Ocular Complications of Targeted Therapy

  • Ashley Neiweem
  • Denis Jusufbegovic
  • Arun D. Singh


The field of oncology is a rapidly enhancing one, with transition from traditional cytotoxic chemotherapeutic agents to molecularly targeted therapies for the treatment of a variety of cancers. Novel targeted therapies are selected and designed through cellular signaling pathways necessary for growth and survival of neoplastic cells to provide maximal antitumor effect with minimal alteration of normal cellular function. However, the complexity of cellular pathways proves difficult to design therapeutic agents that do not overlap with the physiologic activities of normal human cellular function. As novel molecularly targeted therapies continue to emerge in the clinical setting, defining prevalence and characteristics of their side effects becomes important for the ophthalmologist to recognize and effectively manage in this patient population when presented with ocular complaints.


Oncology Ophthalmology Ocular side effects Molecular targeted therapy Ocular toxicity Cellular signaling pathway Kinase inhibitor Cellular signaling pathway inhibitor Growth factor receptor inhibitor Immunotherapy MEK inhibitors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol. 2012;6(2):155–76.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Myskowski PL, Halpern AC. Skin reactions to the new biologic anticancer drugs. Curr Opin Support Palliat Care. 2009;3(4):294–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Hedhli N, Russell KS. Cardiotoxicity of molecularly targeted agents. Curr Cardiol Rev. 2011;7(4):221–33.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289(5486):1938–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Fletcher JA. Role of KIT and platelet-derived growth factor receptors as oncoproteins. Semin Oncol. 2004;31(2 Suppl 6):4–11. Review.PubMedCrossRefGoogle Scholar
  7. 7.
    Heuchel R, Berg A, Tallquist M, et al. Platelet-derived growth factor B receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3kinase signaling. Proc Natl Acad Sci U S A. 1999;96:11410–5.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Demetri G, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.PubMedCrossRefGoogle Scholar
  9. 9.
    Fraunfelder FW, Solomon J, Druker BJ, et al. Ocular side effects associated with imatinib mesylate (Gleevec). J Ocul Pharmacol Ther. 2003;19:371–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Esmaeli B, Prieto VG, Butler CE, et al. Severe periorbital edema secondary to STI571 (Gleevec). Cancer. 2002;95:881.PubMedCrossRefGoogle Scholar
  11. 11.
    Esmaeli B, Diba R, Ahmadi MA, et al. Periorbital Oedema and epiphora as ocular side effects of imatinib Mesylate (Gleevec). Eye (Lond). 2004;18(7):760–2.CrossRefGoogle Scholar
  12. 12.
    Breccia M, Gentilini F, Cannella L, et al. Ocular side effects in chronic myeloid leukemia patients treated with imatinib. Leuk Res. 2008;32(7):1022.PubMedCrossRefGoogle Scholar
  13. 13.
    Radaelli F, Vener C, Ripamonti F, et al. Conjunctival hemorrhagic events associated with imatinib mesylate. Int J Hematol. 2007;86:390.PubMedCrossRefGoogle Scholar
  14. 14.
    Kitzmann AS, Baratz KH, Mohney BG, et al. Histologic studies of the intraocular toxicity of imatinib mesylate in rabbits. Eye (Lond). 2008;22(5):712–4.CrossRefGoogle Scholar
  15. 15.
    Gulati AP, Saif MW. Retinal neovascularization and hemorrhage associated with the use of imatinib (Gleevec(®)) in a patient being treated for gastrointestinal stromal tumor (GIST). Anticancer Res. 2012;32(4):1375–7.PubMedGoogle Scholar
  16. 16.
    Masood I, Negi A, Dua HS. Imatinib as a cause of cystoid macular edema following uneventful phacoemulsification surgery. J Cataract Refract Surg. 2005;31:2427–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Kwon SI, Lee DH, Kim YJ. Optic disc edema as a possible complication of Imatinib mesylate (Gleevec). Jpn J Ophthalmol. 2008;52(4):331–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Babu KG, Attili VSS, Bapsy PP, et al. Imatinib-induced optic neuritis in a patient of chronic myeloid leukemia. Int Ophthalmol. 2007;27:43–4.CrossRefGoogle Scholar
  19. 19.
