Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation

Purpose : We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. Methods and Materials : This single institution, multi-site retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011 to September 2017]; N=448) or afterward (ICI era cohort [October 2017 to December 2021]; N=335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per CTCAE v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. Results : G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs. 20.1%, p<0.001; IPTW-adjusted multivariable sHR 2.03, 95%CI 1.53-2.70, p<0.001). There was no significant interaction between ICI era treatment and either lung V20 or MLD; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and MLD (≥14 Gy). Cutpoint analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs. 19.8% below, p<0.001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs. 6.0%, p=0.39; IPTW-adjusted multivariable sHR 1.12, 95%CI 0.63-2.01, p=0.70). Conclusions : In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in grade ≥2 but not grade ≥3 pneumonitis. With ICI consolidation, stricter lung dose constraints may be warranted.