Assessment of pneumonitis in patients with lung cancer undergoing radioimmunotherapy and immune checkpoint inhibitor rechallenge

Abstract Background: The combination of immune checkpoint inhibitors (ICIs) with radiotherapy (RT) has improved survival in patients with advanced lung cancer, yet treatment-related pneumonitis (TRP) is highly toxic. Current limitations include the absence of robust risk stratification models for TRP and unclear safety criteria for ICI rechallenge, hindering the management of recurrent TRP (rTRP). Methods: In this multicenter retrospective study, we analyzed 262 lung cancer patients receiving radioimmunotherapy. The data included baseline demographics, immunotherapy regimens, and radiotherapy parameters. TRP was graded per CTCAE v5.0. Univariate and multivariate logistic regression identified predictors of TRP and rTRP severity. Results: The incidence of TRP is 57.6% (151/262), with grade 1, 2, and ≥ 3 TRP occurring in 24.4%, 25.6%, and 7.6% of patients, respectively. The median time to TRP onset is 113 days (IQR, 73–155). Multivariate analysis reveals PD-1 inhibitors and ICI cycle number as predictors of G ≥ 1 TRP, whereas Dmean predicts all grades. Dose‒response modeling reveals Dmean thresholds for 50% TRP risk: 8.7 Gy (G ≥ 1), 15.3 Gy (G ≥ 2), and 23.4 Gy (G ≥ 3). Among the 53 patients receiving ICI rechallenge, 25.4% (13/53) developed rTRP. Rechallenge within 4 weeks significantly increases rTRP risk (OR, 0.061; 95% CI, 0.010–0.368; P = 0.002). Conclusions: Dmean serves as a continuous risk modifier for TRP severity, with Dmean > 15.3 Gy associated with grade ≥ 2 toxicity. An interval of ≥ 4 weeks after TRP is proposed as a safety window for ICI rechallenge, addressing critical gaps in radioimmunotherapy toxicity management.