    Christoforidis JB, DeAngelo DJ, D’Amico DJ. Resolution of leukemic retinopathy following treatment with imatinib mesylate for chronic myelogenous leukemia. Am J Ophthalmol. 2003;135:398.PubMedCrossRefGoogle Scholar
  20. 20.
    DeLuca C, Shenouda-Awad N, Haskes C, et al. Imatinib mesylate (Gleevec) induced unilateral optic disc edema. Optom Vis Sci. 2012;89:e16.PubMedCrossRefGoogle Scholar
  21. 21.
    Georgalas I, Pavesio C, Ezra E. Bilateral cystoid macular edema in a patient with chronic myeloid leukaemia under treatment with imatinib mesylate: report of an unusual side effect. Graefes Arch Clin Exp Ophthalmol. 2007;245:1585.PubMedCrossRefGoogle Scholar
  22. 22.
    Kusumi E, Arakawa A, Kami M, et al. Visual disturbance due to retinal edema as a complication of imatinib. Leukemia. 2004;18:1138.PubMedCrossRefGoogle Scholar
  23. 23.
    Govind Babu K, Attili VS, Bapsy PP, et al. Imatinib-induced optic neuritis in a patient of chronic myeloid leukemia. Int Ophthalmol. 2007;27:43.PubMedCrossRefGoogle Scholar
  24. 24.
    Ahn J, Wee WR, Lee JH, et al. Vortex keratopathy in a patient receiving vandetanib for non-small cell lung cancer. Korean J Ophthalmol. 2011;25:355.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Yeh S, Fine HA, Smith JA. Corneal verticillata after dual anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor 2 therapy (vandetanib) for anaplastic astrocytoma. Cornea. 2009;28:699.PubMedCrossRefGoogle Scholar
  26. 26.
    Bajel A, Bassili S, Seymour JF. Safe treatment of a patient with CML using dasatinib after prior retinal oedema due to imatinib. Leuk Res. 2008;32(11):1789–90.PubMedCrossRefGoogle Scholar
  27. 27.
    Cho JH, Kim KM, Kwon M, et al. Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Investig New Drugs. 2012;30:2008.CrossRefGoogle Scholar
  28. 28.
    Maurizot A, Beressi JP, Manéglier B, et al. Rapid clinical improvement of peripheral artery occlusive disease symptoms after nilotinib discontinuation despite persisting vascular occlusion. Blood Cancer J. 2014;4:e247.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer. 2013;21(4):1167–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Foerster CG, Cursiefen C, Kruse FE. Persisting corneal erosion under cetuximab (Erbitux) treatment (epidermal growth factor receptor antibody). Cornea. 2008;27:612.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnson KS, Levin F, Chu DS. Persistent corneal epithelial defect associated with erlotinib treatment. Cornea. 2009;28:706.PubMedCrossRefGoogle Scholar
  32. 32.
    Cohen PR, Escudier SM, Kurzrock R. Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors. Am J Clin Dermatol. 2011;12:63.PubMedCrossRefGoogle Scholar
  33. 33.
    Bouché O, Brixi-Benmansour H, Bertin A, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Ann Oncol. 2005;16:1711.PubMedCrossRefGoogle Scholar
  34. 34.
    Melichar B, Nemcová I. Eye complications of cetuximab therapy. Eur J Cancer Care (Engl). 2007;16:439.CrossRefGoogle Scholar
  35. 35.
    Vaccaro M, Pollicino A, Barbuzza O, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Clin Exp Dermatol. 2009;34:402.PubMedCrossRefGoogle Scholar
  36. 36.
    Rodriguez NA, Ascaso FJ. Trichomegaly and poliosis of the eyelashes during cetuximab treatment of metastatic colorectal cancer. J Clin Oncol. 2011;29:e532.PubMedCrossRefGoogle Scholar
  37. 37.
    Roé E, García Muret MP, Marcuello E, et al. Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients. J Am Acad Dermatol. 2006;55:429.PubMedCrossRefGoogle Scholar
  38. 38.
