Evaluation of Pneumonitis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Osimertinib and Thoracic Radiotherapy

Abstract

<h3>Purpose/Objective(s)</h3> In epidermal growth factor receptor mutated (EGFR+) metastatic non-small cell lung cancer (mNSCLC), pneumonitis is a known side effect independently associated with both Osimertinib and thoracic radiotherapy (TRT). The objective of this study was to examine the relationship between concurrent Osimertinib and TRT with regards to pneumonitis, and to observe patterns of practice regarding the cessation of Osimertinib during TRT. <h3>Materials/Methods</h3> In this single institution retrospective cohort study between 2016 and 2020, patients with EGFR+ mNSCLC who received both Osimertinib and TRT were included. TRT was defined as any course of radiotherapy that involved lung parenchyma within the treated field. The primary endpoint was the incidence of symptomatic (CTCAE grade ≥ 2) pneumonitis. Comparisons were made with multivariable Cox proportional hazards regression for both grade ≥ 2 and any grade pneumonitis. <h3>Results</h3> Of the 151 patients receiving Osimertinib during the study period, 41 underwent 147 courses of radiation either during or within 6 months of Osimertinib initiation, with 68 (46.3%) lesions treated with TRT. In total, 5 patients developed RT-related symptomatic pneumonitis (12.2%), of which 1 was grade 4 and another grade 5. Mean (±SD) age at TRT was 65.5 (±12.0) years. Most patients had de novo metastatic disease (n=31; 75.6%), adenocarcinoma histology (n=38; 92.7%), and 16 (39%) were on Osimertinib as first line systemic therapy. The mean (±SD) number of cycles of Osimertinib was 9.6 (±4.3). Median total dose and fractionations were 20 Gy (interquartile range [IQR]: 20-30 Gy) and 5 (IQR: 1-5), respectively. During TRT, Osimertinib was knowingly held in 12 patients (29.3%), most commonly for 1-2 days before and after (n=7; 17.1%) the course of treatment. Osimertinib was knowingly continued during TRT for 5 patients (12.2%), and in 8 patients (19.5%) it was not documented whether the medication was held. Multivariable analysis identified that each additional cycle of Osimertinib was associated with an increased incidence of grade ≥ 2 pneumonitis (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.15-2.07, p=0.004). Total radiation dose was also associated with increased incidence of any grade of pneumonitis (HR per 5 Gy: 1.38, 95% CI: 1.03-1.86, p=0.031). There was no association with incidence of pneumonitis (any grade) if Osimertinib was continued during TRT (HR: 3.36, 95% CI: 0.13-86.56, p=0.47) or if TRT was given within 6 months of Osimertinib initiation (HR: 0.20, 95% CI: 0.02-2.21, p=0.19). <h3>Conclusion</h3> In patients with EGFR+ mNSCLC treated with Osimertinib and TRT, the risk of symptomatic pneumonitis was moderate, and in 2 instances serious. Patterns on whether to hold Osimertinib during TRT, and for how long, were variable. Symptomatic pneumonitis with TRT was associated with prolonged Osimertinib use. Further research is required to further clarify the safety of the combination of these two treatment modalities.