Reversible Nyctalopia and Retinopathy in a Patient With Metastatic Cancer Treated With Anti–Heat Shock Protein 90 Therapy

Munk, Marion R.; Fernandes, João Miguel; Mets, Marilyn B.; Patel, Jyoti D.; Johnson, Melissa L.; Jampol, Lee M.

doi:10.1001/jamaophthalmol.2014.409

Cited by 8 publications

(2 citation statements)

References 7 publications

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“…These symptoms appear to be related to direct damage of the retinal pigment epithelial cells and adjacent photoreceptors by hsp90 inhibitors. It has been reported that hydrophilic agents, including luminespib, result in more sustained retinal exposure and slower exposure, leading to more pronounced visual symptoms than hydrophobic compounds [20]. We found these visual symptoms to be universally reversible when luminespib was held, and generally well-managed with dose interruptions.…”

Section: Discussionsupporting

confidence: 49%

Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions

et al. 2018

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Background: There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20.Patients and methods: Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting 3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype.Results: Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4-5.6) and median OS (mOS) was 13 months (95% CI 4.9-19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD 3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion:The study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted.Study registration (ClinicalTrials.gov): NCT01854034.

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Section: Discussionsupporting

confidence: 49%

Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions

et al. 2018

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“…The anti-α-enolase was found in the serum. Seventeen months after the cessation of AUY922 treatment the symptoms significantly improved, but there were still detectable irregularities within the ellipsoid zone and external limiting membrane in SD-OCT. 27 Audemard et al described a treatment option in the patients not responding to classical surgery and chemotherapy with metastatic melanoma presenting MAR. 24 The ipilimumab has been reported previously to improve survival in previously treated patients with metastatic melanoma and with MAR-like PVtR.…”

Section: Melanoma-associated Retinopathymentioning

confidence: 99%

Immunopathogenesis of ophthalmological paraneoplastic syndromes: Recent findings

Kordyś¹,

Przeździecka-Dołyk²,

Turno-Kręcicka³

et al. 2018

Adv Clin Exp Med

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The aim of this study was to summarize the current knowledge of paraneoplastic syndromes involving eyes. The main interest was the immunopathogenesis of the abovementioned entities. A web search was conducted using Medline, Web of Science and Scopus engines. Key words concerning ocular paraneoplastic syndromes (OPS) such as: "ocular paraneoplastic syndrome", "cancer-associated retinopathy", "cancer-associated cone dysfunction", "melanoma-associated retinopathy", "bilateral diffuse uveal melanocytic proliferation", and "paraneoplastic optic neuritis" were combined with "immunology", "immune response", "antibodies", or "autoantibodies". Numerous papers were found as a result of "ocular paraneoplastic syndrome" search and many of them matched the chosen criteria. We focused on the most recent papers -published in the last 5 years -and eventually, 92 items were found. Only several papers from each detailed category fulfilled both OPS and immunologic criteria. Site-specific paraneoplastic syndromes still remain a difficult clinical challenge. The immunopathogenesis of some of them seems to be more complex than previously thought.

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Luminespib

2014

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Luminespib Nyctalopia and retinopathy: case reportA man in his late seventies [age not stated] developed nyctalopia and retinopathy during treatment with luminespib [AUY922].The man, who had metastatic EGFR-mutated lung adenocarcinoma, was enrolled in a clinical trial of IV luminespib 25 mg/m 2 weekly, with erlotinib. A month after enrolment, he developed nyctalopia, which increased over the following 8 months. His visual acuity was 20/20, -2 in his right eye and 20/40, +2 in his left eye. Spectralis spectral-domain optical coherence tomography revealed loss of his ellipsoid zone and external limiting membrane. Electroretinography results were extinguished in the blue scotopic, and decreased in all modalities including the scotopic and photopic highintensity white. Anti-retinal antibody test results were positive for anti-α-enolase.Luminespib was withdrawn. The man's night vision had improved 3 weeks later, and his ellipsoid zone and external limiting membrane had partly recovered. Four months later, electroretinography revealed considerable recovery; anti-αenolase antibody remained. Eight months later, his visual acuity was normal, and more recovery of his photoreceptors had occurred. He had normal night vision 15 months after luminespib withdrawal, with integration of the ellipsoid zone and external limiting membrane; however, some ellipsoid zone irregularities remained.Author comment: "Retinal toxic effects have been reported for many drugs, particularly anticancer therapies.The HSP90 inhibitor AUY922, tested in several phase 1 and 2 trials, has been reported to induce reversible, dose-dependent photoreceptor damage and vision disturbances; up to 23% of participants developed nyctalopia and 14% developed photopsia or blurred vision." Munk MR, et al. Reversible nyctalopia and retinopathy in a patient with metastatic cancer treated with anti-heat shock protein 90 therapy. JAMA Ophthalmology 132: 899-901, No. 7, Jul 2014. Available from: URL: http://doi.

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Reversible Nyctalopia and Retinopathy in a Patient With Metastatic Cancer Treated With Anti–Heat Shock Protein 90 Therapy

Cited by 8 publications

References 7 publications

Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions

Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions

Immunopathogenesis of ophthalmological paraneoplastic syndromes: Recent findings

Luminespib

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