Radiol Oncol 2018; 52(2): 213-219. doi: 10.2478/raon-2018-0002
213
research article
Ocular changes in metastatic melanoma 
patients treated with MEK inhibitor 
cobimetinib and BRAF inhibitor vemurafenib
Ana Ursula Gavric1, Janja Ocvirk2,3, Polona Jaki Mekjavic1,3
1 Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
2 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 
3 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2018; 52(2): 213-219.
Received 4 October 2017
Accepted 20 November 2017
Correspondence to: Assoc. Prof. Polona Jaki Mekjavić, M.D., Ph.D.; Eye Hospital, University Medical Centre Ljubljana, Grablovičeva 46, 
1000 Ljubljana. Phone: +386 1 522 1750; Fax: +386 1 522 1940; E-mail: polona.jaki@guest.arnes.si 
Disclosure: No potential conflicts of interest were disclosed.
Background. Mitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral 
oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated 
metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study 
was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combina-
tion with vemurafenib.
Patients and methods. In the prospective, observational study, patients with BRAF-mutated metastatic melanoma 
treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to par-
ticipate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, 
slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT). 
Results. Five out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all 
patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated 
with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes 
in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid 
macular edema.
Conclusions. Multiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in 
patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be 
aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, 
including the discontinuance of a potentially life-prolonging therapy. 
Key words: metastatic malignant melanoma; eye; MEKAR; MEK inhibitor 
Introduction
Malignant melanoma is a significant health prob-
lem, the incidence of melanoma is steadily in-
creasing, fastest among all cancers.1 At diagnosis, 
metastases are present in approximately 2-5% of 
patients.2
In recent years several new targeted drugs and 
immunotherapy have been approved for the treat-
ment of metastatic melanoma. Mitogen-activated 
protein kinase kinase (MEK) inhibitors and V-raf 
murine sarcoma viral oncogene homolog B1 
(BRAF) inhibitors are a newer group of drugs that 
act on the target enzymes of MAPK / ERK sign-
aling pathway. The combination treatment with 
BRAF and MEK inhibitors is amongst the current 
standard of care for stage IIIC/IV BRAF-mutated 
melanoma. Combined BRAF and MEK inhibition 
seems to provide a greater benefit than BRAF or 
MEK inhibitor monotherapy.3,4
Radiol Oncol 2018; 52(2): 213-219.
Gavric AU et al. / Ocular changes during MEK and BRAF inhibitors214
The BRAF protein is a key part of “mitogen-acti-
vated protein kinase signaling pathway” (MAPK), 
which regulates the division and proliferation of 
cells and plays a central role in the progression of 
melanoma. MEK inhibitors inhibit the mitogen-ac-
tivated protein kinase kinase MEK1 and/or MEK2. 
A specific mutation in the BRAF gene causes exces-
sive activity, leading to uncontrolled growth and 
cell division. About 50% of melanomas harbors ac-
tivating BRAF mutations.5 Therapy with the selec-
tive inhibitor of mutant BRAF Val600, vemurafenib 
in combination with MEK inhibitor cobimetinib 
showed major tumor responses, resulting in im-
proved progression-free and overall survival in 
patients with metastatic disease, compared with 
chemotherapy.3,6
MEK inhibitors have been associated with 
changes in retina by means of small localized se-
rous neuroretinal detachments, which have been 
named MEK inhibitor-associated retinopathy 
(MEKAR).7,8 The most common ocular side effect 
associated with BRAF inhibitor vemurafenib in 
monotherapy are uveitis, conjunctivitis and dry 
eyes.9 
When used cobimetinib in combination with ve-
murafenib the most commonly observed adverse 
effects in the coBRIM phase III trial were rash, 
photosensitivity, MEKAR, alopecia, hyperkerato-
sis, diarrhea, nausea, arthralgia, fatigue, vomiting, 
blood creatine phosphokinase (CPK) increase and 
alanine aminotransferase (ALT) increase. Most ad-
verse effects occurred within the first treatment cy-
cle and decrease substantially over time.10
A pattern of ocular toxicity has followed these 
drugs through clinical trials and their association 
with ocular toxicity is only just beginning to be rec-
ognized. 
The aim of our study was to look prospectively at 
the incidence, symptomatology, course, and revers-
ibility of ocular toxicity in patients with BRAFV600 
metastatic melanoma treated with MEK/BRAF in-
hibitor cobimetinib plus vemurafenib.
