# Immune-Related Adverse Events in Anti–PD-1 Therapy

## What immune-related adverse events are associated with anti–PD-1 therapy and how are they managed?

Anti-PD-1 therapy is associated with immune-related adverse events (irAEs) affecting 38-69% of patients, primarily in endocrine, gastrointestinal, dermatologic, pulmonary, and hepatic systems. Common irAEs include thyroiditis (4-34%), colitis (2.8-22%), rash (1-18%), pneumonitis (3-13%), and hepatotoxicity (0.8-11%). Most irAEs are mild to moderate (grade 1-2), with grade 3-4 events occurring in approximately 7-20% of patients. While most irAEs develop within 12-14 weeks of treatment initiation, delayed onset beyond 12 months occurs in 5.3% of patients. Corticosteroids at 1-2 mg/kg/day manage irAEs, with approximately 80% resolving in a median of 5 weeks. Treatment modifications include temporary holds for grade 2 toxicity and permanent discontinuation for grades 3-4, affecting 14-15% of patients. Successful management depends on early recognition, multidisciplinary collaboration, and systematic monitoring protocols.

## Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria, focusing on PD-1 therapy population, approved PD-1 inhibitors, irAE reporting, management strategies, and study design.

## Results

### Characteristics of Included Studies

The review included 10 sources examining immune-related adverse events associated with anti-PD-1 therapy, with sample sizes ranging from 27 to 999 patients. Most studies focused on melanoma or lung cancer populations.

### Anti-PD-1 Agents and Treatment Regimens

Primary anti-PD-1 agents examined were nivolumab and pembrolizumab, with regimens including nivolumab 3 mg/kg IV every 2 weeks and pembrolizumab at 2 or 10 mg/kg every 3 weeks.

### Incidence and Spectrum of Immune-Related Adverse Events

The incidence of any irAE varied across studies: 69.0% of patients experienced acute irAEs during treatment, while 38% were noted by Iacono et al. in their study.

#### Organ System Involvement and Specific irAEs
| Organ System  | Specific irAEs | Incidence     | Severity       | Time to Onset   | Source  |
|---------------|----------------|---------------|----------------|-----------------|---------|
| Endocrine     | Thyroiditis    | 4-7%          | Typically grade 1-2 | 9-12 weeks     | O’Kane et al., Weber et al. |
| Gastrointestinal | Colitis       | 14%           | Grade 3-4 common  | ~7 weeks         | Weber et al., Iacono et al. |
| Dermatologic  | Rash           | 18%           | Variable       | ~2 weeks         | Weber et al., Iacono et al. |
| Pulmonary     | Pneumonitis    | 3%            | High-grade     | 15.1-31.1 weeks median | Weber et al., O’Kane et al. |
| Hepatic       | Hepatotoxicity | 2.3% (nivolumab) | High-grade   | 9-12 weeks        | Weber et al., O’Kane et al. |

### Management of Immune-Related Adverse Events

Corticosteroids at 1-2 mg/kg/day are the primary immunosuppressive treatment. Supportive measures include hydration, loperamide for diarrhea, and hospitalization for grade 3 or higher irAEs. Early initiation of steroid treatment has proven effective in mitigating serious gastrointestinal irAEs.

### Treatment Outcomes

Resolution rates and times varied by irAE type. Approximately 80% resolved within a median of 5 weeks with standard management. Fatal irAEs were uncommon but documented, with some patients experiencing chronic impairments. Importantly, steroid treatment did not affect the efficacy of PD-1 inhibitors, and early management facilitated resumption of therapy and maintained disease control.

## Conclusion

The incidence and management of irAEs associated with anti-PD-1 therapy highlight a complex interplay between immune activation and potential adverse effects. A need for continued vigilance and systematic approaches to monitoring and managing these events is essential for optimizing patient outcomes in immunotherapy.