Vemurafenib in a BRAF V600E-Mutated
Lung Adenocarcinoma
Case Report
A 66-year-old man, a never-smoker, was referred to our oncolo-
gy department in April 2011 for stage IV non–small-cell lung cancer
(NSCLC). The patient had developed progressive left thoracic pain
followed by dyspnea and fatigue. A subsequent chest computed to-
mography (CT) scan showed massive left pleural effusion and pleural
thickening, mainly involving the mediastinal pleura. Histologic exam-
ination of pleural biopsies revealed poorly differentiated adenocarci-
noma that was positive for CK7 and thyroid transcription factor 1 and
negative for Wilms tumor 1 and calretinin. [18F]fluorodeoxyglucose
(FDG) positron emission tomography (PET)/CT scanning addition-
ally showed intense metabolic activity in the left pleura and celiac
lymph nodes. Brain magnetic resonance imaging was negative.
Polymerase chain reaction (PCR) and pyrosequencing did
not reveal any activating epidermal growth factor receptor
(EGFR) mutation. Reverse transcriptase PCR did not show any
specific ALK rearrangement. Given the patient’s never-smoker
status, additional molecular analyses were performed and re-
vealed a BRAF V600E mutation.
The patient underwent left pleurodesis and subsequently
completed four cycles of chemotherapy with cisplatin and pem-
etrexed, with a partial response. Eleven cycles of continuation
maintenance chemotherapy with pemetrexed, with a nearly com-
plete radiologic response, were delivered; however, PET/CT scan-
ning in May 2012 showed progression in a single left pleural nodule
and a left internal mammary lymph node, with high FDG uptake in
both lesions. A left extrapleural pneumonectomy was discussed
and performed in June 2012. Histologic examination showed a
solid adenocarcinoma measuring 3 cm in largest diameter, with
vascular invasion, positive resection margins in multiple pleural
locations, and 14 metastatic lymph nodes, including six nonre-
gional lymph nodes. The patient underwent hemithoracic
external-beam radiotherapy with a total dose of 66 Gy encompass-
ing all sites of incomplete tumor resection. After 10 sessions of
radiotherapy at a dose of 2 Gy per day, and exactly 2 months after
surgery, a follow-up CT scan revealed multiple new hepatic metas-
tases involving both hepatic lobes (Fig 1). Off-label vemurafenib
was started in September 2012 at a dose of 960 mg administered
twice per day.
Concurrent radiotherapy that was restricted to the location of
the positive resection margins was resumed, using a schedule of
seven daily doses of 3 Gy, for a local total dose of 51 Gy, to prevent
local symptomatic chest wall recurrence. Within 2 weeks, the pa-
tient developed a grade 3 rash covering the entire previously irra-
diated field that was consistent with a strong photosensitizing
Journal of Clinical Oncology, Vol 31, No 20 (July 10), 2013: pp e341-e344
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D I A G N O S I S I N O N C O L O G Y
Fig 1.
effect associated with a recall-like phenomenon; the rash persisted
for more than 4 weeks (Figs 2A and 2B).
Follow-up CT scanning in September 2012 showed excellent
partial response (Fig 3). PET/CT scanning in October 2012 after 6
weeks of treatment showed complete response, with no residual met-
abolic activity in the hepatic lesions (Fig 4). The patient is currently
asymptomatic except for mild fatigue. During the third week of treat-
ment, he developed common secondary skin lesions, such as kerato-
acanthoma, and treatment is ongoing under active surveillance.
Discussion
A growing number of distinct subtypes of NSCLC have been
shown to be driven by a specific genetic alteration. So-called
oncogene-addicted tumors are thus sensitive to inhibition of the
corresponding activated oncogenic pathway. This new paradigm
has substantially affected lung cancer treatment, shifting it from
classical chemotherapy that is tailored according to the expected
toxicity and histologic subtype to customized therapy for molecu-
larly defined subsets of NSCLC, according to the specific onco-
genic alteration.
Tumor genotype analysis has identified driver alterations in
approximately 50% to 80% of patients with NSCLC. Sequist et al1
described a genetic driver change in 51% of more than 500 cases of
NSCLC, mostly adenocarcinomas. The most common alterations
identified were KRAS or EGFR mutations and ALK rearrange-
ments, as well as several rare alterations, including BRAF muta-
tions, in 1% of cases. Similarly, the National Cancer Institute’s
Lung Cancer Mutation Consortium reported a prevalence of 54%
of genetically defined, oncogene-addicted lung adenocarcinomas
among 1,000 patients with NSCLC; BRAF mutations were found in
3% of the samples.2
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from 186.217.60.59
 Peters, Michielin, and Zimmermann

