Adverse Effects of Anti-PD-L1 Therapy
Anti-PD-L1 therapy commonly causes immune-related adverse events (irAEs) that can affect multiple organ systems, with the most frequent irAEs involving the skin, colon, endocrine organs, liver, and lungs, though they occur less frequently and with lower severity compared to anti-CTLA-4 or anti-PD-1 therapies. 1
Overview of Anti-PD-L1 Associated Adverse Events
Anti-PD-L1 therapies are immune checkpoint inhibitors (ICPis) that block the interaction between PD-1 and its ligand PD-L1, removing inhibition of the immune response. This mechanism can lead to immune-mediated adverse reactions that vary in severity and organ involvement.
Incidence and Severity
- Anti-PD-L1 agents generally have a more favorable toxicity profile compared to anti-PD-1 or anti-CTLA-4 agents 1, 2
- Fatigue is the most frequently reported adverse event with anti-PD-L1 therapy (12-24% incidence) 1
- Overall incidence of treatment-related adverse events with anti-PD-L1 monotherapy is lower than with anti-PD-1 therapy 2
Organ-Specific Immune-Related Adverse Events
Cutaneous Toxicities
- Most common irAEs with ICPis, including anti-PD-L1 therapy 1
- Manifestations include:
- Rash (lower risk compared to anti-PD-1 agents) 2
- Pruritus (with or without eruption)
- Inflammatory dermatoses (spongiotic, granulomatous, panniculitis)
- Vitiligo (primarily in melanoma patients)
- Alopecia areata
- Typically appear within 6 weeks of treatment initiation 1
- Severe cutaneous adverse reactions (SCAR) like Stevens-Johnson syndrome are rare but serious 1
Gastrointestinal Toxicities
- Colitis and diarrhea
- Lower risk of colitis (both any-grade and grade ≥3) with anti-PD-L1 compared to anti-PD-1 agents 2
- May require temporary or permanent discontinuation of therapy in severe cases
Hepatic Toxicities
- Elevated liver enzymes (ALT/AST)
- Lower risk of elevated ALT with anti-PD-L1 compared to anti-PD-1 agents 2
- May require monitoring of liver function tests during treatment
Endocrine Toxicities
- Hypothyroidism (lower risk compared to anti-PD-1 agents) 2
- Hypophysitis/hypopituitarism
- Adrenal insufficiency
- May require hormone replacement therapy
Pulmonary Toxicities
- Pneumonitis (immune-mediated)
- Incidence varies by tumor type (higher in lung cancer patients) 3
- Can be severe and potentially fatal in rare cases
- Durvalumab: 1.1% incidence of immune-mediated pneumonitis, including fatal (<0.1%), Grade 4 (0.1%), Grade 3 (0.3%) cases 4
- Avelumab: 1.1% incidence of immune-mediated pneumonitis 5
Other Less Common but Serious irAEs
- Neurological disorders
- Myocarditis
- Nephritis (higher risk in genitourinary cancers) 3
- Ocular adverse events (3.3-7.4% prevalence) 6
- Can occur early after drug initiation (median 6-11 weeks)
- May require ophthalmological evaluation
Management of irAEs
General Principles
- Early recognition and prompt intervention are essential 1
- Monitor patients closely for symptoms of underlying immune-mediated reactions
- Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment 4, 5
- Grade-based approach to management:
- Grade 1-2: Symptomatic management, consider withholding therapy
- Grade 3-4: Withhold or permanently discontinue therapy, systemic corticosteroids
Corticosteroid Management
- For moderate to severe irAEs: Systemic corticosteroids (1-2 mg/kg/day prednisone or equivalent) 4, 5
- Continue until improvement to Grade 1 or less
- Taper corticosteroids over at least 1 month
- Consider prophylaxis for opportunistic infections, gastritis, and hypertension 1
- For steroid-refractory cases: Consider other immunomodulatory agents (infliximab, mycophenolate mofetil, etc.) 1
Combination Therapy Considerations
When anti-PD-L1 inhibitors are combined with other therapies, the adverse event profile changes:
- Anti-PD-L1 + chemotherapy: 97.7% all-grade adverse events, 68.3% grade ≥3 7
- Anti-PD-L1 + targeted therapy: 94.5% all-grade adverse events, 47.3% grade ≥3 7
- Anti-PD-L1 + immunotherapy: 86.8% all-grade adverse events, 35.9% grade ≥3 7
- Anti-PD-L1 + radiotherapy: 89.4% all-grade adverse events, 12.4% grade ≥3 7
Important Clinical Considerations
- Tumor type may influence specific irAE risk (e.g., pneumonitis in lung cancer, hepatitis in melanoma) 3
- Prior thoracic radiation increases pneumonitis risk 1
- irAEs can occur at any time during treatment or even after discontinuation 4, 5
- Patient education on potential irAEs is crucial for early reporting of symptoms
- Interprofessional management with early specialist consultation improves outcomes 1