3. Immune-related pneumonitis
What is pneumonitis?
Pneumonitis occurs when an irritating substance causes the alveoli in the lungs to become inflamed, which makes it difficult for oxygen to pass through the alveoli into the bloodstream. If left undiagnosed and untreated, pneumonitis can cause irreversible lung damage and, in severe cases, result in the death of the patient. In such cases, there is chronic inflammation of the alveoli, which become scarred and then rigid, resulting in pulmonary fibrosis.
Pneumonitis on a chest x-ray
Incidence and onset of pneumonitis in patients receiving immunotherapy
There have been several large meta-analyses that have examined the incidence of pneumonitis. One meta-analysis looked at 15 prospective phase II and II studies of nivolumab or pembrolizumab in different cancer types, encompassing 5005 patients . It was found that the overall incidence of all grades of pneumonitis was 2.9% in these patients. When compared with the patients in the clinical trials who did not receive anti-PD-1 treatment, the number of patients experiencing pneumonitis in the anti-PD-1 treatment arm was significantly higher, whether the PD-1 inhibitor studied was nivolumab or pembrolizumab (both showed comparable incidences of pneumonitis). Further subgroup analysis revealed that the incidence of all grades of pneumonitis was higher in non-melanoma patients. A second meta-analysis across 915 patients who had received an anti-PD-1 or anti-PD-L1 ICI as monotherapy or in combination with an anti-CTLA-4 ICI, found that the overall incidence of pneumonitis was 5% . Pneumonitis was seen in 3% of those receiving anti-PD-1 or anti-PD-L1 monotherapy and 10% of those treated with a combination that included a CTLA-4 inhibitor. It was reported that pneumonitis developed in patients who were smokers, ex-smokers, or those who had never smoked. Patients who experienced pneumonitis also tended to experience additional irAEs, which covered all six groups of AEs. Of all irAEs, pneumonitis has led to the most fatalities with anti-PD-1/PD-L1 therapy .
Generally, pneumonitis appears later than other irAEs, but has a wide range of reported times of onset, appearing as early as 9 days  and as late as 24 months . The onset appears to be earlier in those patients who have received combination therapy than in those patients who have received monotherapy .
Symptoms and management of pneumonitis
While the majority of patients in clinical trials experienced grade 1–2 AEs, there is a risk that pneumonitis can rapidly escalate to a grade 3–4 in a short space of time and can, in rare cases, result in death if not treated in a timely manner. The importance of regular monitoring of patients on ICIs, particularly PD-1 inhibitors, cannot be underestimated.
The most commonly reported symptoms of pneumonitis that patients should be assessed for are:
- Radiographic changes
- New or worsening cough
- Chest pain
- Loss of appetite
As the onset of these symptoms can be severe and rapidly worsen in a very short interval, HCPs must be watchful for any signs or indications of pneumonitis and instigate timely management. Of note, patients need to be informed that pneumonitis can occur after a single treatment, continuous treatment for months, or even after treatment cessation, so continuous vigilance is needed. Patients also need to be given clear and detailed written information and pre-treatment counseling on the signs and symptoms of pneumonitis, and how to report these to an appropriate HCP for expert advice. The patient should report any changes that occur to ensure more frequent assessment, swift identification of cause, and intervention if needed. Consistent assessment questions at every treatment can aid in identification of changes occurring over time as patients may not be aware that a symptom is treatment-related, and may fail to report it unless specifically asked .
Baseline assessment of the patient is very important; for example, in the NSCLC population, it is critical to establish the baseline severity of any respiratory symptoms to better identify changes during treatment. Common symptoms such as dyspnea and cough should be thoroughly graded at baseline.
An algorithm for managing immune-related pneumonitis has been published by the Clatterbridge Cancer Centre NHS foundation Trust. This has been utilized and adapted by other cancer centers are user friendly and offer safe, concise and standardized management of pneumonitis.
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- Peng L, Qiong Z, Xianghua Y et al. Incidence and risk of pneumonitis associated with nivolumab and pembrolizumab in patients with cancer: A meta-analysis of clinical trials. J Clin Oncol 2016; 34 (Suppl 15): Advance online publication.
- Naidoo J, Wang X, Woo KM et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2017; 35(7): 709–717.
- Wang DY, Salem J-E, Cohen JV et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol 2018. Advance online publication.
- Haanen JBAG, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(Suppl 4): iv119–iv142.
- Naidoo J, Page DB, Li BT et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26(12): 2375–2391.
- Lewis C. JL211. PD-1 Immune Checkpoint Inhibitors: An Exciting New Approach for the Treatment of Non-Small Cell Lung Cancer. JADPRO 2014; 5(6).