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, while visceral organ toxicities show lower chronicity rates.

Corticosteroids at 1-2 mg/kg/day represent the cornerstone of irAE management, with approximately 80% of irAEs resolving within a median of 5 weeks with immunosuppressive therapy. Steroid-refractory cases may require additional agents such as infliximab, which can provide symptom relief within 24 hours for gastrointestinal irAEs. Treatment modifications include temporary holds for grade 2 toxicity and permanent discontinuation for grades 3-4, required in 14-15% of patients. Critically, immunosuppressive treatment does not impair anti-tumor efficacy, and tumor progression is less frequent in patients experiencing irAEs. Successful management depends on early recognition and prompt corticosteroid initiation, multidisciplinary collaboration, and systematic monitoring protocols. Patients with preexisting autoimmune disease experience higher rates of disease flares (52%), with severity correlating to baseline immunosuppression intensity.

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.

Data extraction

Study Design

• Study type: Retrospective case series
• Sample size: 27 patients
• Follow-up duration: Median (IQR) follow-up of 11.0 (6.0-17.5) months
• irAE grading system: Not mentioned
• Single vs. multi-center: Multi-center

Patient Population

• Cancer type(s): Lung cancer and melanoma
• Preexisting autoimmune conditions: Rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (15%), axial spondyloarthritis (11%)
• Treatment: Anti-PD-1 therapies; 2 patients received additional sequential anti-CTLA-4 therapy

Anti-PD-1 Treatment

• Specific agent(s): Not mentioned
• Dosing regimen and schedule: Not mentioned
• Treatment duration before irAE occurrence: Not explicitly mentioned; median follow-up was 11 months
• Combination with other checkpoint inhibitors: Yes, 2 patients received additional sequential anti-CTLA-4 therapy

irAE Types

• Specific organ systems affected: Musculoskeletal
• Exact irAE diagnoses: Polyarthritis, tenosynovitis
• Severity grade: Severe (14%)
• Time to onset from treatment initiation: Not mentioned
• Incidence rates or frequencies: 52%

irAE Management

• Anti-PD-1 therapy modifications: 14% required ICI discontinuation
• Immunosuppressive treatments: 57% required corticosteroids, 50% required immunosuppression

Management Outcomes

• Frequency and severity of PAD exacerbations: 52% experienced exacerbations, with 14% being severe.
• Management strategies: 57% required corticosteroids, 50% required immunosuppression, and 14% required ICI discontinuation.
• Impact on cancer treatment continuation and efficacy: Tumor progression was not associated with immunosuppressive drug exposure and was less frequent in patients with irAEs.