Neurological adverse effects due to programmed death 1 (PD-1) inhibitors
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Updated: Dec 22, 2025
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Published on: May 2, 2025
Siyu Shi1, Joseph Abi Jaoube1, Ruhi Kanwar1
1Department of Oncology, Stanford School of Medicine, Stanford, CA, USA.
Purpose:
PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab.
Methods:
We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12 months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method.
Results:
In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1 years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value < 0.001). Fifteen patients (88.2%) permanently stopped PD-1 therapy. In 8 patients, treatment termination resolved symptoms attributed to immune checkpoint blockade. The majority of patients developed grade 3 or 4 nAEs (10 patients, 58.8%), and required hospitalization (11 patients, 64.7%). Eight patients died for nAEs referable causes.
Conclusion:
Pembrolizumab and nivolumab are associated with the development of nAEs associated with increased risk of permanent discontinuation of treatment, hospitalization, and death. Melanoma patients might be at a particularly high risk of such side effects. Future studies are still required to better assess which patients benefit most from such therapies, while minimizing the risk of complications.
Insights
Programmed cell death protein 1 (PD-1) immunotherapy, including pembrolizumab and nivolumab, can cause serious neurological adverse events (nAEs). Melanoma patients may face a higher risk of these severe side effects, necessitating further research.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Cancer Treatment
Background:
- Programmed cell death protein 1 (PD-1) inhibitors are crucial in oncology.
- Neurological adverse events (nAEs) are known complications of PD-1 immunotherapy.
- Understanding the spectrum of nAEs is vital for patient safety.
Purpose of the Study:
- To identify the clinical spectrum of neurological adverse events (nAEs) associated with PD-1 inhibitors.
- To compare nAEs between pembrolizumab and nivolumab treatments.
- To analyze risk factors and outcomes of nAEs in cancer patients.
Main Methods:
- Retrospective cohort study of patients receiving pembrolizumab or nivolumab.
- Identification of patients who developed nAEs within 12 months of treatment.
- Descriptive statistics and comparative analysis (Chi-square or t-test).
Main Results:
- 17 out of 649 patients (2.6%) developed nAEs.
- Patients with pre-existing intracranial lesions had a higher risk of nAEs (76.5% vs 27.8%).
- Most nAEs were severe (Grade 3/4), leading to treatment discontinuation (88.2%), hospitalization (64.7%), and death (8 patients).
Conclusions:
- Pembrolizumab and nivolumab are linked to significant nAEs, increasing risks of treatment cessation, hospitalization, and mortality.
- Melanoma patients may be at elevated risk for these neurological complications.
- Further research is needed to optimize PD-1 inhibitor use and mitigate risks.
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