Keytruda (pembrolizumab) is an immunotherapy cancer treatment that harnesses the body’s immune system to fight malignant cells. This monoclonal antibody has significantly improved outcomes for patients with many cancers, including melanoma and non-small cell lung cancer. While highly effective, Keytruda can cause immune-related adverse events (irAEs) due to immune activation. Pneumonitis is one such irAE, defined as non-infectious inflammation of the lung tissue, and is a known serious complication associated with this class of drugs.
How Keytruda Triggers Lung Inflammation
Keytruda’s function depends on manipulating the programmed death 1 (PD-1) pathway. This pathway acts as a crucial “brake” on the immune system, preventing T-cells—the body’s main immune fighters—from mistakenly attacking healthy tissues. Cancer cells exploit this system by displaying PD-L1 proteins, which bind to PD-1 receptors on T-cells, allowing the tumor to evade detection and destruction.
Keytruda, a PD-1 inhibitor, blocks the interaction between the PD-1 receptor and the PD-L1 protein. By removing this brake, the drug reawakens the T-cells, enabling them to recognize and aggressively attack the cancer cells. The challenge is that this powerful immune activation is not perfectly targeted, and the newly unleashed T-cells may mistakenly recognize healthy tissue, such as the lungs, as a foreign threat.
This resulting inflammation is referred to as checkpoint inhibitor pneumonitis. The overall incidence of pneumonitis with Keytruda monotherapy is relatively low, typically affecting around 3.4% to 5% of patients. However, the risk is higher in certain groups, such as patients with non-small cell lung cancer, those who have received prior chest radiation, or those with pre-existing lung conditions. The mechanism involves an excessive immune response and the secretion of inflammatory cytokines, which cause damage to the lung structure.
Recognizing Symptoms and Severity Levels
Pneumonitis symptoms can be subtle and often resemble other lung conditions, such as infection or cancer progression. The most common symptoms include a new or worsening cough, often dry and persistent, and shortness of breath (dyspnea). Patients may also experience fatigue, decreased activity tolerance, chest discomfort or pain, and sometimes a low-grade fever.
Report any new respiratory changes immediately, as the severity of pneumonitis can rapidly increase. The median time for symptoms to appear is approximately 2.5 to 4.6 months after starting treatment, but they can occur at any point, even months after the last dose. Up to one-third of patients may initially be asymptomatic, with inflammation only visible on a chest scan.
The severity of pneumonitis is classified using a four-level grading system based on the Common Terminology Criteria for Adverse Events (CTCAE).
Grade 1
Grade 1 is the mildest, where the patient is without symptoms, and inflammation is only detectable on imaging.
Grade 2
Patients with Grade 2 experience mild-to-moderate symptoms that limit daily activities, such as shortness of breath with exertion.
Grade 3
Grade 3 involves severe symptoms that significantly limit self-care activities, often requiring supplemental oxygen. This level frequently requires hospitalization.
Grade 4
Grade 4 is a life-threatening event that requires urgent medical intervention, such as mechanical ventilation.
Clinical Diagnosis and Treatment Protocols
When pneumonitis is suspected, the diagnostic process begins with imaging, most commonly a high-resolution computed tomography (CT) scan of the chest. CT scans are effective at revealing characteristic signs of lung inflammation, such as ground-glass opacities or areas of consolidation. The imaging findings can vary widely, sometimes mimicking patterns like organizing pneumonia or non-specific interstitial pneumonia.
Confirming the diagnosis requires a process of exclusion, known as differential diagnosis, to rule out other possible causes of lung symptoms. Doctors must ensure the symptoms are not due to an infection, such as bacterial or viral pneumonia, or due to the progression of the underlying cancer itself. In some cases, a bronchoalveolar lavage may be performed to analyze cells and exclude infection.
The management protocol is determined by the severity grade of the pneumonitis. For any Grade 2 or higher event, the immediate action is to hold or permanently discontinue Keytruda treatment. The primary treatment for immune-mediated pneumonitis is high-dose systemic corticosteroids, such as prednisone or methylprednisolone, which suppress the overactive immune response.
Corticosteroid therapy is initiated at a high dose and is continued until symptoms improve to Grade 1 or less. Once the inflammation is under control, the steroid dose is slowly reduced, or tapered, over several weeks to prevent the inflammation from returning. If the patient’s condition does not respond adequately to initial high-dose steroids (refractory pneumonitis), additional immunosuppressive agents like infliximab or mycophenolate mofetil may be considered.