Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

Abstract

IMPORTANCE Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.OBJECTIVE To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTSThis single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.MAIN OUTCOMES AND MEASURES Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.RESULTS Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.CONCLUSIONS AND RELEVANCE Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended....

Clinical Experience of Immunotherapy Treatment: Efficacy and Toxicity Analysis of the Compassionate Use Program of Nivolumab in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer

“…In addition, we discovered other single cases of very rare AEs in our cohort. Cases of rhabdomyolysis [21] or Guillain-Barré syndrome [22] following nivolumab treatment have already been reported, but these are known neurological complications of PD-1 antibodies and rare AEs of immunotherapy treatment [23]. Many results concerning safety data between the phase 3 study of Brahmer et al [10] and our study are similar; however, the frequency of severe AEs was different.…”

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

“…Although neurological irAEs (irAE‐Ns) are rare, they can be severe and even fatal. Although short courses of prednisone started after ICI infusion do not appear to reverse the antitumor effect of the ICI, the influence of immunosuppression for irAEs or longer courses of steroids on cancer outcomes remains unknown . Clinical phenotypes, including encephalitis, neuropathies, myasthenia gravis (MG), and myositis, are described in small case series or case reports .…”

“…Clinical phenotypes, including encephalitis, neuropathies, myasthenia gravis (MG), and myositis, are described in small case series or case reports . However, these reports have generally been limited to single malignancies (melanoma) and/or ICI class (anti–PD‐1 antibodies) . Other studies have reported clinical presentation of MG among patients treated with either nivolumab or ipilimumab monotherapy utilizing pharmaceutical company postmarketing surveillance databases .…”

“…However, these reports have generally been limited to single malignancies (melanoma) and/or ICI class (anti–PD‐1 antibodies) . Other studies have reported clinical presentation of MG among patients treated with either nivolumab or ipilimumab monotherapy utilizing pharmaceutical company postmarketing surveillance databases . Because irAE‐N may present atypically with overlapping neurological manifestations and cancer, mortality and quality of life outcomes of currently recommended treatments are unknown; comprehensive phenotypic characterization and additional real‐world outcome data with longitudinal follow‐up are needed.…”

Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia

“…9,11 Neurologic complications of checkpoint inhibitor therapies are also increasingly recognized, including headache, seizures, cranial neuropathies, and polyneuropathy. 12 A recent report 13 found that 2.9% of a 347-patient cohort treated with anti-PD1 therapy developed neurologic complications (predominantly myopathies and neuropathies). Cerebral vasculitis has been reported as a result of PD-1 inhibition in a recent case report.…”