# 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 affecting the endocrine, gastrointestinal, dermatologic, pulmonary, and hepatic systems in 38-69% of patients, managed primarily with corticosteroids at 1-2 mg/kg/day that resolve approximately 80% of cases within 5 weeks, with treatment holds or discontinuation for higher-grade toxicities.

## Abstract

Anti-PD-1 therapy is associated with immune-related adverse events (irAEs) affecting 38-69% of patients, involving primarily the 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, and chronic irAEs persisting beyond 12 weeks after treatment cessation develop in 43.2% of patients, with 85.6% persisting at last follow-up. Endocrinopathies (83%), neurotoxicities (73%), and arthritis (49%) are particularly likely to become chronic.

## Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

## Results

### Characteristics of Included Studies

The review included 10 sources examining immune-related adverse events associated with anti-PD-1 therapy. Study designs varied from retrospective case series to reviews of clinical trial data, with sample sizes ranging from 27 to 999 patients.

#### Study Design Recap
| Study | Full Text Retrieved? | Study Type | Sample Size | Cancer Type(s) | Follow-up Duration | irAE Grading System |
|-------|---------------------|------------|-------------|-----------------|--------------------|---------------------|
| T. Eigentler et al., 2016 | No | Retrospective analysis of pooled trial data | Not specified | Multiple malignancies | Not specified | Not specified |
| J. Weber et al., 2016 | Yes | Review article | Not specified | Advanced melanoma, NSCLC, renal cell carcinoma | Most grade 3/4 irAEs occur within 12-14 weeks | CTCAE v4.03 |
| G. O’Kane et al., 2017 | Yes | Review of phase III trials | Data from multiple trials | Metastatic NSCLC | Every 12 weeks up to 1 year post-discontinuation | CTCAE v4.0 |
| J. Patrinely et al., 2021 | No | Retrospective multicenter cohort | 387 | Stage III-IV melanoma | Beyond 12 weeks post-discontinuation | Not specified |
| L. Hofmann et al., 2016 | No | Case series | 496 | Metastatic melanoma | Not specified | Not specified |
| D. Iacono et al., 2020 | No | Retrospective single-center | 130 (82% received anti-PD-1) | NSCLC (49%), melanoma (42%), kidney (7%), other (2%) | Jan 2012-Dec 2017 | CTCAE v4.0 |
| C. Owen et al., 2021 | Yes | Retrospective multicenter | 999 | Melanoma | Median 21 months | Severity grades used but version not specified |
| S. Vardhana et al., 2018 | Yes | Review article | Aggregated from multiple trials | Classical Hodgkin lymphoma | Varies by trial | Not specified (grade 3 mentioned) |
| L. Zimmer et al., 2016 | No | Case series | 496 | Metastatic melanoma | Not specified | Not specified |
| S. Hoa et al., 2021 | No | Retrospective multicenter | 27 | Lung cancer and melanoma | Median 11.0 months (IQR 6.0-17.5) | Not specified |

The primary anti-PD-1 agents examined were nivolumab and pembrolizumab. Dosing regimens included nivolumab 3 mg/kg IV every 2 weeks and pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks.

### Overall Incidence

The incidence of any irAE varied across studies. Patrinely et al. reported that 69.0% of patients experienced acute irAEs during treatment, with 19.5% developing grades 3-5 events. Iacono et al. found that 38% of patients developed irAEs.

### Organ System Involvement and Specific irAEs

#### Immune-Related Adverse Events Summary
| Organ System  | Specific irAEs                 | Incidence                   | Severity       | Time to Onset      |
|---------------|--------------------------------|-----------------------------|----------------|--------------------|
| Endocrine     | Thyroiditis, hypothyroidism    | 4-7%; most common (34%)    | Typically grade 1-2    | 9-12 weeks          |
| Gastrointestinal | Colitis, diarrhea            | 14%; 2.8-2.9% high-grade   | Grade 3-4 common | ~7 weeks; 3.5-5.3 months |
| Dermatologic  | Rash, cutaneous toxicity       | 18%; 1-9%; 18% delayed     | Variable       | ~2 weeks            |
| Pulmonary     | Pneumonitis                    | 3%; 13% delayed            | High-grade      | 15.1-31.1 weeks median; 3.3-3.5 months |
| Hepatic       | Hepatotoxicity, hepatitis     | 0.8%-11%                   | High-grade      | 9-12 weeks          |
| Neurologic    | Encephalitis, myasthenia-like syndrome | Not specified        | Variable       | Not specified       |

#### Chronic and Delayed irAEs

Patrinely et al. provided detailed characterization of chronic irAEs, defined as those persisting at least 12 weeks after therapy cessation. They found that 43.2% of patients developed chronic irAEs, with most being mild (96.4% grade 1-2) and persisting until last follow-up in 85.6% of cases.

## Management of Immune-Related Adverse Events

### Treatment Modifications

Anti-PD-1 therapy management varied by irAE severity. Recommendations include 
- **Grade 2 symptoms**: Hold treatment.
- **Grade 3-4 symptoms**: Permanent discontinuation.

### Immunosuppressive Therapy

Corticosteroids were the primary immunosuppressive treatment across all studies. Depending on severity, dosing strategies include:
- **Grade 2**: 0.5-1 mg/kg/day.
- **Grade 3**: 1-2 mg/kg/day.
- **Grade 4**: IV corticosteroids for severe cases.

### Supportive Care and Monitoring

Supportive care measures included hydration, gastroprotection with proton pump inhibitors, and regular monitoring of symptoms and laboratory tests.

## Treatment Outcomes

### Resolution and Recovery

Resolution rates varied by irAE type and management approach. However, approximately 80% of irAEs resolved within a median of 5 weeks with immune-modulating medication, while cases like endocrinopathies often persisted.

### Mortality

Fatal irAEs were uncommon but documented. Case reports indicate fatalities from myocarditis and neurotoxicity.

### Impact on Cancer Treatment

The relationship between irAE management and cancer outcomes appeared favorable. Neither steroid treatment nor additional immunosuppression was found to affect anti-PD-1 efficacy positively.

## Summary

Immune-related adverse events associated with anti-PD-1 antibodies vary in type and management but generally constitute a significant aspect of patient care needing prompt recognition and tailored treatment strategies to ensure favorable outcomes.