Patients and methods
Patients
All patients with BRAFV600 metastatic melano-
ma treated at the Institute of Oncology Ljubljana 
with MEK/BRAF inhibitor cobimetinib and vemu-
rafenib from January to June 2017, were offered the 
chance to be included in the study at Eye Hospital 
of University Medical Centre Ljubljana. Seven out 
of eight patients were willing to participate. The 
TABLE 1. Patient characteristics
Patient N° 1 2 3 4 5 6 7
Sex M M F M M M M
Age (years) 41 58 64 74 71 45 55
No of cycles at first eye exam 2 11 15 3 3 3 6
No of cycles at last eye exam 3 13 24 8 5 4 7
Change in dosage yes* no no no no no no
BCVA RE 1.0 1.0 1.0 0.7 – 0.9 0.8 1.0 1.0
BCVA LE 1.0 1.0 1.0 0.7 – 0.9 0.7 1.0 1.0
Symptoms circle centrally
blurred 
vision no
blurred 
vision
floaters in LE, 
blurred vision
circle 
centrally no
Occurrence of symptoms 
after starting the therapy 1 week 1 week - 1 week 1 month 1 week -
Fluctuations of symptoms spontan. resolution no -
different 
spectacles 
needed
better after 
topical therapy
spontan. 
resolution needs spectacles
OCT changes in the fovea elongation of IZ SRF SRF SRF
elongation of IZ 
in RE, SRF in LE SRF SRF
Extrafoveal SRF multiple bilateral
multiple 
bilateral
multiple 
bilateral
multiple 
bilateral no no multiple bilateral
Other ocular findings - - -
incipient 
senile 
cataract ou
uveitis in LE; 
incipient 
cataract ou
-
dilatated 
conjuctival 
vessels in the RE
 * adjusted dose = lower dose due to the cutaneous side effects; BCVA = best corrected visual acuity; F = female; IZ = interdigitation zone; LE = left eye; M = male, OCT = optical 
coherence tomography; ou = both eyes; RE = right eye; SRF = subretinal fluid.
Radiol Oncol 2018; 52(2): 213-219.
Gavric AU et al. / Ocular changes during MEK and BRAF inhibitors 215
study adhered to the tenets of the Declaration of 
Helsinki and was submitted and approved by The 
Slovenian National Medical Ethics Committee. All 
patients signed an informed consent form and all 
attended the ophthalmology visits.
Treatment
All patients received BRAF/MEK inhibitor com-
bination therapy for metastatic melanoma, 
vemurafenib (Zelboraf, Roche Products Ltd, 
Hertfordshire, UK) plus cobimetinib (Cotellic, 
Roche Products Ltd, Hertfordshire, UK) in the 
standard doses: cobimetinib 60 mg orally once 
daily on days 1-21 of an every 28-day cycle and ve-
murafenib 960 mg orally twice daily on days 1-28. 
Doses were reduced in the course of the treatment 
in one patient due to a severe cutaneous side effect.
Outcome measures
All patients had undergone a complete ophthalmo-
logic examination, including best-corrected visual 
acuity (BCVA) and intraocular pressure measure-
ment, slit-lamp biomicroscopy, funduscopy, and 
noninvasive imaging: color fundus photography 
(Topcon Fundus Camera), fundus autofluores-
cence (FAF), infrared-reflectance (IR) and spec-
tral-domain optical coherent tomography (SD-
OCT). Images were obtained with the Heidelberg 
Spectralis HRA+OCT (Heidelberg Engineering, 
Heidelberg, Germany). Every patient had at least 
two examinations in Eye Hospital of University 
Medical Centre Ljubljana.
Information about primary cancer diagnosis, 
other adjuvant treatments, the number of cycles, 
and the dosage of chemotherapy was collected 
from medical charts.
Results
Patient characteristics
There were 7 participants with BRAF mutated met-
astatic melanoma. The mean age was 58.3 years (± 
9.8 years) with a median age of 58 years (range of 
41‒74 years). Time from the beginning of the ther-
apy to the last control ranged from 2 to 24 months. 
Patient characteristics are shown in Table 1.
Ophthalmic characteristics
Ocular adverse effects were documented in all of 
the patients, giving an incidence of 100%. Bilateral 
serous neuroretinal detachments were observed in 
all 7 patients, additionally, in 1 eye, there was an 
associated anterior uveitis with cystoid macular 
edema (CME).
