Pneumonitis in Advanced Non-Small Cell Lung Cancer: No Interaction between Immune Checkpoint Inhibition and Radiation Therapy

Abstract

<h3>Purpose/Objective(s)</h3> Pneumonitis is a common complication of treatment for advanced non-small cell lung cancer (NSCLC). Radiation pneumonitis and immune-related pneumonitis have been studied independently, but little information has emerged on the interactions between radiation therapy (RT) and immune checkpoint inhibition (ICI). In this study, we aim to examine if RT and ICI interact in causing pneumonitis. <h3>Materials/Methods</h3> A retrospective cohort was assembled using the Surveillance, Epidemiology, and End Results-Medicare database, including Medicare beneficiaries diagnosed with American Joint Committee on Cancer 7th ed. (AJCC) stages 3B-4 NSCLC between 2013-2017. Exposures to RT and ICI were determined by evaluating for treatment codes in the 12 months after diagnosis and evaluating for a second exposure (e.g., ICI after RT) within 3 months after the first exposure. A previously validated algorithm for identifying cases of pneumonitis in inpatient and outpatient claims was used to evaluate for the outcome in the 6 months after treatment. Cox regression was performed to estimate hazard ratios of pneumonitis for patients treated with RT, ICI, and both therapies (RT+ICI), relative to a cohort unexposed to RT and ICI. Presence of an additive interaction was determined by computing the relative excess risk due to interaction (RERI) and constructing 95% confidence intervals (95% CI) through bootstrapping. <h3>Results</h3> There were 18,780 patients included in the analysis with 9,345 (49.8%), 7,533 (40.2%), 1,332 (7.1%), and 550 (2.9%) in the control, RT, ICI, and RT+ICI groups. There were more patients with squamous histology and AJCC stage 3B disease in the RT group (p<0.01). The incidence and hazard ratios of pneumonitis are presented in Table 1. The RERIs were -6.1 (95% CI: -13.1–0.6, p=0.97) and -4.0 (95% CI: -10.7-1.5, p=0.91) in the unadjusted and adjusted analyses, respectively, consistent with no evidence of additive interaction (RERI≤0) between RT and ICI. These results were stable when varying the allowable time to be exposed, time to develop pneumonitis, algorithms for identifying pneumonitis, and limiting immortal-time bias through landmark analyses and measuring RT and ICI exposure as time-varying covariates. <h3>Conclusion</h3> In this retrospective study of Medicare beneficiaries with advanced NSCLC, there was no clear synergy between RT and ICI in causing pneumonitis. The risk of pneumonitis in patients treated with RT and ICI is not more than could be expected from each therapy alone. These data support the safety of combining RT and ICI in clinical practice.