Clinical and Morphologic Characteristics of Fibroblast Growth Factor Receptor Inhibitor–Associated Retinopathy

Abstract

IMPORTANCE Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor-associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy.OBJECTIVE To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors. DESIGN, SETTING, AND PARTICIPANTSIn this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021. MAIN OUTCOMES AND MEASURES Characteristics of treatment-emergent choroidal and retinalOCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution.RESULTS A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor-associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was −0.1 (−0.2 to −0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (−0.03 to 0). No patient discontinued drug therapy on account of their retinopathy.CONCLUSIONS AND RELEVANCE FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

Favorable Management of Repeated Serous Retinal Detachment with Continued Tumor Response in a Patient with Intrahepatic Cholangiocarcinoma during Treatment with Pemigatinib

“…SRD is also reported in patients treated with targeted therapies, such as MEK inhibitors, which modulate the MAPK pathway, causing eye disorders such as retinal detachment (at frequencies ranging from 5% to 38%) ( 15 ). Similar to MEK inhibitor-associated retinopathy, pemigatinib-induced retinopathy showed no substratum changes, including a distinguishable RPE, interdigitation zone (IZ), and ellipsoid zone (EZ) after fluid disappearance, unlike central serous chorioretinopathy, which is usually accompanied by hyperreflective foci, loss of hyperreflective IZ and EZ, and disturbed RPE after resolution ( 20 ). These tyrosine kinase inhibitor-related ocular toxicities are easily manageable in the clinical setting as they are immediately identified by patients and straightforward to confirm by prompt ophthalmic examination at the time of the first visual disturbance.…”

Serous Retinopathy Associated With Combination MEK and Fibroblast Growth Factor Receptor Inhibitor

“…7 A similar retinopathy has been more recently described among inhibitors of the upstream target, FGFR. 8,9 The majority of previous reports largely involved patients who had routine asymptomatic screening after initiation of treatment; in most cases the treatment is continued despite the presence of mild retinal dysfunction, which often resolves over time. 8,10 In our case, the patient became profoundly symptomatic with large areas of subfoveal fluid bilaterally as well as multifocal pockets of SRF.…”

“…8,9 The majority of previous reports largely involved patients who had routine asymptomatic screening after initiation of treatment; in most cases the treatment is continued despite the presence of mild retinal dysfunction, which often resolves over time. 8,10 In our case, the patient became profoundly symptomatic with large areas of subfoveal fluid bilaterally as well as multifocal pockets of SRF. Alekseev et al 11 reported a patient who developed similar OCT findings after treatment of pemigatinib, another small molecule inhibitor of FGFR.…”

Mitogen-Activated Pathway Kinase Inhibitor-Associated Retinopathy: Do Features Differ with Upstream versus Downstream Inhibition?

“…Additional demographics and patient-specific data were extracted retrospectively under an IRB approved protocol. One-hundred twentyeight eyes exhibited subretinal fluid on optical coherence tomography (OCT; previously published [7][8][9]) and were compared in the present study.…”

“…In an effort to better understand this topic, this study systematically compared drug-induced retinopathy observed in patients undergoing FGFR, MEK, or ERK inhibitor treatment within prospective clinical trials. Data were pooled from previously published series on FGFR, MEK, or ERK inhibitor retinopathy [7][8][9] to explore differences among drug types with the intent of bringing ophthalmologists and oncologists a step forward to better balance benefits and harms of these drugs. In the present study, clinical and morphological characteristics were compared across patients receiving FGFFR, MEK, or ERK inhibition, along with the associated retinal, RPE, and choroidal changes of the fluid foci that were then compared with the drug-induced retinopathy.…”