    Lane K, Goldstein SM. Erlotinib-associated trichomegaly. Ophthal Plast Reconstr Surg. 2007;23:65–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Dranko S, Kinney C, Ramanathan RK. Ocular toxicity related to cetuximab monotherapy in patients with colorectal cancer. Clin Colorectal Cancer. 2006;6:224.PubMedCrossRefGoogle Scholar
  40. 40.
    Jazayeri F, Malhotra R. A case of acquired trichomegaly following treatment with erlotinib. BMJ Case Rep. 2009;2009:bcr01.2009.1473.Google Scholar
  41. 41.
    Garibaldi DC, Adler RA. Cicatricial ectropion associated with treatment of metastatic colorectal cancer with cetuximab. Ophthal Plast Reconstr Surg. 2007;23:62.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang G, Basti S, Jampol LM. Acquired trichomegaly and symptomatic external ocular changes in patients receiving epidermal growth factor receptor inhibitors: case reports and a review of literature. Cornea. 2007;26(7):858–60.PubMedCrossRefGoogle Scholar
  43. 43.
    Chow VW, Jhanji V, Chi SC. Erlotinib-related corneal melting. Ophthalmology. 2013;120:1104.e1.PubMedCrossRefGoogle Scholar
  44. 44.
    Saint-Jean A, Sainz de la Maza M, Morral M, et al. Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: report of 5 cases. Ophthalmology. 2012;119(9):1798–802.PubMedCrossRefGoogle Scholar
  45. 45.
    Lim LT, Blum RA, Cheng CP, et al. Bilateral anterior uveitis secondary to erlotinib. Eur J Clin Pharmacol. 2010;66:1277.PubMedCrossRefGoogle Scholar
  46. 46.
    Ali K, Kumar I, Usman-Saeed M, et al. Erlotinib-related bilateral anterior uveitis. BMJ Case Rep. 2011;2011:bcr03.2011.3988.Google Scholar
  47. 47.
    Sequist LV, Lynch TJ. EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med. 2008;59:429–42.PubMedCrossRefGoogle Scholar
  48. 48.
    Tullo AB, Esmaeli B, Murray PI, et al. Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in phase I and II clinical trials. Eye (Lond). 2005;19(7):729–38.CrossRefGoogle Scholar
  49. 49.
    Holubec L, Liska V, Matejka VM, et al. The role of cetuximab in the treatment of metastatic colorectal cancer. Anticancer Res. 2012;32(9):4007–11.PubMedGoogle Scholar
  50. 50.
    Specenier P, Koppen C, Vermorken JB. Diffuse punctate keratitis in a patient treated with cetuximab as monotherapy. Ann Oncol. 2007;18:961.PubMedCrossRefGoogle Scholar
  51. 51.
    Van Cutsem E, Siena S, Humblet Y, et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol. 2008;19:92–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-over-expressing metastatic breast cancer. J Clin Oncol. 2002;20:719–26.PubMedCrossRefGoogle Scholar
  53. 53.
    Guler M, Yilmaz T, Ozercan I, et al. The inhibitory effects of trastuzumab on corneal neovascularization. Am J Ophthalmol. 2009;147:703–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29(4):398–405.PubMedCrossRefGoogle Scholar
  55. 55.
    Saleh M, Bourcier T, Noel G, et al. Bilateral macular ischemia and severe visual loss following trastuzumab therapy. Acta Oncol. 2011;50(3):477–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Braghiroli MI, Sabbaga J, Hoff PM. Bevacizumab: overview of the literature. Expert Rev Anticancer Ther. 2012;12(5):567–80.PubMedCrossRefGoogle Scholar
  57. 57.
    CATT Research Group, Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.CrossRefGoogle Scholar
  58. 58.
    Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Sherman JH, Aregawi DG, Lai A, et al. Optic neuropathy in patients with glioblastoma receiving bevacizumab. Neurology. 2009;73(22):1924–6.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006;354:980–2.PubMedCrossRefGoogle Scholar
  61. 61.
    Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006;354:980–2.PubMedCrossRefGoogle Scholar
  62. 62.
    Martin G, Bellido L, Cruz JJ. Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol. 2007;25:3559.PubMedCrossRefGoogle Scholar
  63. 63.
    Khan KH, Fenton A, Murtagh E, et al. Reversible posterior leukoencephalopathy syndrome following sunitinib therapy: a case report and review of the literature. Tumori. 2012;98(5):139e–42.PubMedCrossRefGoogle Scholar
  64. 64.
    Yoong J, Chong G, Hamilton K. Bilateral papilledema on sunitinib therapy for advanced renal cell carcinoma. Med Oncol. 2011;28(Suppl 1):S395–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Wegner A, Khoramnia R. Neurosensory retinal detachment due to sunitinib treatment. Eye (Lond). 2011;25(11):1517–8.CrossRefGoogle Scholar
  66. 66.
    Richardson PG, Eng C, Kolesar J, et al. Perifosine, an oral, anti-cancer agent and inhibitor of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity. Expert Opin Drug Metab Toxicol. 2012;8(5):623–33.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Dogan SS, Esmaeli B. Ocular side effects associated with imatinib mesylate and perifosine for gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009;23(1):109–14, ix.PubMedCrossRefGoogle Scholar
  68. 68.
    Keenan JD, Fram NR, McLeod SD, et al. Perifosine-related rapidly progressive corneal ring infiltrate. Cornea. 2010;29(5):583–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Curran MP. Crizotinib: in locally advanced or metastatic non-small cell lung cancer. Drugs. 2012;72(1):99–107.PubMedCrossRefGoogle Scholar
  70. 70.
    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Salgia R, Solomon BJ, Shaw AT, et al. Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients treated with crizotinib. J Clin Oncol. 2012;30(Suppl; abstract no. 7596).Google Scholar
  72. 72.
  73. 73.
    Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):103–19.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.PubMedCrossRefGoogle Scholar
  77. 77.
    Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–81.PubMedCrossRefGoogle Scholar
  78. 78.
    Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.CrossRefPubMedGoogle Scholar
  79. 79.
    LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16:1924.PubMedCrossRefGoogle Scholar
  80. 80.
    US Prescribing information for trametinib. Retrieved and available online at:
  81. 81.
    Niro A, Strippoli S, Alessio G, et al. Ocular toxicity in metastatic melanoma patients treated with mitogen-activated protein kinase kinase inhibitors: a case series. Am J Ophthalmol. 2015;160:959.PubMedCrossRefGoogle Scholar
  82. 82.
    Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16:2450.PubMedCrossRefGoogle Scholar
  83. 83.
    Long G, Stroyakovsky D, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2014;32(Suppl): abstract 9011.Google Scholar
  84. 84.
    Leijen S, Middleton MR, Tresca P, et al. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res. 2012;18(17):4794–805.PubMedCrossRefGoogle Scholar
  85. 85.
    Joshi L, Karydis A, Gemenetzi M, et al. Uveitis as a result of MAP kinase pathway inhibition. Case Rep Ophthalmol. 2013;4:279.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lim J, Lomax AJ, McNeil C, et al. Uveitis and papillitis in the setting of dabrafenib and trametinib therapy for metastatic melanoma: a case report. Ocul Immunol Inflamm. 2018;26:628–31.PubMedGoogle Scholar
  87. 87.
    Draganova D, Kerger J, Caspers L, et al. Severe bilateral panuveitis during melanoma treatment by Dabrafenib and Trametinib. J Ophthalmic Inflamm Infect. 2015;5:17.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sarny S, Neumayer M, Kofler J, et al. Ocular toxicity due to trametinib and dabrafenib. BMC Ophthalmol. 2017;17:146. Scholar
  89. 89.
    McCannel TA, Chmielowski B, Finn RS, et al. Bilateral subfoveal neurosensory retinal detachment associated with MEK inhibitor use for metastatic Cancer. JAMA Ophthalmol. 2014;132(8):1005–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Huang W, Yang AH, Matsumoto D, 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 Ther. 2009;25:519–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Choe CH, McArthur GA, Caro I, et al. Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. Am J Ophthalmol. 2014;158:831.PubMedCrossRefGoogle Scholar
  92. 92.
