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, 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. 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.

Records from Elicit search

n = 200

Papers screened using: PD-1 Therapy Population, Approved PD-1 Inhibitors, Immune-Related Adverse Events Reporting, Management Strategies, Study Design, PD-1 Specificity, PD-1 Attribution, Publication Type

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

Screening

We screened in sources based on their abstracts that met these criteria:

• PD-1 Therapy Population: Does this study include patients receiving anti-PD-1 therapy for any malignancy?
• Approved PD-1 Inhibitors: Does this study investigate pembrolizumab, nivolumab, cemiplimab, dostarlimab, or other FDA/EMA-approved PD-1 inhibitors?
• Immune-Related Adverse Events Reporting: Does this study report immune-related adverse events as primary or secondary outcomes?
• Management Strategies: Does this study describe management strategies, treatment protocols, or interventions for immune-related adverse events?
• Study Design: Is this study a randomized controlled trial, cohort study, case-control study, case series with ≥10 patients, systematic review, or meta-analysis?
• PD-1 Specificity: Does this study focus on PD-1 inhibitors rather than exclusively on PD-L1 inhibitors, CTLA-4 inhibitors, or other non-PD-1 checkpoint inhibitors?
• PD-1 Attribution: If this study involves combination therapies, can the immune-related adverse events be attributed specifically to the PD-1 component, OR does the study focus on PD-1 monotherapy?
• Publication Type: Is this study something other than a case report, editorial, letter, conference abstract, or opinion piece?

Data extraction

We extracted each data column from each paper as follows:

Study Design

• Study type: Retrospective/prospective, case series, clinical trial, etc.
• Sample size of patients receiving anti-PD-1 therapy
• Follow-up duration for irAE monitoring
• irAE grading system used
• Single vs. multi-center

Patient Population

• Cancer type(s) and stage
• Treatment line
• Age and relevant demographics
• Performance status (ECOG, KPS)
• Preexisting autoimmune conditions or immunosuppression
• Prior cancer treatments that might affect irAE risk

Anti-PD-1 Treatment

• Specific agent(s)
• Dosing regimen and schedule
• Treatment duration before irAE occurrence
• Combination with other checkpoint inhibitors
• Concomitant medications that might affect irAE risk

irAE Types

• Specific organ systems affected
• Exact irAE diagnoses
• Severity grade
• Time to onset from treatment initiation
• Incidence rates or frequencies
• Duration of irAEs

irAE Management

• Anti-PD-1 therapy modifications
• Immunosuppressive treatments
• Supportive care measures and symptom management
• Hospitalization requirements and duration
• Specialist consultations required
• Monitoring protocols during treatment
• Criteria for treatment resumption

Management Outcomes

• Resolution rates and time to resolution
• Effectiveness of different management approaches
• irAE recurrence after treatment resumption
• Long-term sequelae or permanent effects
• Treatment-related mortality from irAEs
• Impact on cancer treatment continuation and efficacy
• Patient quality of life effects
• Factors associated with successful vs. unsuccessful management

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.

Anti-PD-1 Agents and Treatment Regimens

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.

Incidence and Spectrum of Immune-Related Adverse Events

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. In patients with preexisting autoimmune disease, Hoa et al. observed PAD exacerbations in 52% of cases.

Management of Immune-Related Adverse Events

Treatment Modifications

Anti-PD-1 therapy management varied by irAE severity. O’Kane et al. recommended holding treatment for grade 2 symptoms and permanent discontinuation for grades 3-4.

Immunosuppressive Therapy

Corticosteroids were the primary immunosuppressive treatment across all studies.

Healthcare Utilization

The management of irAEs required substantial healthcare resources.

Supportive Care and Monitoring

Beyond immunosuppression, supportive care measures are crucial.

Treatment Outcomes

Resolution and Recovery

Resolution rates varied by irAE type and management approach. Approximately 80% of irAEs resolved within a median of 5 weeks with immune-modulating medication.

Mortality

Fatal irAEs were uncommon but documented.

Impact on Cancer Treatment

The relationship between irAE management and cancer outcomes appeared favorable.

Factors Associated with Management Success

Several factors emerged as important for successful irAE management.

Synthesis

The evidence reveals several important patterns regarding immune-related adverse events with anti-PD-1 therapy.