Immune checkpoint inhibitors (ICIs), which include antiprogrammed death 1 agents (such as cemiplimab, dostarlimab, nivolumab, and pembrolizumab), antiprogrammed death ligand-1 agents (such as atezolizumab, avelumab, and durvalumab), and the anticytotoxic T lymphocyte–associated antigen 4 agent, ipilimumab. ICIs block the inhibitory pathways of T-cell activation, which allows T cells to recognize tumor antigens to generate an antitumor immune response.
While this class of immunomodulatory agents has revolutionized the treatment of oncologic diseases, there is concern about its potential NAEs, which can be fatal. Yet, there is a paucity of information on the risk of neurologic adverse events (NAEs) associated with ICIs.
Researchers conducted a systemic review and meta-analysis of bibliographic databases (Embase, Ovid, MEDLINE, and Scopus) and a trial registry (Clinicaltrials.gov) from inception to March 1, 2020, to compare NAEs reported in randomized, controlled phase II and III clinical trials for ICIs, other forms of chemotherapy, and placebo. Studies included adult patients with any form of cancer treated by one of these agents. The intervention group included only ICIs, and the comparator group included drug regimens that used monotherapy or a combination of chemotherapy, targeted therapy, vaccines, or any medication used to treat cancer or placebo or supportive care groups.
Studies were searched for evidence of any grade NAEs including altered mentation, cerebral edema, cerebrovascular accident, cranial nerve VII palsy, decreased appetite, dizziness, dysgeusia, fatigue, headache, insomnia, intracranial hemorrhage, paraplegia, paresthesia, peripheral neuropathy (PN), seizures, and trigeminal nerve disorder, and for severe NAEs, which included Guillain-Barre syndrome (GBS), myasthenia gravis (MG), transverse myelitis, encephalitis, and meningitis.
The primary outcome was the assessment of NAEs of all grades in the ICI group compared with the control group.
A total of 39 trials representing 23,705 patients (13,110 patients in the control group and 10,595 in the ICI group) were included in this systematic review and meta-analysis. Among the cancers treated in these studies were melanoma, renal cell carcinoma, multiple myeloma, mesothelioma, and non-small cell lung, small cell lung, head and neck, colorectal, gastric, bladder, gastroesophageal junction, urothelial, and prostate cancers.
The investigators found that all-grade NAEs were significantly lower in the ICI group compared with those in the control group (15.0% vs. 19.9%, risk ratio [RR] 0.59, 95% CI 0.45-0.77, P <.001). The particular NAEs that were found to be significantly lower in the ICI group than in the controls were peripheral neuropathy, headache, and dysgeusia. Other NAEs that occurred with similar frequency between the control group and the ICI group included dizziness, altered mental status, paresthesia, and insomnia.
A subgroup analysis found that the overall risk of NAE was 78% lower in the ICI group than in the chemotherapy arm (RR 0.22, 95% CI 0.13-0.39, P <.001). Particularly noted was a significantly reduced rate of PN, dysgeusia, and paresthesia in the ICI group. However, the risk of headache, insomnia, and dizziness were similar between the groups.
When compared with placebo, ICIs were associated with a 1.57-fold higher rate of NAEs (17.5% in the ICI group vs. 12.4% in the placebo group, RR 1.57, 95% CI 1.30-1.89, P = .25). In particular, headache was more frequent in the ICI group. Despite a P value of >.5, the authors stated that the results are considered statistically significant because the confidence intervals serve as a superior measure of significance since there were few studies in the meta-analysis.
Severe NAEs such as MG or GBS occurred rarely and were not analyzed further.
This study provides reassuring information for pharmacists who care for patients receiving ICIs that NAEs are occur less frequently in patients treated with ICIs than with other standard chemotherapeutic modalities. Further, the occurrence of severe NAEs was uncommon.
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