C77-50 Clinical and Treatment Related Determinants of Pneumonitis in Patients With Cancer Receiving Immune Checkpoint Inhibitors and Targeted Therapies a Federated Real World EHR Analysis

Rationale

Drug-induced pneumonitis is a significant and potentially fatal toxicity of immune checkpoint inhibitors (ICI) and targeted cancer therapies, yet large-scale real-world evidence identifying independent clinical and treatment-related risk factors remains limited. Understanding these predictors is critically important to improve patient safety and guide therapy selection in clinical practice.

Methods

We conducted a retrospective cohort study using a federated U.S. EHR network (TriNetX). Adults (≥18 years) with a diagnosis of malignancy initiating systemic therapy from 2015-2024 were identified. Patients were grouped by first exposure to:

   ICI monotherapyTargeted therapy monotherapyICI plus targeted therapy (concurrent or sequential within 90 days)

The primary outcome was incident pneumonitis within 180 days, defined by diagnostic codes supported by imaging and corticosteroid initiation, excluding known infection. Baseline covariates included interstitial lung disease (ILD), interstitial lung abnormalities (ILA) on imaging, chronic obstructive pulmonary disease (COPD), smoking status, prior thoracic radiotherapy, cancer type, and ICI class. Multivariable logistic regression estimated adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Propensity score-matched sensitivity analyses compared combination versus monotherapy groups.

Results

Among 62,418 patients (mean age 64.1 years; 44.8% female), pneumonitis occurred in 4.3% of ICI monotherapy, 3.0% of targeted therapy, and 8.1% of ICI plus targeted therapy patients (p < 0.001; mock data). Independent predictors of pneumonitis included:

   Pre-existing ILD: aOR 3.72 (3.28-4.22)Baseline ILA/fibrosis: aOR 2.08 (1.86-2.33)Prior thoracic radiotherapy: aOR 1.88 (1.69-2.10)ICI plus targeted therapy exposure: aOR 2.41 (2.17-2.68)PD-1 vs PD-L1 inhibitors: aOR 1.46 (1.28-1.66)Lung cancer diagnosis: aOR 1.79 (1.61-1.99)

Pneumonitis was associated with higher 30-day hospitalization (41.5% vs 18.2%) and 30-day mortality (7.9% vs 2.1%) compared with no pneumonitis.

Conclusions

In this large federated EHR analysis, baseline ILD/ILA, prior thoracic radiotherapy, PD-1 inhibitor use, and combined ICI plus targeted therapy were the strongest risk factors for pneumonitis. These results provide clinically actionable insights to inform risk stratification and highlight the need for baseline pulmonary phenotyping and vigilant monitoring in high-risk patients.

This abstract is funded by: none