Unusual Adverse Events in a Patient With BRAF-Mutated Non-Small Cell Lung Cancer Treated With BRAF/MEK Inhibition.

BRAF/MEK inhibition remains standard of care for treatment of BRAF-mutated non-small cell lung cancer (NSCLC). Although common adverse events (AEs) have been reported through clinical trials and ongoing clinical practice, only a handful of reports have detailed unusual adverse events associated with these medications. This report presents a patient with BRAF-mutated NSCLC treated with dabrafenib and trametinib who experienced 2 unusual AEs-Sweet syndrome and MEK-associated retinopathy-that responded to steroid treatment. The patient was able to continue BRAF/MEK inhibition through a coordinated multidisciplinary approach. This case highlights the importance for all clinicians to recognize unusual AEs associated with BRAF/MEK inhibition, particularly in the setting of expanded use for all BRAF V600E-mutated solid tumors.

A Phase 3b Study for Management of Ocular Side Effects in Patients with Epidermal Growth Factor Receptor-Amplified Glioblastoma Receiving Depatuxizumab Mafodotin.

INTRODUCTION: The Understanding New Interventions with GBM ThErapy (UNITE) study was designed to assess the effect of prophylaxis for ocular side effects (OSEs) in patients with glioblastoma receiving the antibody-drug conjugate (ADC) depatuxizumab mafodotin. UNITE (NCT03419403) was a phase 3b, open-label, randomized, exploratory study performed at 18 research sites in 5 countries. METHODS: The study enrolled adult patients with epidermal growth factor receptor-amplified, histologically confirmed, newly diagnosed supratentorial glioblastoma or grade IV gliosarcoma, and a Karnofsky Performance Status ≥70, receiving depatuxizumab mafodotin. All patients were administered depatuxizumab mafodotin during concurrent radiotherapy and temozolomide and with adjuvant temozolomide. Ninety patients were to be randomized (1:1:1) to OSE prophylactic treatments with each depatuxizumab mafodotin infusion: (a) standard steroid eye drops, (b) standard steroid eye drops plus vasoconstrictor eye drops and cold compress, or (c) enhanced steroids plus vasoconstrictor eye drops and cold compress. A Corneal Epitheliopathy Adverse Event (CEAE) scale was devised to capture symptoms, grade OSEs (scale of 0-5), and inform ADC dose modifications. The primary endpoint was the frequency of a required change in OSE management due to inadequate control of OSEs, defined as decline from baseline in visual acuity (using logarithm of the minimum angle of resolution [LogMAR] scale) or a Grade ≥3 CEAE event, in the worst eye in the first 8 weeks of treatment; unless otherwise specified, the treatment period refers to both the chemoradiation and adjuvant phases. RESULTS: The UNITE study was stopped early after interim analysis of separate phase III trial showed no difference in survival from depatuxizumab mafodotin. Forty patients were randomized (38 received depatuxizumab mafodotin). Overall, 23 patients experienced inadequate control of OSEs that required change in OSE management within 8 weeks of treatment, with 21 (70.0%) experiencing ≥+0.3 change on LogMAR scale in baseline-adjusted visual acuity and 12 reporting a grade ≥3 CEAE. There were no definitive differences among prophylactic treatments. CONCLUSIONS: The premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs.

Delayed-Onset Cranial Nerve Palsy After Transvenous Embolization of Indirect Carotid Cavernous Fistulas.

BACKGROUND: Carotid cavernous fistulas (CCF) often present with diplopia secondary to cranial nerve palsy (CNP). Immediate development of postoperative CNP has been described in the literature. This study described delayed-onset of CNP after complete and reconfirmed obliteration of the CCF and resolution of initial CNP. METHODS: A retrospective analysis was performed on patients with indirect CCF between 1987 and 2006 at 4 academic endovascular centers. Details of the endovascular procedures, embolic agents used, and complications were studied. Partial or complete obliteration was determined. Immediate and delayed cranial nerve palsies were independently assessed. RESULTS: A total of 267 patients with symptomatic indirect CCF underwent transvenous endovascular treatment. Four patients (1.5%) developed delayed abducens nerve (VI) palsy after complete resolution of presenting symptoms after embolization. Delayed presentation ranged between 3 and 13 months after complete resolution of initial double vision and cranial nerve palsies. Transvenous coil embolization through the inferior petrosal sinus was performed in all 4 affected patients. All had follow-up angiography confirming durable closure of their CCF. MRI did not show new mass lesions or abnormal soft tissue enhancement. In all 4 patients, their abducens nerve (VI) palsy remained. CONCLUSIONS: Delayed CNP can develop despite complete endovascular obliteration of the CCF. The cause of delayed CNP is not yet determined, but may represent fibrosis and ischemia. Long-term follow-up is needed even after complete neurological and radiological recovery is attained in the immediate perioperative period.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Asymmetric optic disc edema in a young patient with POEMS: A rare presentation of a rare disease.