Five patients reported eye symptoms, 3 had 
fluctuations of blurry vision and 2 reported a circle 
centrally in the visual field. Best corrected visual 
acuity (BCVA) was 1.0 in 5 patients. Two patients 
had reduced BCVA; one presented with incipient 
senile cataract, his BCVA fluctuated from of 0.7 to 
0.9 in both eyes, another patient presented with 
unilateral uveitis and cataract in both eyes, he has 
FIGURE 1. (A) Discrete bilateral lesions in the fovea seen on fundus photography(blue 
arrows); (B) Infrared reflectance imaging showing lesions with a hyperreflective 
center, surrounded by a hyporeflective zone scattered throughout the posterior 
pole (some are marked with red arrows); (C) Some lesions showed increased signal 
in autofluorescence imaging (some are marked with yellow arrows).
A
B
C
Radiol Oncol 2018; 52(2): 213-219.
Gavric AU et al. / Ocular changes during MEK and BRAF inhibitors216
BCVA of 0.6. IOP remained stable in all patients 
(from 14 to 22 mmHg).
Ophthalmoscopy revealed discrete bilateral 
transparent to yellowish lesions of less than 1/3 of 
the disc diameter in the fovea and extrafoveally. 
Not all lesions were seen with ophthalmoscopy 
(Figure 1A).
IR imaging showed lesions with a hyper reflec-
tive center, surrounded by a hyporeflective zone 
and multiple smaller lesions with similar reflec-
tance characteristics scattered throughout the pos-
terior pole. The location and number of lesions 
were relatively symmetrical between both eyes 
(Figure 1B). 
Some lesions showed increased signal in auto-
fluorescence imaging (Figure 1C).
Dome-shaped accumulations of subretinal fluid 
(SRF) with elongation of outer part of the interdigi-
tation zone of photoreceptors into hyporeflective 
SRF were detected on OCT. During the following 
cycles of therapy, OCT findings showed fluctua-
tions (Figure 2).
One patient presented with anterior uveitis and 
cystoid macular edema in the left eye, which re-
solved after a 3-week course of topical 0.1% dexa-
methasone. 
Besides noninvasive imaging, fluorescein and 
indocyanine green (ICG) angiography was per-
formed in one patient, showing no vascular abnor-
malities, no leakage or staining, only mild masking 
effect of subretinal fluid on the location of lesions 
was observed (Figure 3). 
Discussion
We studied the incidence, symptoms and clinical 
characteristics of ocular toxicity in patients with 
BRAFV600 metastatic melanoma treated with cobi-
metinib in combination with vemurafenib. 
Our results show 100% incidence of MEKAR 
in our patients. In contrast, in the coBRIM study 
patients were receiving the same therapy, but 
MEKAR was reported in only 26% of patients.11 
The authors of this study do not specify the day 
and hour of the examination, which according to 
Urner-Bloch is very relevant. On the basis of our 
observations, we concur with Urner-Bloch that 
the fluctuations in the MEKAR lesions are also 
dependent of the day within the treatment cycle.7 
In patients that were also examined during the in-
ter-treatment interval, we noted a decrease in the 
magnitude of the lesions. Some patients reported 
fluctuation of the symptoms, and one of them was 
able to compensate fluctuated blurry vision with 
different hyperopic refractive correction. 
The results of a meta-analysis of the ocular safe-
ty of MEK inhibitors reveals an increased risk for 
ocular problems, particularly disturbed vision, and 
retinal changes such as “chorioretinopathy and ret-
inal detachment”. They did not report any statisti-
cally significant increase in the risk for uveitis or 
eye hemorrhage.12
Similar results to ours were reported in a pro-
spective observational study, in which 62 melano-
ma patients were treated with MEK inhibitor bini-
metinib in monotherapy or in combination with 
BRAF inhibitor. Bilateral retinopathy was diag-
nosed in 92% of patients on monotherapy and 100% 
in those with combination therapy. Retinopathy 
was described as dose- and time-dependent and 
was reversible in all patients.7
There is some confusion regarding the descrip-
tion of MEKAR in the literature. Some groups and 
authors have defined MEKAR as “chorioretin-
opathy”, “retinal pigment epitelium detachement 
(PED)” or “central serous retinopathy-like”.12-15
A
A
B
B
C
C
D
D
E
F
FIGURE 2. (A-C) IR imaging of foveal lesion during cycles; (D-F) OCT showed 
fluctuations of dome-shaped accumulation of subretinal fluid with elongation of 
interdigitation zone (green arrows) in the foveal region; A+D = imaging during 3rd 
cycle; B+E = imaging during 6th cycle; C+F = imaging during 8th cycle.
