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 (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.
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 | 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 |
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. In the Iacono cohort, nivolumab was used in 60% of patients, pembrolizumab in 21%, and atezolizumab in 1%.
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.
Organ System Involvement and Specific irAEs
| Organ System | Specific irAEs | Incidence | Severity | Time to Onset | Source |
|---|---|---|---|---|---|
| Endocrine | Thyroiditis, hypothyroidism | 4-7%; most common (34%); 9-16% hypothyroidism | Typically grade 1-2 | 9-12 weeks | O’Kane et al., Weber et al., Iacono et al., Vardhana et al. |
| Gastrointestinal | Colitis, diarrhea | 14%; 2.8-2.9% high-grade; | Grade 3-4 common | ~7 weeks; 3.5-5.3 months | Weber et al., Iacono et al., Vardhana et al., Owen et al. |
| Dermatologic | Rash, cutaneous toxicity | 18%; 1-9%; 18% delayed | Variable | ~2 weeks | Weber et al., Iacono et al., Vardhana et al., Owen et al. |
| Pulmonary | Pneumonitis | 3%; 13% delayed | High-grade | 15.1-31.1 weeks median; 3.3-3.5 months | Weber et al., O’Kane et al., Vardhana et al., Owen et al. |
| Hepatic | Hepatotoxicity, hepatitis | 2.3% nivolumab, 0.8% pembrolizumab; up to 11%; | High-grade | 9-12 weeks; 1-3 months | Weber et al., O’Kane et al., Vardhana et al. |
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. Across studies, 14-15% of patients required permanent ICI discontinuation due to irAEs.
Immunosuppressive Therapy
Corticosteroids were the primary immunosuppressive treatment across all studies. Weber et al. recommended oral prednisone at 1-2 mg/kg/day for moderate symptoms, with IV methylprednisolone for severe cases requiring hospitalization.
Healthcare Utilization
The management of irAEs required substantial healthcare resources. Iacono et al. documented 373 unscheduled accesses to healthcare facilities due to irAEs.
Supportive Care and Monitoring
Beyond immunosuppression, supportive care measures included hydration and symptom management. Specialist consultations were frequently necessary.
Treatment Outcomes
Resolution and Recovery
Resolution rates varied by irAE type and management approach. Weber et al. reported approximately 80% of irAEs resolved within a median of 5 weeks with immune-modulating medication.
Mortality
Fatal irAEs were uncommon but documented. Patrinely et al. reported one patient each with fatal myocarditis and neurotoxicity.
Impact on Cancer Treatment
The relationship between irAE management and cancer outcomes appeared favorable. O’Kane et al. reported that steroid treatment did not affect PD-1 inhibitor efficacy.
Factors Associated with Management Success
Several factors emerged as important for successful irAE management. Eigentler et al. identified early diagnosis and close clinical monitoring as essential.
Synthesis
The evidence reveals several important patterns regarding immune-related adverse events with anti-PD-1 therapy. The spectrum of irAEs showed consistency across cancer types. However, certain populations demonstrated distinct patterns, such as increased vulnerability of Hodgkin lymphoma patients to pneumonitis.
Chronicity emerged as a critical aspect, with 43.2% of patients developing chronic irAEs. The management strategies showed consistency with corticosteroids at 1-2 mg/kg/day being effective across various irAE types. The findings highlight the need for systematic monitoring protocols and trained networks for managing irAEs.