Background: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. Methods: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC 025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14. 5-18.9]; IC 025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 025 3.15), peripheral neuropathy (1. 16% vs. 0.67%, IC 025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping. Conclusions: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

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BackgroundImmune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown.MethodsWe performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity.ResultsAmong 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS).ConclusionsBody composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Amgen and Merck.Dr. Genevieve M. Boland has a sponsored research agreements with Takeda Oncology, Palleon Pharmaceuticals, InterVenn Biosciences, and Olink Proteomics; serves as a consultant for Merck, InterVenn Biosciences, and Ankyra Therapeutics; served as a speaker for Novartis; and served on a scientific advisory board and steering committee for Nektar Therapeutics.All remaining authors have declared no conflicts of interest.

Immune checkpoint inhibitors block key mediators of immune tolerance, producing antitumor responses and autoimmunelike toxic effects. 1 Toxic effects indicate immune activation against host tissues, although it remains controversial whether this offtarget activity indicates concurrent antitumor immunity. [2][3][4] Herein, we retrospectively studied whether cutaneous toxic effects correlated with outcomes in patients with advanced melanoma treated with immune checkpoint inhibitors.Methods | We reviewed electronic medical records of patients treated with anti-programmed cell death 1 (anti-PD-1) with or without ipilimumab from a single center. We assessed demographics, cutaneous toxic effects, steroid administration, and outcomes by retrospective review. The Vanderbilt University Medical Center institutional review board approved the study, with a waiver of patient consent.Results | Among 318 patients (202 men [63%]; median [range] age, 63 [22-89] years) from a single center, 120 (38%) who developed cutaneous toxic effects were more likely to have received combination ipilimumab-nivolumab; had similar age, sex, stage, lactate dehydrogenase (LDH) levels; and had prior systemic therapies, including immune or targeted therapies, compared with those without cutaneous toxic effects (Table ). Patients with cutaneous toxic effects had superior response rate (RR) (60.0% vs 28.6%; χ 2 P < .001), progression-free survival (PFS) (median, 797 vs 112 days; log rank P < .001), and overall survival (OS) (median, 1691 vs 526 days; P < .001) (Figure, A)

Background Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life‐threatening immune‐related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies. Case Presentation We describe herein a patient with metastatic melanoma who developed epididymo‐orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo‐orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad‐spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next‐generation sequencing assay, was negative. He received high‐dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5‐week taper of oral steroids. Discussion Here, we report a case of epididymo‐orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents. Key Points Epididymo‐orchitis is a rare and potentially life‐threatening complication of anti‐programmed death protein 1 (anti‐PD‐1) therapy. For patients on anti‐PD‐1 therapy who develop either epididymo‐orchitis or epididymitis without clear infectious cause, immune‐related adverse events should be considered in the differential diagnosis. If severe, epididymo‐orchitis related to anti‐PD‐1 therapy may be treated with high‐dose corticosteroids.

Conflicts of interest statements can be found in Appendix 1. Data availabilityDeidentified patient data will be made available upon reasonable request when legally and ethically possible. Ethics statementThis study was conducted in compliance with local institutional review board policies.X.B. and A.N.S. contributed equally.

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