Elicit: Immune-Related Adverse Events in Anti–PD-1 Therapy

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

Immunosuppressive Therapy

Corticosteroids were the primary immunosuppressive treatment across all studies. Depending on severity, dosing strategies include:

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.