Pneumonitis Risk After Chemoradiotherapy With and Without Immunotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Purpose Chemoradiotherapy (CRT) combined with immune checkpoint inhibitors (ICIs) is the standard of care for patients with unresectable and locally advanced non-small cell lung cancer. This study aimed to determine whether the addition of ICIs to CRT is associated with an increased risk of pneumonitis. Methods and Materials PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies published between January 1, 2015 and July 31, 2023. The outcome of interest was the incidence rate of pneumonitis. A random-effects model was used for statistical analysis. Results A total of 185 studies with 24527 patients were included. The pooled rate of grade ≥2 pneumonitis for CRT plus ICIs was significantly higher than that for CRT alone (29.6%, 95% CI: 25.7%-33.6% vs. 20.2%, 95% CI: 17.7%-22.8%; P < 0.0001), but with no significant differences in rates of grade ≥3, and grade 5 pneumonitis (grade ≥3: 5.7%, 95% CI: 4.8%-6.6% vs. 5.6%, 95% CI: 4.7%-6.5%; P = 0.64; grade 5: 0.1%, 95% CI: 0.0%-0.2% vs. 0.3%, 95% CI: 0.1%-0.4%; P = 0.68). The results from the subgroup analyses of prospective studies, retrospective studies, Asian and non-Asian studies, concurrent CRT (cCRT), and durvalumab consolidation were comparable to the overall results. However, CRT or cCRT plus PD-1 inhibitors not only significantly increased the incidence of grade ≥2 but also that of grade ≥3 pneumonitis compared to CRT alone or cCRT plus PD-L1 inhibitors. Conclusions Durvalumab consolidation after CRT is likely to be associated with a higher incidence of moderate pneumonitis than CRT alone, while CRT plus PD-1 inhibitors also appears to increase the risk of severe pneumonitis. Nevertheless, these findings are based on observational studies, and need to be validated in future large head-to-head studies.