Ocular Toxicity of Tyrosine Kinase Inhibitors

Davis, Mary E.

doi:10.1188/16.onf.235-243

Cited by 29 publications

(17 citation statements)

References 29 publications

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“… 18 21 Ocular toxicities have been reported with FGFR inhibitors. 22 In this study, only a single case of grade 3 punctate keratitis was reported with ODM-203 and was classified as a DLT after administration of an 800 mg dose. Most of the ocular events reported with ODM-203 (19.0%) were mild in severity, with conjunctivitis being the most frequently reported event.…”

Section: Discussionmentioning

confidence: 80%

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

et al. 2020

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BackgroundGenetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor.MethodsOpen-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours.ResultsOverall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets.ConclusionThis study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.Trial registration numberNCT02264418.

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Section: Discussionmentioning

confidence: 80%

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

et al. 2020

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“…Previous studies have reported that systemic anticancer therapies with TKIs cause ocular complications, including acute and chronic damage to the eye. 44 Interestingly, however, several TKIs, including human epidermal growth factor receptor 2 inhibitors and epidermal growth factor receptor inhibitors, have been reported to cause ophthalmic side effects, such as dry eye syndrome, whereas the two common ocular side-effects related to imatinib are periorbital edema and epiphora. 45 In this regard, it should be noted that the beneficial effect on DED in animal models can be obtained with a low dose of imatinib compared with the human equivalent dose that is currently used for anti-cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Efficacy of Imatinib Mesylate, a Tyrosine Kinase Inhibitor, in the Treatment of Chemically Induced Dry Eye in Animal Models

Baek

Sung

Choi

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface accompanied by ocular discomfort, visual disturbance, tear film instability, and ocular surface inflammation. In the present study, we evaluated the efficacy of the tyrosine kinase inhibitor imatinib mesylate for the treatment of DED. Methods Experimental models of DED were generated in Sprague Dawley rats using a combination of benzalkonium chloride (BAC) with atropine sulfate and in New Zealand White rabbits using BAC. The animals were treated twice daily with eye drops of vehicle, imatinib (0.01%–0.3%), or a positive control (Restasis). The improvement in DED due to imatinib was assessed by staining with fluorescein, lissamine green, impression cytology, and histological analysis. In addition, immunofluorescence staining was performed at the end of the study to evaluate the inflammatory response in the ocular surface. Results Topical application of imatinib significantly reduced ocular surface damage compared with vehicle-treated animals. Imatinib restored the morphology and structure of the conjunctival epithelium and reduced the recruitment of immune cells in the corneal epithelium. Furthermore, imatinib significantly reduced the impression cytology score, thus demonstrating that imatinib prevents the loss of goblet cells in DED animal models. The therapeutic efficacy of imatinib was similar to or better than that of cyclosporine treatment. Conclusions In this study, we provide an animal in vivo proof of concept of the therapeutic potential of imatinib for the treatment of DED. Translational Relevance With this study we show the possibility of developing imatinib as a new ophthalmic drop to treat DED.

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“…Owing to the fact that nearly 90% of the genome is expressed in the tissues of the eye, there are many molecular cross-reactive targets for kinase inhibitors [ 76 ]. Toxicity can be idiosyncratic and may range from mild conjunctivitis to optic disc edema and optic neuritis which have been noted in patients treated with dasatinib, imatinib, and nilotinib [ 77 ]. A rare toxicity of EGFR inhibitor therapy includes trichomegaly, or abnormal growth of the eyelashes, which can lead to back-growth of the lashes onto the conjunctiva and cornea, leading to corneal ulcerations in severe cases [ 78 ].…”

Section: Methodsmentioning

confidence: 99%

A Review of Cancer Immunotherapy Toxicity II: Adoptive Cellular Therapies, Kinase Inhibitors, Monoclonal Antibodies, and Oncolytic Viruses

Chhabra

Kennedy

2021

J. Med. Toxicol.

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Immunotherapy for cancer has undergone a rapid expansion in classes, agents, and indications. By utilizing aspects of the body’s innate immune system, immunotherapy has improved life expectancy and quality of life for patients with several types of cancer. Adoptive cellular therapies, including chimeric antigen receptor T (CAR T) cell therapy, involve the genetic engineering of patient T cells to allow for targeting of neoplastic cells. Monitoring of patients during the lymphodepletion prior to therapy and following CAR T cell infusion is necessary to detect toxicity of therapy. Specific toxicities include cytokine release syndrome and neurologic toxicity, both of which may be life-threatening. Tocilizumab and/or corticosteroids should be considered for moderate to severe toxicity. Kinase inhibitor toxicity can occur as “on target” effects or “off target” effects to multiple organ systems due to shared protein epitopes. Treatments are organ-specific. Infusion reactions are common during treatment with monoclonal antibodies and treatment is largely supportive. Clinical experience with oncolytic viruses is limited, but local reactions including cellulitis as well as systemic influenza-like syndromes have been seen but are typically mild. Although clinical experience with adverse effects due to newer immunotherapy agents is growing, an up-to-date understanding of their mechanisms and potential toxicities is critical.

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Ocular Toxicity of Tyrosine Kinase Inhibitors

Cited by 29 publications

References 29 publications

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

In Vivo Efficacy of Imatinib Mesylate, a Tyrosine Kinase Inhibitor, in the Treatment of Chemically Induced Dry Eye in Animal Models

A Review of Cancer Immunotherapy Toxicity II: Adoptive Cellular Therapies, Kinase Inhibitors, Monoclonal Antibodies, and Oncolytic Viruses

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