ORLANDO, Fla. — Pembrolizumab monotherapy was linked to a lower risk for several major adverse pulmonary outcomes when researchers compared the checkpoint inhibitor to standard chemotherapy among people with lung cancer.

A more than two times higher risk for interstitial pneumonitis associated with pembrolizumab did not surprise lead investigator Juan Martinez Ortega, MD, internal medicine resident at Lincoln Medical Center, New York City Health & Hospitals in Bronx, New York. He added that PD-1 and PD-L1 inhibitor pneumonitis is a well-recognized class effect.

However, little is known about the risk for other pulmonary complications, including acute respiratory distress syndrome (ARDS), pulmonary fibrosis, and bacterial pneumonia in real-world use.

“We have a lot of patients with lung cancer that are receiving immune checkpoint inhibitors. We know about the relationship between pembrolizumab and interstitial pneumonitis. But we don’t have enough information to talk to patients and describe other adverse effects in the lung system, which is their major concern,” Martinez Ortega said during a session at the American Thoracic Society (ATS) 2026 International Conference.

Background

Pembrolizumab is the preferred first-line treatment for advanced or metastatic non-small cell lung cancer positive for PD-L1 expression of 50% or greater with no actionable genetic mutations, Martinez Ortega said.

To better inform patients about possible adverse effects (AEs) involving the lungs, he and colleagues compared 10,460 adults taking pembrolizumab with 10,460 adults receiving standard chemotherapy using data from the TriNetX Research Network database. The two cohorts were matched using propensity scoring for age, sex, smoking, obesity, prior radiation treatment, and comorbidities.

The investigators looked at risk ratios (RRs) for the outcomes of interest.

Key Findings

The rate of ARDS was significantly lower in the pembrolizumab group (RR, 0.59; P < .001). Similarly, the rate of pulmonary fibrosis (RR, 0.77; P = .009) and bacterial pneumonia (RR, 0.78; P < .001) also favored the checkpoint inhibitor therapy over standard chemotherapy.

In contrast, viral pneumonia risk slightly favored chemotherapy (RR, 1.06; P = .540) but was not statistically significant.

The rate of interstitial pneumonitis significantly favored the chemotherapy group (RR, 2.30; P = .001).

Among patients who developed one of these major adverse outcomes, there was no significant difference between groups in 30-day mortality rates for ARDS (RR, 1.02; P = .893), pulmonary fibrosis (RR, 0.85 ; P = .348), or viral pneumonia (RR, 0.85; P = .273). However, the difference in 30-day mortality was significant for bacterial pneumonia favoring pembrolizumab (RR, 0.83; P = .046).

The retrospective cohort study design was a limitation. Additional limitations included use of International Classification of Diseases, 10th Revision codes; an inability to fully match PD-L1 status and tumor histology between groups; and the heterogeneity of chemotherapy regimens.

Outside Perspective

“Regarding pneumonitis, the findings are well known. There is a higher risk with pembrolizumab,” said David Carbone, MD, PhD, a medical oncology professor at The Ohio State University Comprehensive Cancer Center in Columbus (OSUCCC), Ohio, when asked to comment. “This is more than outweighed by the dramatic survival benefits and sometimes cures of metastatic lung cancer with pembrolizumab. There are no cures with chemotherapy.”

“The other conditions are generally only a problem as preexisting conditions in the lung cancer population, and can limit our therapies,” added Carbone, who is also director of the James Thoracic Center at OSUCCC.

Clinical Advice and Future Directions

Given the 2.3 higher risk for interstitial pneumonitis in the pembrolizumab group, Martinez Ortega and colleagues suggest screening patients for dyspnea, cough, and hypoxia. If detected, intervene early with corticosteroids as indicated, they added.

The investigators plan to expand the research. In particular, they plan to explore the adverse pulmonary outcomes when patients receive pembrolizumab in combination with standard chemotherapy. “We also want to see how that affects overall survival,” he added.

The study was independently supported. Martinez Ortega reported having no relevant disclosures. Carbone reported being consultant for multiple companies, including Merck, but has no stock or leadership positions.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. McNamara has a BA in chemistry and an MA in science, health and environmental reporting/journalism.