Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies

Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. We performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab monotherapy or concurrent with other immunologic agents, such as ipilimumab. Sixty-one publications on 85 patients (mean age 66.9 years [range 34-86]; male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD1 inhibitor treatment cycles prior to onset of symptoms was 3.6 (range 1-28). Symptoms included oculomotor (47%), respiratory (43%), bulbar (35%), and proximal weakness (35%), as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%), or a combination of these (16%). After a critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 25% of patients had signs of additional NMDs. Cardiac complications occurred in more than 30% of patients diagnosed with myasthenia gravis or myositis. Mortality was high in these patients, despite adequate treatment strategies including corticosteroid, IV immunoglobulins, and plasma exchange. The clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with considerable overlap between myasthenia gravis and myopathy, and cardiac/respiratory complications are common.