Risk of checkpoint inhibitor pneumonitis associated with anti-angiogenic agents in non–small cell lung cancer: An integrated analysis of meta-analysis of randomized controlled trials, FAERS, and real-world data.

Abstract

e24163 Background: Immunotherapy with immune checkpoint inhibitors (ICIs) and antiangiogenic treatment represent the standard-of-cares for advanced non-small cell lung cancer (NSCLC). checkpoint inhibitor pneumonitis (CIP) is one of common and life-threatening immune-related adverse events. This study aimed to comprehensively evaluate the effect of anti-angiogenic agents on the risk of CIP in NSCLC using multi-level evidence. Methods: A triangulated research design integrating a meta-analysis of randomized controlled trials (RCTs), pharmacovigilance analysis, and a single-center real-world cohort study was conducted. RCTs published between January 1, 2005, and July 1, 2025, were identified from PubMed, Google Scholar, Scopus, and ClinicalTrials.gov for meta-analysis. Adverse event data were extracted from the FAERS for NSCLC patients treated with ICIs between January 1, 2015, and December 31, 2023, and multivariable logistic regression was applied to estimate adjusted odds ratios (ORs). A retrospective real-world cohort of advanced NSCLC patients treated between January 2019 and July 2025 was analyzed. CIP was defined and graded according to CTCAE version 5.0, in conjunction with radiologic assessment. Results: Meta-analysis including 7 eligible trials selected from 1,454 studies demonstrated that ICI combined with anti-angiogenic agents significantly reduced the risk of CIP compared with ICIs (OR: 0.72; 95% CI: 0.52-0.99; p=0.043). The FAERS data analysis showed that 2,800 of 31,755 NSCLC patients (8.8%) receiving ICIs developed CIP. Among 2,540 patients receiving combined ICI and anti-angiogenic therapy, 184 (7.2%) of CIP were reported. Subgroup analyses revealed a protective signal with anti-VEGF therapy for CIP risk (OR: 0.76; 95% CI: 0.64-0.91; p=0.003), whereas anti-VEGFR-2 agents and VEGFR tyrosine kinase inhibitors did not demonstrate a significant reduced risk of CIP. In a single-center cohort with 218 advanced NSCLC, CIP occurred in 7.4% of those receiving combined ICIs and anti-angiogenic agents vs. 24.0% of patients receiving ICIs (OR: 0.25; 95% CI: 0.09-0.67; p=0.005). However, combined ICIs and anti-angiogenic agents did not affect the incidence of ≥ grade 3 CIP (2.9% vs. 6.7%; OR: 0.42; 95% CI: 0.09-1.99; p=0.264). The median time to onset of CIP (167 vs. 143 days; p=0.936) and cycles of ICIs (6.0 vs. 5.0; p=0.873) was comparable in patients with combined ICIs and anti-angiogenic agents vs. those with ICIs. Conclusions: Consistent evidence from multiple data sources indicate that anti-angiogenic therapy particularly anti-VEGF agents are associated with a reduced risk of CIP in NSCLC receiving ICIs. These findings support risk-adapted combination strategies to mitigate immune-related pulmonary toxicity in NSCLC.