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   Table of Contents      
CASE REPORT
Year : 2019  |  Volume : 67  |  Issue : 12  |  Page : 2073-2075

A novel side effect of mitogen-activated protein kinase inhibitor cobimetinib: Acute corneal decompensation


Department of Ophthalmology, Hitit University Erol Olcok Education and Research Hospital, Corum, Turkey

Date of Submission07-Feb-2018
Date of Acceptance30-Apr-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Yonca Asfuroğlu
Department of Ophthalmology, Hitit University Erol Olcok Education and Research Hospital, Corum, Uctutlar Mahallesi Ahc.lar 15, Sokak 27/13 Corum
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijo.IJO_2025_18

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  Abstract 


A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60-mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily. The patient had symptoms of blurred vision and photophobia in his right eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema Involvement was more severe in the right eye compared with the left eye. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved. We suggest that endothelium pump failure was involved in this acute corneal decompensation case similar to the mechanism in retinal pigment epithelium.

Keywords: Corneal decompensation, cobimetinib, MEK inhibitor


How to cite this article:
Asfuroglu M, Asfuroğlu Y. A novel side effect of mitogen-activated protein kinase inhibitor cobimetinib: Acute corneal decompensation. Indian J Ophthalmol 2019;67:2073-5

How to cite this URL:
Asfuroglu M, Asfuroğlu Y. A novel side effect of mitogen-activated protein kinase inhibitor cobimetinib: Acute corneal decompensation. Indian J Ophthalmol [serial online] 2019 [cited 2019 Dec 14];67:2073-5. Available from: http://www.ijo.in/text.asp?2019/67/12/2073/271373



Malignant melanoma is a steadily increasing, significant health problem. It is a dangerous form of skin tumor that causes 90% of skin cancer-related mortality.[1] At diagnosis, metastases are present in approximately 2–5% of patients.[2] The mitogen-activated protein kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated unresectable-metastatic melanoma.[3] One of the most commonly reported ocular adverse effects of this treatment is called MEK inhibitor-associated retinopathy. Herein, we describe a case of acute corneal epithelial and stromal edema with normal retinal findings after MEK inhibitor treatment and BRAF inhibitor immunotherapy, which has never been reported before.


  Case Report Top


A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60 mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily at Corum Erol Olcok Research and Education Hospital Oncology department. The patient had symptoms of blurred vision and photophobia in his right eye. His visual acuity was 3/10 and 9/10 according to the Snellen chart in his right and left eyes, respectively. The intraocular pressure was 14 mm Hg in the right eye and 17 mm Hg in the left eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema [Figure 1]a and [Figure 1]b. Involvement was more severe in the right eye compared with the left eye. There were no cells/flare in the anterior chamber. The fundoscopic examination was normal, bilaterally. Topical preservative-free lubricant drops were administered for symptomatic relief. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved [Fig. 1c and d]. The patient's visual acuity was 10/10 bilaterally.
Figure 1: (a) Central corneal stromal opacity and epitelial microcystic edema in the right eye. (b) Central corneal stromal opacity and epitelial microcystic edema in the left eye. (c) Corneal edema nearly resolved after 2 weeks in the right eye (d) Corneal edema resolved after 2 weeks in the left eye

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  Discussion Top


Several ocular signs and symptoms have been observed following this treatment. It was reported that vemurafenib caused ocular adverse effects in 22% of subjects in patients with advanced-stage melanoma, including uveitis, dry eye, and conjunctivitis as the most common toxicities.[4] Retinal vein occlusion (RVO)[5] and iritis[6] have been reported less frequently.

When we reviewed through the literature, we found that one of the most reported adverse effects of this treatment involved the posterior segment of the eye, called MEK inhibitor- associated retinopathy. It is characterized by retinal pigment epithelium (RPE) dysfunction and neurosensorial retinal detachment.[7] The main mechanism of this phenomenon still remains unresolved. There are some reports suggesting that dysfunction of RPE may play a major role in the pathogenesis.[8] Several preclinical studies showed that MEK inhibition led to acute RPE toxicity, which resulted in RPE hyperpermeability and breakdown of the retinal–blood barrier.[9],[10] It was reported that most adverse effects occurred within the first treatment cycle, and these could be managed through observation alone. It was shown that symptoms resolved with continuation of the treatment without dose modification.[11] Urner-Bloch et al. showed that MEK inhibitor-associated retinopathy was dose–time dependent and reversible in all patients.[12] Gavric et al. claimed that MEK inhibitor-associated retinopathy lesions had no or only mild influence on visual function and needless interventions including the discontinuance of the treatment should be avoided.[13] Likewise, in our case, at the end of the first treatment cycle of the drug therapy, corneal symptoms were apparent but were substantially relieved in 2 weeks, during the intertreatment interval.{Figure 1}