FIGURE 3. Fluorescein (A,B) and indocyanine green (C,D) angiography showed only 
mild masking effect of subretinal fluid on the location of lesions (red arrows).
Radiol Oncol 2018; 52(2): 213-219.
Gavric AU et al. / Ocular changes during MEK and BRAF inhibitors 217
By means of optical coherent tomography (OCT) 
which became widely used diagnostic tool for reti-
na, the morphology of MEKAR lesions is clarified. 
Lesions in MEKAR are not PED, because RPE is not 
detached and the fluid is accumulated above it. It 
is also not chorioretinopathy, as there are no visible 
changes in the choroid, no pachycoroid is observed 
in MEKAR and also no observable changes on ICG 
angiography. All mentioned changes are typical 
for central serous chorioretinopathy.8
Characteristically, in MEKAR, the choroidal 
thickness is normal, and focal lesions in the outer 
retinal layers are notable. The ellipsoid layer is un-
changed and is clearly distinguishable from inter-
digital zone (IZ) which has elongations into sub-IZ 
space. Sub-IZ is filled with hypo reflective fluid 
(SRF). RPE layer is not disturbed. During the cycles 
hypo reflective sub-IZ fluid fluctuates, can vanish, 
but elongations of IZ remain (Figure 2). Previous 
studies have described similar retinal lesions as-
sociated with other MEK inhibitors treatment.7,16,17
If lesion is located in the strict center of the 
macula, in the foveola, patients can describe symp-
toms such as a circle centrally in the visual field or 
blurred near vision. Accumulation of SRF thickens 
retina in the place of lesion hence the axial length 
of the eye is shortened. That results in blurred near 
vision due to induced hyperopia. Patients com-
plain of difficulty reading without or with inappro-
priate reading glasses. Because lesions in MEKAR 
are thin, changes in vision are not dramatic and do 
not importantly influence patients’ quality of life. If 
the symptoms are disturbing, they can be corrected 
with mild hyperopic correction.
One patient noticed a circle centrally in the vis-
ual field few days after starting the therapy. The 
therapy was promptly discontinued due to cutane-
ous side effects and after cessation of the therapy, 
the ocular symptoms also disappeared. Two weeks 
later patient started taking low dose therapy (cobi-
metinib 40 mg/day for 3 weeks, and vemurafenib 
720 mg/12 h) and the ocular symptoms did not re-
appear. Morphological changes were present but 
barely detectable (Figure 4). It has been reported 
that patients treated with MEK inhibitor biminetin-
ib experience visual disturbances, particularly in 
the first 4 weeks of treatment. Subsequent treat-
ment, initiated after a given interval, causes less 
pronounced symptoms.7 It has not been reported 
whether the dosage within a given cycle influences 
the occurrence of the symptoms or the amount of 
sub-IZ fluid. 
The mechanism of MEK inhibitor ocular toxic-
ity still remains unresolved. Dysfunction of retinal 
pigmented epithelium (RPE) may play a major role 
in pathogenesis.18 Ophthalmoscopy revealed mul-
tiple barely noticeable lesions of less than 1/3 of the 
disc diameter distributed in the posterior part of 
the both eyes, in the fovea and scattered around 
it extrafoveally, mainly near the vascular arcades. 
It is speculated that these are the sites where the 
concentration of the drug is the highest.8 Prior pre-
clinical studies showed that MEK inhibition leads 
to acute RPE toxicity, which results in RPE hyper 
permeability and breakdown of the retinal–blood 
barrier.19,20 RPE is an epithelial barrier that main-
tains the outer blood-retinal barrier. Adherent 
and tight junctions, facilitated and active trans-
porters perform important barrier functions in 
the physiological processes of the retina, by trans-
porting nutrients, water, and ions, and removing 
metabolic wastes. The removal of excessive water 
from the subretinal space to the choriocapillaris, 
which is critical to the health of the retina, is regu-
lated by the active transport systems in the RPE.21 
Inappropriate function of RPE may lead to SRF ac-
cumulation observed in MEKAR. Lesions in the fo-
veola are observed to be thicker than extrafoveally. 
