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Milluzzo et al. Metab Target Organ Damage 2024;4:5 https://dx.doi.org/10.20517/mtod.2023.43 Page 9 of 14

The combination of MAPK and BRAF inhibitors, namely trametinib and dabrafenib, determined, in a 39-
year-old woman with metastatic melanoma, the onset of multiple serious retinal detachments and severe
[42]
acute granulomatous panuveitis two weeks after the treatment starting . The recovery of a good visual
acuity was obtained after two weeks since drugs discontinuation and corticosteroids administration,
although an extensive extra-macula retinal fibrosis remained .
[42]
The pathogenesis of MEKAR is unclear. There is evidence that the MAPK/MEK pathway regulates tight
junctions in retinal epithelial cells, and thus anticancer drugs modulating these pathways could interfere
with fluid transport determining retinal oedema [36,37] . Other possible pathogenetic mechanisms include the
generation of antibodies against the retinal pigment epithelium cells, found in the serum of subjects treated
[40]
with binimetinib .

Tyrosine-kinase inhibitors (TKIs) are known to increase the risk for renal (asymptomatic albuminuria or
nephrotic syndrome) and cardiovascular (hypertension and myocardial ischemia) adverse events . Few
[4]
studies evaluated the risk of TKIs to determine retinal injury [Table 1]. In particular, imatinib, used in
[19]
subjects affected by chronic myelogenous lymphoma and gastrointestinal stromal cancers (400-800 mg/
day), has been rarely (less than 1% of treated subjects) associated with the onset of retinal haemorrhages and
macular oedema, usually resolved after imatinib discontinuation [43,44] . The ocular events mostly occurred in
patients treated with high doses of imatinib (600–800 mg/day). Some of these studies also recruited subjects
affected by diabetes . Retinal necrosis and oedema were observed in rabbits after the intraocular injection
[44]
of imatinib .
[45]

Molecules inhibiting the angiogenesis of cancer cells by targeting the vascular endothelial growth factor
(VEGF) signalling are widely used in the treatment of a variety of malignancies. Fraunfelder and colleagues
explored the “National Registry of Drug-Induced Ocular Side Effects” to investigate the association between
the use of three oral VEGF inhibitors, namely pazopanib, sorafenib, and sunitinib, with the onset of ocular
[46]
adverse events [Table 1]. Macular oedema or retinal bleeding occlusion and detachments were observed
in 15% of the cases after 2-3 months since the drug initiation. The authors assumed that the changes in
vascular permeability and the occurrence of microemboli and microvascular events are responsible for the
retinal damage. This large number of serious retinal adverse events associated with oral VEGF inhibitors
suggests a close monitoring of eye health in treated subjects.

Recent studies reported the retinal side effects associated with fibroblast growth factor receptor 2 inhibitors
(FGFR). A multicentre, open-label, single-arm, phase 2 study investigated the efficacy and safety of
infigratinib (125 mg/day, orally administered for 21 days of 28-day cycles), a fibroblast growth factor
receptor 2 inhibitor, in 108 subjects affected by cholangiocarcinoma. Central serious retinopathy-like and
retinal pigment epithelial detachment-like events occurred in 17% of the enrolled subjects. The median time
to first onset of ocular side effects was 39 days. No information about the effect of infigratinib on DR is
[47]
reported . The occurrence of asymptomatic bilateral subretinal fluid, detected on optical coherence
tomography scans, was observed in a phase 2 trial of subjects treated with an oral FGFR inhibitor
(AZD4547) for malignant pleural mesothelioma . All patients received twice-daily dosing of 80 mg
[48]
AZD4547 on a nominal 3-weekly cycle. The subretinal fluid emerged between 3 and 19 weeks following the
first dose of the drug, did not require any dose interruptions or reductions, and disappeared after the last
dose.

In the last decade, therapies targeting the immune response against cancer cells have taken a crucial role in
the treatment of metastatic melanoma, non-small-cell lung cancer, renal cell carcinoma, bladder carcinoma,