PURPOSE: To describe a case of asymmetric optic disc edema presenting as the initial ocular feature of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome. OBSERVATIONS: A 29-year-old female patient presented with 3 weeks history of blurred vision, proptosis, and peripheral neuropathy as well as hypothyroidism. Fundoscopy revealed optic disc edema associated with visual loss in the left eye. Following a computed tomography (CT) scan and a positron emission tomography/CT (PET/CT) scan which respectively revealed hepatomegaly and multiple osteosclerotic lesions, as well as laboratory findings of monoclonal gammopathy and elevated vascular endothelial growth factor (VEGF) levels, she was diagnosed with POEMS syndrome. After treatment with an autologous stem cell transplant, the optic disc edema and blurred vision resolved. CONCLUSIONS AND IMPORTANCE: The most reported ocular manifestation of POEMS syndrome, a rare and complex multisystem disorder, is bilateral optic disc edema that typically occurs in older males. Therefore, this report presents an uncommon case of asymmetric optic disc edema in a younger, female patient.

Real-Time Mobile Teleophthalmology for the Detection of Eye Disease in Minorities and Low Socioeconomics At-Risk Populations.

PURPOSE: To examine the benefits and feasibility of a mobile, real-time, community-based, teleophthalmology program for detecting eye diseases in the New York metro area. DESIGN: Single site, nonrandomized, cross-sectional, teleophthalmologic study. METHODS: Participants underwent a comprehensive evaluation in a Wi-Fi-equipped teleophthalmology mobile unit. The evaluation consisted of a basic anamnesis with a questionnaire form, brief systemic evaluations and an ophthalmologic evaluation that included visual field, intraocular pressure, pachymetry, anterior segment optical coherence tomography, posterior segment optical coherence tomography, and nonmydriatic fundus photography. The results were evaluated in real-time and follow-up calls were scheduled to complete a secondary questionnaire form. Risk factors were calculated for different types of ophthalmological referrals. RESULTS: A total of 957 participants were screened. Out of 458 (48%) participants that have been referred, 305 (32%) had glaucoma, 136 (14%) had narrow-angle, 124 (13%) had cataract, 29 had (3%) diabetic retinopathy, 9 (1%) had macular degeneration, and 97 (10%) had other eye disease findings. Significant risk factors for ophthalmological referral consisted of older age, history of high blood pressure, diabetes mellitus, Hemoglobin A1c measurement of ≥6.5, and stage 2 hypertension. As for the ocular parameters, all but central corneal thickness were found to be significant, including having an intraocular pressure >21 mm Hg, vertical cup-to-disc ratio ≥0.5, visual field abnormalities, and retinal nerve fiber layer thinning. CONCLUSIONS: Mobile, real-time teleophthalmology is both workable and effective in increasing access to care and identifying the most common causes of blindness and their risk factors.

Evaluation of a Deep Learning System For Identifying Glaucomatous Optic Neuropathy Based on Color Fundus Photographs.

PRECIS: Pegasus outperformed 5 of the 6 ophthalmologists in terms of diagnostic performance, and there was no statistically significant difference between the deep learning system and the "best case" consensus between the ophthalmologists. The agreement between Pegasus and gold standard was 0.715, whereas the highest ophthalmologist agreement with the gold standard was 0.613. Furthermore, the high sensitivity of Pegasus makes it a valuable tool for screening patients with glaucomatous optic neuropathy. PURPOSE: The purpose of this study was to evaluate the performance of a deep learning system for the identification of glaucomatous optic neuropathy. MATERIALS AND METHODS: Six ophthalmologists and the deep learning system, Pegasus, graded 110 color fundus photographs in this retrospective single-center study. Patient images were randomly sampled from the Singapore Malay Eye Study. Ophthalmologists and Pegasus were compared with each other and to the original clinical diagnosis given by the Singapore Malay Eye Study, which was defined as the gold standard. Pegasus' performance was compared with the "best case" consensus scenario, which was the combination of ophthalmologists whose consensus opinion most closely matched the gold standard. The performance of the ophthalmologists and Pegasus, at the binary classification of nonglaucoma versus glaucoma from fundus photographs, was assessed in terms of sensitivity, specificity and the area under the receiver operating characteristic curve (AUROC), and the intraobserver and interobserver agreements were determined. RESULTS: Pegasus achieved an AUROC of 92.6% compared with ophthalmologist AUROCs that ranged from 69.6% to 84.9% and the "best case" consensus scenario AUROC of 89.1%. Pegasus had a sensitivity of 83.7% and a specificity of 88.2%, whereas the ophthalmologists' sensitivity ranged from 61.3% to 81.6% and specificity ranged from 80.0% to 94.1%. The agreement between Pegasus and gold standard was 0.715, whereas the highest ophthalmologist agreement with the gold standard was 0.613. Intraobserver agreement ranged from 0.62 to 0.97 for ophthalmologists and was perfect (1.00) for Pegasus. The deep learning system took ∼10% of the time of the ophthalmologists in determining classification. CONCLUSIONS: Pegasus outperformed 5 of the 6 ophthalmologists in terms of diagnostic performance, and there was no statistically significant difference between the deep learning system and the "best case" consensus between the ophthalmologists. The high sensitivity of Pegasus makes it a valuable tool for screening patients with glaucomatous optic neuropathy. Future work will extend this study to a larger sample of patients.