    Guedj M, Quéant A, Funck-Brentano E, et al. Uveitis in patients with late-stage cutaneous melanoma treated with vemurafenib. JAMA Ophthalmol. 2014;132:1421.PubMedCrossRefGoogle Scholar
  93. 93.
    Yin VT, Wiraszka TA, Tetzlaff M, et al. Cutaneous eyelid neoplasms as a toxicity of Vemurafenib therapy. Ophthal Plast Reconstr Surg. 2015;31:e112.PubMedCrossRefGoogle Scholar
  94. 94.
    Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jordan EJ, Kelly CM. Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012;13(17):2533–43.PubMedCrossRefGoogle Scholar
  96. 96.
    Francis JH, Habib LA, Abramson DH, et al. Clinical and morphologic characteristics of MEK inhibitor-associated retinopathy: differences from central serous Chorioretinopathy. Ophthalmology. 2017;124(12):1788–98.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Urner-Bloch U, Urner M, Stieger P, et al. Transient MEK inhibitor-associated retinopathy in metastatic melanoma. Ann Oncol. 2014;25:1437.PubMedCrossRefGoogle Scholar
  98. 98.
    van der Noll R, Leijen S, Neuteboom GH, et al. Effect of inhibition of the FGFR-MAPK signaling pathway on the development of ocular toxicities. Cancer Treat Rev. 2013;39:664.PubMedCrossRefGoogle Scholar
  99. 99.
    van Dijk EH, van Herpen CM, Marinkovic M, et al. Serous retinopathy associated with mitogen-activated protein kinase kinase inhibition (Binimetinib) for metastatic cutaneous and uveal melanoma. Ophthalmology. 2015;122:1907.PubMedCrossRefGoogle Scholar
  100. 100.
    Martinez-Garcia M, Banerji U, Albanell J, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18:4806.PubMedCrossRefGoogle Scholar
  101. 101.
    Giuffrè C, Miserocchi E, Modorati G, et al. Central serous chorioretinopathy like mimicking multifocal vitelliform macular dystrophy: an ocular side effect of mitogen/extracellular signal-regulated kinase inhibitors. Retin Cases Brief Rep. 2018;12:172–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Signorelli J, Shah Gandhi A. Cobimetinib. Ann Pharmacother. 2017;51:146.PubMedCrossRefGoogle Scholar
  103. 103.
    De La Cruz-Merino L, Di Guardo L, Grob JJ, et al. Clinical features of cobimetinib (COBI)–associated serous retinopathy (SR) in BRAF-mutated melanoma patients (pts) treated in the coBRIM study (abstract). J Clin Oncol. 2015;33(suppl; abstr 9033).Google Scholar
  104. 104.
    Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613.PubMedCrossRefGoogle Scholar
  106. 106.
    Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009;69:6839.PubMedCrossRefGoogle Scholar
  107. 107.
    Schoenberger SD, Kim SJ. Bilateral multifocal central serous-like Chorioretinopathy due to MEK inhibition for metastatic cutaneous melanoma. Case Rep Ophthalmol Med. 2013;2013:673796.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Stjepanovic N, Velazquez-Martin JP, Bedard PL. Ocular toxicities of MEK inhibitors and other targeted therapies. Ann Oncol. 2016;27:998.PubMedCrossRefGoogle Scholar
  109. 109.
    US Prescribing information for trametinib available online at
  110. 110.
    Dréno B, Ribas A, Larkin J, et al. Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol. 2017;28:1137.PubMedCrossRefGoogle Scholar
  111. 111.
    Clinical trial number NCT00527735 at phase II study for previously untreated subjects with Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC).
  112. 112.
    First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial CarcinomaClinical trial number NCT01524991 at
  113. 113.
    Clinical trial number NCT00323882 at phase I/II study of MDX-010 in patients with metastatic hormone-refractory prostate cancer (MDX010–21) (COMPLETED).
  114. 114.
    Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12:1005.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Nallapaneni NN, Mourya R, Bhatt VR, et al. Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash. J Natl Compr Cancer Netw. 2014;12:1077.CrossRefGoogle Scholar
  116. 116.
    Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27:478–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Wong RK, Lee JK, Huang JJ. Bilateral drug (ipilimumab)-induced vitritis, choroiditis, and serous retinal detachments suggestive of Vogt-Koyanagi-Harada syndrome. Retin Cases Brief Rep. 2012;6:423.PubMedCrossRefGoogle Scholar
  120. 120.
    Crosson JN, Laird PW, Debiec M, et al. Vogt-Koyanagi-Harada-like syndrome after CTLA-4 inhibition with ipilimumab for metastatic melanoma. J Immunother. 2015;38:80.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Witmer MT. Treatment of ipilimumab-induced Vogt-Koyanagi-Harada syndrome with oral dexamethasone. Ophthalmic Surg Lasers Imaging Retina. 2017;48:928.PubMedCrossRefGoogle Scholar
  122. 122.
    Hahn L, Pepple KL. Bilateral neuroretinitis and anterior uveitis following ipilimumab treatment for metastatic melanoma. J Ophthalmic Inflamm Infect. 2016;6:14. Scholar
  123. 123.
    McElnea E, Ní Mhéalóid A, Moran S, et al. Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab. Orbit. 2014;33:424.PubMedCrossRefGoogle Scholar
  124. 124.
    McMillen B, Dhillon MS, Yong-Yow S. A rare case of thyroid storm. BMJ Case Rep. 2016;2016.
  125. 125.
    Borodic G, Hinkle DM, Cia Y. Drug-induced graves disease from CTLA-4 receptor suppression. Ophthal Plast Reconstr Surg. 2011;27(4):e87–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521.PubMedCrossRefGoogle Scholar
  127. 127.
    Ribas A, Hamid O, Daud A, et al. Association of Pembrolizumab with Tumor Response and Survival among Patients with Advanced Melanoma. JAMA. 2016;315:1600.PubMedCrossRefGoogle Scholar
  128. 128.
    Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    United States prescribing information for avelumab. Retrieved and available online at:
  130. 130.
    United States prescribing information for atezolizumab. Retrieved and available online at:
  131. 131.
    Richardson DR, Ellis B, Mehmi I, et al. Bilateral uveitis associated with nivolumab therapy for metastatic melanoma: a case report. Int J Ophthalmol. 2017;10(7):1183–6. CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    de Velasco G, Bermas B, Choueiri TK. Autoimmune arthropathy and uveitis as complications of programmed cell death 1 inhibitor treatment. Arthritis Rheumatol. 2016;68(2):556–7.PubMedCrossRefGoogle Scholar
  133. 133.
    Karlin J, Gentzler R, Golen J. Bilateral anterior uveitis associated with nivolumab therapy. Ocul Immunol Inflamm. 2016;6:1–3.Google Scholar
  134. 134.
    Arai T, Harada K, Usui Y, et al. Case of acute anterior uveitis and Vogt-Koyanagi-Harada syndrome-like eruptions induced by nivolumab in a melanoma patient. J Dermatol. 2017 Aug;44(8):975–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Abu Samra K, Valdes-Navarro M, Lee S, et al. A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab. Eur J Ophthalmol. 2016;26(3):e46–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Patnaik A, Socinski MA, Gubens MA, et al. Phase I study of pembrolizumab (pembro MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D9 abstract. J Clin Oncol. 2015;33(Suppl; abstr 8011). Abstract available online at
  137. 137.
    Medina Mendez CA, Ma PC, Singh AD. Acquired trichomegaly. JAMA Ophthalmol. 2014;132(9):1051.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ashley Neiweem
    • 1
  • Denis Jusufbegovic
    • 1
  • Arun D. Singh
    • 2
  1. 1.Department of OphthalmologyIndiana University School of Medicine/Glick Eye InstituteIndianapolisUSA
  2. 2.Department of Ophthalmic OncologyCole Eye Institute, Cleveland ClinicClevelandUSA

Personalised recommendations