Different from the entire related literature, we describe a different ocular adverse effect of cobimetinib–vemurafenib combination treatment. We strongly suggest that MEK inhibitors damage the RPE pump and affect corneal endothelial function, which could lead to acute corneal stromal and microcystic epithelial edema. Just as the retinopathy adverse effect of this anticancer therapy was reported as reversible; similarly, the corneal edema resolved in our case despite continuation of the drug therapy. We could suggest that corneal endothelium pump failure was involved in this case, similar to the mechanism in RPE. However, more cases should be reported to gain a certain opinion.

There are some limitations in this study. If we had had specular or confocal microscopy in our clinic, it would have made a significant contribution to this case. The patient also rejected being transferred to another ophthalmology clinic for specular/confocal microscopy due to his poor state of health. Nevertheless, we think that this side effect of treatment with cobimetinib–vemurafenib combination is self-resolving and cessation of a life-prolonging treatment should be avoided.


  Conclusion Top


We report a novel side effect of acute corneal epithelial and stromal edema with normal after MEK inhibitor treatment and BRAF inhibitor immunotherapy, implying the need for baseline ophthalmic evaluation and follow-up of such patients by an ophthalmologist.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Arnold M, Holterhues C, Hollestein LM, Coebergh JW, Nijsten T, Pukkala E, et al. Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatol Venereol 2014;28:1170-8.  Back to cited text no. 1
    
2.
Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Bastholt L, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016. Eur J Cancer 2016;63: 201-17.  Back to cited text no. 2
    
3.
Ascierto PA, McArthur GA, Dréno B. Cobimetinib combined with vemurafenib in advanced BRAF (V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17:1248-60.  Back to cited text no. 3
    
4.
Choe CH, McArthur GA, Caro I, Kempen JH, Amaravadi RK, et al. Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. Am J Ophthalmol 2014;158:831-7.  Back to cited text no. 4
    
5.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015;372:30-9.  Back to cited text no. 5
    
6.
Singh P, Singh A. Ocular adverse effects of anti-cancer chemotherapy. J Cancer Ther Res 2012;1:5.  Back to cited text no. 6
    
7.
McCannel TA, Chmielowski B, Finn RS, Goldman J, Ribas A, Wainberg ZA, et al. Bilateral subfoveal neurosensory retinal detachment associated with MEK inhibitor use for metastatic cancer. JAMA Ophthalmol 2014;132:1005-9.  Back to cited text no. 7
    
8.
Stjepanovic N, Velazquez-Martin JP, Bedard PL. Ocular toxicities of MEK inhibitors and other targeted therapies. Ann Oncol 2016;27:998-1005.  Back to cited text no. 8
    
9.
Jiang Q, Cao C, Lu S, Kivlin R, Wallin B, Chu W, et al. MEK/ERK pathway mediates UVB-induced AQP1 downregulation and water permeability impairment in human retinal pigment epithelial cells. Int J Mol Med 2009;23:771-7.  Back to cited text no. 9
    
10.
Huang W, Yang AH, Matsumoto D, Collette W, Marroquin L, Ko M, et al. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol 2009;25:519-30.  Back to cited text no. 10
    
11.
Cruz-Merino L, Guardo LD, Grob JJ, Venosa A, Larkin J, McArthur GA, et al. Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study. J Transl Med 2017;15:146.  Back to cited text no. 11
    
12.
Urner-Bloch U, Urner M, Jaberg-Bentele N, Frauchiger AL, Dummer R, Goldinger SM. MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects. Eur J Cancer 2016;65:130-8.  Back to cited text no. 12
    
13.
Gavric AU, Ocvirk J, Mekjavic PJ. Ocular changes in metastatic melanoma patients treated with MEK inhibitor cobimetinib and BRAF inhibitor vemurafenib. Radiol Oncol 2018;52:213-9.  Back to cited text no. 13
    


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