Pulmonary Toxicities of Pembrolizumab (Keytruda)

Clinical Presentation

Progressive dyspnea, chest pain, and fever are common manifestations of pembrolizumab‑related pneumonitis in cancer patients. 1

Obtain a high‑resolution contrast‑enhanced chest CT immediately when pneumonitis is suspected to define the radiographic pattern and exclude alternative diagnoses. 1
Perform bronchoalveolar lavage with comprehensive bacterial, fungal, viral, and acid‑fast bacilli cultures to rule out infectious causes. 1
Collect blood and urine cultures when clinically indicated to exclude systemic infection. 1
Exclude other etiologies such as tumor progression, pulmonary embolism, cardiac events (heart failure, myocarditis), and pleural carcinomatosis. 1
If CT is nondiagnostic but clinical suspicion remains high, consider pulmonary function testing. 1

Organizing pneumonia pattern accounts for ~23 % of pembrolizumab‑related pneumonitis cases and is characterized on CT by patchy consolidation, ground‑glass opacities, and nodules. [2][3]
Diffuse alveolar damage (DAD) pattern is associated with the highest toxicity grades and worst prognosis, carrying the greatest mortality risk. 2

Grade 1 (asymptomatic, radiographic only): Withhold pembrolizumab, monitor with serial imaging, and consider resumption once findings return to baseline. 1
Grade 2 (symptomatic, not limiting ADLs): Withhold pembrolizumab, start prednisone 1 mg/kg/day (or equivalent), taper over 4–6 weeks after improvement to <grade 1, and rechallenge may be contemplated after complete resolution. 1
Grade 3 (severe, limiting ADLs): Permanently discontinue pembrolizumab, initiate IV methylprednisolone 1–2 mg/kg/day, taper over 6–8 weeks after improvement; if no response within 48–72 h, add second‑line immunosuppression (infliximab 5 mg/kg, tocilizumab 8 mg/kg, mycophenolate mofetil 1 g twice daily, or IVIG 2 g/kg). 1
Grade 4 (life‑threatening): Permanently discontinue pembrolizumab, give immediate high‑dose IV corticosteroids, add second‑line immunosuppression without delay, and provide ICU‑level supportive care. 1
Grade 5 (fatal): Represents 0.22 % of all treated patients and is the most common cause of immune‑checkpoint inhibitor‑related death. 2

Premature steroid tapering can precipitate recurrent pneumonitis; a prolonged taper of 4–8 weeks, adjusted to the initial grade, is recommended. 1

Approximately 2 % of patients develop a chronic form of immune‑related pneumonitis that requires long‑term immunosuppression for ≥12 weeks. 1

Before starting pembrolizumab, obtain baseline chest imaging; perform pulmonary function tests in patients with COPD or pre‑existing interstitial lung disease, and involve a specialist for those with underlying ILD. 1

The American Thoracic Society notes that 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) 4
The overall pneumonitis incidence is 3.8% in NSCLC patients treated with pembrolizumab monotherapy, with 2.7% all-grade and 0.8% grade 3+ pneumonitis across cancer types 4
Higher-risk populations include patients with prior thoracic radiation (6.0% incidence), those with underlying asthma or COPD (5.3% incidence), NSCLC and renal cell carcinoma patients compared to melanoma patients, and male patients and current/former smokers 4
The median onset of pneumonitis is 2.1 months in lung cancer patients versus 5.2 months in melanoma patients 4

The most common CT patterns of pembrolizumab-induced pneumonitis are organizing pneumonia (OP) pattern (23% of cases), hypersensitivity pneumonitis (HP) pattern (16% of cases), NSIP pattern, and diffuse alveolar damage (DAD) pattern 4
Common symptoms of pneumonitis include significant dry cough, fatigue, chest pain, and dyspnea 5

Fatal pneumonitis accounts for 35% of all PD-1/PD-L1-related deaths, making it the most common fatal toxicity 4
In one series, 66% had grade 2-3 pneumonitis, 9% had grade 4, and 9% had grade 5 (fatal) pneumonitis 4

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 4
The CT pattern correlates with toxicity grade: DAD pattern has highest grades, followed by OP pattern, while NSIP and HP patterns have lower grades 4

Immediately discontinue pembrolizumab when pneumonitis is suspected, and initiate corticosteroids for grade 2 or higher pneumonitis 4
Consider additional immunosuppression with infliximab or mycophenolate mofetil if no improvement after 48 hours of high-dose steroids 4

Do not rechallenge with pembrolizumab after grade 3-4 pneumonitis; in one series, 2 of 7 patients re-treated developed recurrent pneumonitis 4