Retrospective Data Show Feasibility of Checkpoint Inhibition in Patients With Cancer and Neurologic Autoimmune Disorders

Findings from a retrospective cohort study demonstrated that immune checkpoint inhibitors may be viable treatment options in appropriate indications for patients with cancer who have pre-existing neurologic autoimmune disorders (NAIDs).

Data published in JAMA Network Open showed that neurologic disease exacerbation was most common among patients with pre-existing myasthenia gravis (MG; n = 18), occurring in 67% of patients. In this subgroup, all instances of exacerbation were due to new inflammatory disease; other neurologic immune-related adverse effects (irAEs) occurred in 17% of patients with MS; 33% of patients required hospitalization, 39% of patients needed steroids for their NAID, 44% of patients had non-neurologic irAEs, and 11% of patients died due to neurologic events.

However, rates of neurologic disease exacerbation were lower among patients with other pre-existing NAIDs, including 18% for patients with multiple sclerosis (MS; n = 45), 21% for patients with Parkinson’s disease (PD; n = 57), and 0% for those with Guillain-Barré syndrome (GBS; n = 10) and those with other NAIDs (n = 5). In the MS cohort, 25% of patients (n = 8) experienced exacerbation due to new inflammatory disease, and the remaining 75% of exacerbation events were due to recrudescence. All instances of disease exacerbation in the PD cohort (n = 12) were due to recrudescence. Hospitalization was required for 4% of patients in the MS cohort, 20% of patients in the GBS cohort, 4% of patients in the PD cohort, and 0% of patients in the other cohort. The rates of death due to neurologic events were 2%, 10%, 0%, and 0%, respectively.

Regarding efficacy, progression-free survival (PFS) and overall survival (OS) outcomes did not vary between the subgroups, and differences in overall response rates (ORRs) were not statistically significant. Notably, statistically significant differences were not observed for PFS (HR, 0.87; 95% CI, 0.56-1.34; P = .65), OS (HR, 0.81; 95% CI, 0.50-1.31; P = .40), and non-neurologic irAEs (P = .94) for patients with PD vs those with any other NAID, although PFS and OS were numerically lowest in the PD group. The median PFS was 9.1 months for those with PD vs 12.9 months for those with any other NAID; the median OS was 18.7 months vs 33.5 months, respectively, and the respective rates of non-neurologic irAEs were 44% and 43%.

“To our knowledge, this study is the largest to characterize the safety and clinical outcomes of immune checkpoint inhibitors in patients with an NAID. We observed that exacerbations of NAID in patients receiving immune checkpoint inhibitors varied significantly between different underlying disease states,” lead study author Kylie Fletcher, BS, of the Vanderbilt School of Medicine in Nashville, Tennessee, and colleagues wrote in the publication. “Patients with MG had high rates of exacerbations [often clinically severe] with less frequent exacerbations in other disease cohorts. Additionally, clinical outcomes associated with immune checkpoint inhibitor therapy did not vary by pre-existing NAID, and durable responses were observed in some patients.”

Rationale Behind the Retrospective Study

Although immune checkpoint inhibitors have become part of the standard of care in multiple solid tumor and hematologic malignancies, prospective clinical trials evaluating these agents have generally excluded patients with pre-existing NAIDs. Past studies have demonstrated that patients with autoimmune diseases have generally been able to tolerate immune checkpoint inhibition, but clinicians lack data on the use of these agents in patients with pre-existing NAIDs.

“Exacerbations of an NAID can pose life-threatening risks in many disorders…with reports suggesting frequent flares in patients receiving immune checkpoint inhibitors,” study authors wrote. “Furthermore, patients with NAIDs may be at higher risk of neurologic irAEs. However, NAIDs encompass a range of disorders that greatly vary in their underlying pathophysiology and clinical manifestations, and which evolve over a patient’s lifetime.”

To further assess the safety and efficacy of immune checkpoint inhibition in patients with pre-existing NAIDs, investigators conducted the retrospective, multicohort study by pulling patient data from 9 institutional databases. They included patients with MS, MG, and GBS; patients with transverse myelitis, nonparaneoplastic Lambert-Eaton myasthenic syndrome, or multifocal motor neuropathy were grouped into the other NAIDs cohort due to small sample sizes. A control group of patients with PD was also identified. Notably, investigators excluded patients with pre-existing paraneoplastic neurologic disease.

All patients included received at least 1 dose of an immune checkpoint inhibitor–containing regimen and were evaluable for efficacy and safety outcomes.

The primary objectives of the study included ORR and PFS per RECIST 1.1 criteria; OS; the incidence of irAEs; and the rate of exacerbation of pre-existing NAIDs.

Study Limitations and Clinical Implications

Authors noted that the study was limited by its retrospective nature and small numbers within each individual cohort. They also explained that the NAID exacerbation can also occur in conjunction with other irAEs and disease progression, which can make symptom attribution difficult in some instances. The study may have also missed patients with severe or aggressive pre-existing NAIDs, who may have forgone immune checkpoint inhibition due to concerns regarding disease exacerbation.

Given these results, study authors explained that close monitoring is required for patients with NAIDs when immune checkpoint inhibition is considered, and collaboration between oncology and neurology specialists is key for risk stratification, disease assessment, and treatment optimization.

“Ongoing multidisciplinary care may help minimize the effects of potential disease exacerbations. Immune checkpoint inhibitor therapy can be considered in cases of preexisting NAID on a case-by-case basis and requires a careful risk benefit discussion,” study authors concluded.

Reference

Fletcher K, Machaalani M, El Hajj Chehade R, et al. Immune checkpoint inhibitors for patients with preexisting autoimmune neurologic disorders. JAMA Netw Open. 2025;8(6):e2513727. doi:10.1001/jamanetworkopen.2025.13727