A B

Fig 2.

BRAF mutations are found in approximately 1% to 5% of
NSCLCs, almost exclusively in adenocarcinomas.3,4 BRAF func-
tions as a kinase that links RAS guanosine triphosphatase to down-
stream proteins of the mitogen-activated protein kinase (MAPK)
pathway by directly phosphorylating MEK. BRAF mutations have
been shown to activate this proliferative pathway through a consti-
tutive kinase activation and subsequently to activate MAPK2 and
MAPK3, culminating in transcription of genes that favor prolifer-
ation and survival. The transforming ability was demonstrated in
an inducible transgenic mouse model of BRAF V600E, in which
mutant BRAF was sufficient for the development and necessary for
the maintenance of lung adenocarcinoma.5
The mutations found in NSCLC are distinct from the mela-
noma setting: whereas BRAF-mutated melanoma harbors a V600E
amino acid substitution in more than 80% of cases, NSCLC
harbors non-V600E mutations in approximately 40% to 50%
of cases; these mutations are located in exons 11 and 15. Remark-
ably, in recent reports, BRAF mutations were reported mainly in
current or former smokers, and possibly predominantly in white
patients.3,4,6 Screening 1,046 patients with NSCLC, Marchetti et al3
described BRAF mutations in 4.9% of adenocarcinomas and 0.3%
of squamous NSCLCs. All non-V600E mutations (2%) that were
detected in adenocarcinomas were found in smokers, and V600E
mutations (2.8%) were substantially more frequent in women and
in never-smokers. In this series, patients with BRAF V600E muta-
tions had a more aggressive tumor histotype— characterized by
micropapillary features— and phenotype, with shorter disease-
free survival and overall survival. Interestingly, mutations in BRAF
were mutually exclusive with EGFR and KRAS mutations and
ALK rearrangements.

Fig 3. Fig 4.

