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

Abstract

<div class="section"> <a class="named-anchor" id="ab-noi170052-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e383">Question</h5> <p id="d7290510e385">What are the frequency and characteristics of neurological complications from anti–programmed death 1 (PD-1) antibody use? </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e388">Findings</h5> <p id="d7290510e390">Among 347 patients treated with anti–programmed death 1 (PD-1) antibody use (pembrolizumab or nivolumab), this cohort study supports a low frequency (2.9%) of neurological complications associated with anti–PD-1 therapy. The range and severity of complications are diverse, including necrotizing myopathy, various neuropathies, cerebellar ataxia, internuclear ophthalmoplegia, retinopathy, and headache; the median modified Rankin Scale score of 2.5 indicates mild to moderate disability. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e393">Meaning</h5> <p id="d7290510e395">Subacute presentation of neurological symptoms in a patient receiving anti–PD-1 therapy should prompt consideration of an association and discontinuation of anti–PD-1 antibody use and possible treatment with corticosteroids or other immune treatment depending on the severity. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e399">Importance</h5> <p id="d7290510e401">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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e404">Objective</h5> <p id="d7290510e406">To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 therapy. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e409">Design, Setting, and Participants</h5> <p id="d7290510e411">This 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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e414">Main Outcomes and Measures</h5> <p id="d7290510e416">Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e419">Results</h5> <p id="d7290510e421">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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi170052-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d7290510e424">Conclusions and Relevance</h5> <p id="d7290510e426">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. In some cases, immune rescue treatment may be required. </p> </div><p class="first" id="d7290510e429">This cohort study investigates the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 inhibitor use. </p>