Pulmonary Complications of Keytruda (Pembrolizumab)
Pneumonitis is the primary pulmonary complication of pembrolizumab, occurring in 3-4% of patients across all grades, with higher rates in lung cancer patients (up to 6% in those with prior thoracic radiation), and represents the most common cause of fatal toxicity from PD-1 inhibitors. 1, 2
Incidence and Risk Factors
Overall pneumonitis incidence: 3.8% in NSCLC patients treated with pembrolizumab monotherapy, with 2.7% all-grade and 0.8% grade 3+ pneumonitis across cancer types 1
Higher-risk populations include:
Timing: Median onset is 2.1 months in lung cancer patients versus 5.2 months in melanoma patients 1
Clinical Presentation and Patterns
The most common CT patterns of pembrolizumab-induced pneumonitis are 1:
Organizing pneumonia (OP) pattern (23% of cases) - most frequent, characterized by patchy consolidation in subpleural or peribronchial distribution 1
Hypersensitivity pneumonitis (HP) pattern (16% of cases) - ground-glass opacities with small nodular lesions 1
NSIP pattern - associated with lower toxicity grades 1
Diffuse alveolar damage (DAD) pattern - associated with highest toxicity grades and worst prognosis 1
Common symptoms include significant dry cough, fatigue, chest pain, and dyspnea 1
Severity and Mortality
- Fatal pneumonitis: Accounts for 35% of all PD-1/PD-L1-related deaths, making it the most common fatal toxicity 1
- In one series, 66% had grade 2-3 pneumonitis, 9% had grade 4, and 9% had grade 5 (fatal) pneumonitis 1
- Pneumonitis was the most common adverse reaction leading to permanent discontinuation of pembrolizumab (3.0% in KEYNOTE-042,1.4% in KEYNOTE-057) 2
Diagnostic Approach
When pneumonitis is suspected, obtain chest CT immediately to identify the radiographic pattern, establish temporal correlation with pembrolizumab administration, and exclude infectious causes through bronchoscopy with bronchoalveolar lavage. 1
- The CT pattern correlates with toxicity grade: DAD pattern has highest grades, followed by OP pattern, while NSIP and HP patterns have lower grades 1
- Exclusion of infection is critical, as opportunistic infections can complicate steroid treatment for pneumonitis 3, 4
- Serologic workup should include CBC, procalcitonin, viral respiratory panel, and fungal studies 5
Management Algorithm
Immediately discontinue pembrolizumab when pneumonitis is suspected, and initiate corticosteroids for grade 2 or higher pneumonitis. 1, 2
Grade-Based Treatment:
- Grade 1 (asymptomatic): Withhold pembrolizumab and monitor closely 2
- Grade 2 (symptomatic): Withhold pembrolizumab and initiate prednisone 1-2 mg/kg/day or equivalent 2
- Grade 3-4 (severe/life-threatening): Permanently discontinue pembrolizumab and initiate high-dose methylprednisolone 1-2 mg/kg/day IV 2
Steroid Tapering:
- Continue corticosteroids for at least 4-6 weeks with gradual taper over 4-6 weeks 2
- Monitor for pneumonitis flare-up during steroid taper, which can occur even without pembrolizumab rechallenge 1
Refractory Cases:
- Consider additional immunosuppression with infliximab or mycophenolate mofetil if no improvement after 48 hours of high-dose steroids 1
Critical Caveats and Pitfalls
Do not rechallenge with pembrolizumab after grade 3-4 pneumonitis; in one series, 2 of 7 patients re-treated developed recurrent pneumonitis. 1
- Infection risk: High-dose corticosteroids for pneumonitis treatment significantly increase risk of opportunistic infections including Nocardia, Aspergillus, and Pneumocystis 3, 4
- Consider prophylaxis: When prescribing prednisone ≥20 mg daily for ≥4 weeks, strongly consider Pneumocystis prophylaxis 4
- Maintain high suspicion for infection: The clinical and radiographic presentation of pneumonitis overlaps significantly with infection, making initial differentiation challenging 5, 3
- Monitor closely: Regular follow-up imaging and clinical assessment are essential during steroid treatment, as bacterial superinfection can complicate fungal infections in immunosuppressed patients 4