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 Diagnosis in Oncology
Current type I inhibitors that target BRAF, such as vemurafenib,
have been designed to target the activated V600E mutant kinase, given
that this specific mutation is largely predominant in metastatic mela-
noma, and vemurafenib has induced high response rates and pro-
longed survival.7 The activity of these type I inhibitors against other
BRAF mutations found in NSCLC, such as G469A (39%) and D594G
(11%), is unknown. Preclinical data suggest that non-V600E–mu-
tated BRAF kinases are resistant to vemurafenib.8 In addition, there
are preclinical data that suggest that BRAF mutations predict sensitiv-
ity of NSCLC cells to MEK inhibitors.9,10
Clinical data on efficacy and resistance to BRAF pathway
inhibitors in the lung cancer setting are scarce, and this subject is
the focus of ongoing research. It has been observed that patients
with colon cancer harboring BRAF V600E mutations show only a
limited response to vemurafenib.11 In this setting, BRAF inhibition
leads to rapid feedback activation of EGFR, and additional block-
ade of the EGFR pathway results in a strong synergy with BRAF
V600E inhibition in vitro.12 The EGFR activation as an acquired
mechanism of resistance has therefore been described in colorectal
cancer and suggested in melanoma, in which vemurafenib inhibi-
tion of BRAF relieves an extracellular regulated kinase– dependent
negative feedback loop that maintains EGFR in an inactive state.
EGFR activation in turn activates the protein RAS, which promotes
dimerization of BRAF. As RAF dimers are resistant to vemu-
rafenib, activation of EGFR abrogates the drug’s inhibitory effect.
Ubiquitous expression of EGFR in lung cancer cells might result in
primary resistance to vemurafenib, as described with respect to
colorectal cancer cells.
Response to vemurafenib in BRAF V600E–mutated lung ade-
nocarcinoma has been reported in a single patient, who unfortu-
nately experienced early death.13 In this article, we report a
complete metabolic response in a patient with BRAF-mutated
lung cancer.
The remarkable radiologic response of our patient argues against
a similar pattern of EGFR feedbacks, at least in some BRAF V600E–
mutated lung cancers, and suggests a potentially interesting activity of
vemurafenib in this indication. Additional data are needed to prove
this concept and describe tumor evolution and patient outcome under
BRAF-targeted treatment. In addition to vemurafenib, other BRAF
inhibitors are currently being tested. An ongoing phase II study is eval-
uating the selective BRAF kinase inhibitor dabrafenib (GSK2118436;
GlaxoSmithKline, Philadelphia, PA) in patients with advanced
NSCLC harboring BRAF mutations (A Phase II Study of the Selective
BRAF Kinase Inhibitor GSK2118436 in Subjects With Advanced
Non-Small Cell Lung Cancer and BRAF Mutations). A phase I study
testing the multiple RAF kinase inhibitor (including CRAF, BRAF,
and the activated mutant BRAF V600E) XL281 (BMS-908662; Bristol-
Myers Squibb, Princeton, NJ) has also been completed (Safety and
Efficacy Study of BMS-908662 Alone or in Combination With Cetux-
imab in Subjects With K-RAS or B-RAF Mutation Positive Advanced
or Metastatic Colorectal Cancer), and results are awaited.
Targeting the MAPK pathway downstream of BRAF may ab-
rogate signal transduction and inhibit tumor growth. MEK is such
a target, and selumetinib (AZD6244; AstraZeneca, Wilmington,
DE), a novel and highly selective MEK inhibitor, is being tested in
an ongoing phase II clinical trial for patients with solid tumors
harboring a BRAF mutation (AZD6244 in Cancers With
BRAF Mutations).
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7, 2015
Completion of radiotherapy concomitant with vemurafenib
induced an impressive radiodermatitis that extended largely be-
yond the boundaries of the radiotherapy treatment field, and this
hints at a radiation recall-like phenomenon. A high and frequent
photosensitizing effect has been reported for vemurafenib7 that
seems to be related to ultraviolet A.14 Our patient case suggests that
x-ray toxicity could be based on a similar mechanism, and stresses
the concept that vemurafenib should probably never be delivered
concomitantly with radiotherapy.
In our patient, vemurafenib monotherapy induced rapid and
complete metabolic and radiologic response. Close imaging
follow-up with serial and multiple tumor biopsies on progression
are planned and will be reported. Given that vemurafenib is already
available on the market, such a case report is of importance to help
guide innovative clinical research in a rapid and efficient manner,
particularly in rare subsets of NSCLC. For the accumulating data to
be applied to clinical practice, a continuous international collab-
orative effort is required to complete trials and provide a satisfac-
tory level of evidence in terms of safety and outcome improvement
for our patients.
Solange Peters, Olivier Michielin, and Stefan Zimmermann
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
ACKNOWLEDGMENT
S.P., O.M., and S.Z. contributed equally to this article.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U”
are those for which no compensation was received; those relationships
marked with a “C” were compensated. For a detailed description of the
disclosure categories, or for more information about ASCO’s conflict of
interest policy, please refer to the Author Disclosure Declaration and the
Disclosures of Potential Conflicts of Interest section in Information
for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Olivier Michielin, Bristol-Myers Squibb (C), Roche (C) Stock
Ownership: None Honoraria: None Research Funding: None Expert
Testimony: None Patents: None Other Remuneration: None
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