The possible explanation for that might be the fact 
that in the fovea the concentration of photorecep-
tors is the greatest, hence this is the region of great-
est active transport from the retina to choroid.
OCT reveals some changes in outer retinal lay-
ers, observed changes are focal: clearly distinguish-
able IZ with elongations into sub-IZ space, sub-IZ 
space can be additionally thickened due to accu-
mulation of hyporeflective SRF above RPE layer 
which remains unchanged.
During the subsequent treatment, OCT find-
ings showed minimal fluctuations in SRF. In our 
patients, the follow-up was up to 2 years from the 
FIGURE 4. Discrete morphological changes with focal elongations of interdgitation 
zone in the fovea (red arrows) and near the vascular arcades (green arrows) seen 
on OCT.
Radiol Oncol 2018; 52(2): 213-219.
Gavric AU et al. / Ocular changes during MEK and BRAF inhibitors218
beginning of the treatment. During this time, le-
sions did not completely resolve. Despite persis-
tent SRF, no permanent changes in RPE layer were 
observed in this short-term follow up. Van Dijk et 
al. analyzed the molecular mechanism and cell pro-
liferation using neuroretina and cell models of RPE 
treated with MEK inhibitor binimetinib in vitro and 
found that cell proliferation was not inhibited dur-
ing treatment and retinal cells were able to regain 
the activation after binimetinib treatment, mimick-
ing the reversibility of the retinopathy.16 The effect 
on RPE on long-term follow up is to be studied fur-
ther.
We also observed discrete focal dilatation of 
conjunctival vessels by slit lamp microscopy in one 
patient. These changes were not previously report-
ed in the literature and could be the result of local 
irritation due to some other factor. 
Patient number 5 presented with reduced vi-
sion in his left eye. His BCVA was reduced to 0.7, 
and he observed floaters. We found cells in the an-
terior chamber with posterior synechiae as well as 
slight macular edema. After topical corticosteroid 
therapy, the signs and symptoms resolved. This is 
in line with previous case reports of patients with 
metastatic melanoma and clinical signs of inflam-
mation in both eyes. The bilateral uveitis was re-
ported as an adverse effect of vemurafenib thera-
py, which was treated with topical corticosteroid 
therapy.22,23 In our patient number 5, MEKAR 
with lesions in both foveas was observed three 
weeks after the onset of inflammation in the left 
eye. Previous studies have reported that the most 
common ocular toxicity associated with BRAF in-
hibitor monotherapy is uveitis, occurring in 2.1% 
of patients receiving vemurafenib and in 1% of 
patients treated with dabrafenib across clinical tri-
als. Current algorithms suggest management with 
a temporary dose interruption, ophthalmological 
review, a course of topical steroids and in most 
cases a dose reduction.13
We have observed a high incidence of ocular 
side effects in this small group of patients taking 
combined cobimetinib and vemurafenib. They 
were mild and prone to spontaneous resolution. 
Morphological changes were located in outer reti-
nal layers. They did not significantly effect visual 
function. Overall, we have shown that therapy 
with MEK/BRAK inhibitor combination therapy 
is safe with respect to ocular adverse effects, for a 
duration of up to 2 years. However, the results of 
the present study must be viewed as a hypothesis-
generating pilot study, and the results interpreted 
with caution, because of the small sample sizes. 
We would recommend that patients treated 
with MEK and BRAF inhibitors have regular oph-
thalmologic examinations, which include BCVA, 
slit lamp examination, and OCT of macular region, 
and when available IR imaging. The long-term fol-
low-up of MEK inhibitor therapy is to be studied 
to evaluate the potential irreversible effects of MEK 
on outer retinal layers, which could permanently 
influence visual function. 
Retinal changes named MEKAR are observed 
in metastatic melanoma patients treated with 
MEK inhibitor in combination with BRAF inhibi-
tor. Lesions are either solitary or multiple bilateral 
foveal and extrafoveal serous neurosensory retinal 
detachments. MEKAR lesions can be recognized 
and differentiated from serous retinal detachments 
of other etiology using noninvasive diagnostic im-
aging methods such as OCT and IR imaging. They 
have no, or only mild influence on visual function 
and are self-limited.
Ophthalmologists and oncologists need to be 
aware of this common, yet relatively benign and 
often transient ocular side effect of treatment with 
MEK inhibitor in combination with BRAF inhibi-
tor to avoid needless intervention, including the 
discontinuance of a potentially life-prolonging 
therapy.
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