Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years

Abstract

Although the immunotherapy advent has revolutionized cancer treatment, it, unfortunately, does not spare cancer patients from possible immune-related adverse events (irAEs), which can also involve the peripheral nervous system. Immune checkpoint inhibitors (ICIs), blocking cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), can induce an immune imbalance and cause different peripheral neuropathies (PNs). Considering the wide range of PNs and their high impact on the safety and quality of life for cancer patients and the availability of large post-marketing surveillance databases, we chose to analyze the characteristics of ICI-related PNs reported as suspected drug reactions from 2010 to 2020 in the European real-world context. We analyzed data collected in the European pharmacovigilance database, Eudravigilance, and conducted a systematic and disproportionality analysis. In our study, we found 735 reports describing 766 PNs occurred in patients treated with ICIs. These PNs included Guillain-Barré syndrome, Miller-Fisher syndrome, neuritis, and chronic inflammatory demyelinating polyradiculoneuropathy. These ADRs were often serious, resulting in patient disability or hospitalization. Moreover, our disproportionality analysis revealed an increased reporting frequency of PNs with tezolizumab compared to other ICIs. Guillain-Barré syndrome is a notable potential PN related to ICIs, as it is associated with a significant impact on patient safety and has had unfavorable outcomes, including a fatal one. Continued monitoring of the safety profile of ICIs in real-life settings is necessary, especially considering the increased frequency of PNs associated with atezolizumab compared with other ICIs.

Keywords: immune checkpoint inhibitors; immune-related adverse events; immunotherapy; neurological toxicity; peripheral neuropathies; post-marketing surveillance; translational research.

Figure 1

The mechanism of action of ICIs and possible associated neuropathies.

Figure 2

Drugs reported as concomitants in the Individual Case Safety Reports (ICSRs) collected in Eudravigilance, categorized by therapeutic reference class (Level II ATC). A02, Antacids; A03, Combinations of psycholeptics and antispasmodics; A04, Antiemetics and antinausea; A05, Biliary and hepatic therapy; A06, Drugs for constipation; A07, Antidiarrheals, anti-inflammatory/anti-infective agents; A10, Drugs used in diabetes; A11, Vitamins; A12, Mineral supplements; B01, Antithrombotic agents; B02, Antihemorrhagics; B03, Antianemic preparations; B05, Blood substitutes and perfusion solutions; C01, Cardiac therapy; C02, Antihypertensives; C03, Diuretics; C05, Vasoprotectives; C07, Beta blocking agents; C08, Calcium channel blockers; C09, Agents acting on the renin–angiotensin; C10, Lipid modifying agents; D07, Corticosteroids. dermatological preparations; D10, Anti-acne preparations; D11, Other dermatological preparations; G01, Gynecological anti-infectives and antiseptics; G02, Other gynecologicals; G03, Sex hormones and modulators of the genital system; G04, Urologicals; H02, Corticosteroids for systemic use; H03, Thyroid therapy; H04, Pancreatic hormones; J01, Antibacterials for systemic use; J02, Antimycotics for systemic use; J05, Antivirals for systemic use; J06, Immune sera and immunoglobulins; L01, Antineoplastic agents; L02, Endocrine therapy; L03, Immunostimulants; L04, Immunosuppressants; M01, Anti-inflammatory and antirheumatic products; M02, Topical products for joint and muscular pain; M03, Muscle relaxants; M04, Antigout preparations; M05, Drugs for treatment of bone diseases; N01, Anesthetics; N02, Analgesics; N03, Antiepileptics; N04, Anti-Parkinson drugs; N05, Psycholeptics; N06, Psychoanaleptics; R01, Nasal preparations; R02, Throat preparations; R03, Drugs for obstructive airway diseases; R05, Cough and cold preparations; R06, Antihistamines for systemic use; S01, Ophthalmologicals; V01, Allergens; V03, All other therapeutic products; V04, Diagnostic agents. Six drugs (0.5%) reported as concomitant were officinal drugs.

Figure 3

Reporting odds ratio (ROR) for disproportionality analysis of the most frequently reported peripheral neuropathies as suspected ADRs associated with ICIs. ROR was performed for the following p-term “neuropathy peripheral” (A), “Guillain-Barre syndrome” (B) and “demyelinating polyneuropathy” (C).