Symptomatic Pneumonitis Rates Among Patients with Stage III Non-Small Cell Lung Cancer Receiving Adjuvant Durvalumab

Abstract

Adjuvant durvalumab after definitive chemoradiation for stage III non-small cell lung cancer (NSCLC) has improved overall survival with low reported pneumonitis rates in clinical trials. However, real-world rates of treatment-associated pneumonitis remain poorly defined. We sought to describe pneumonitis rates among a largest-to-date real-world cohort of stage III NSCLC patients receiving adjuvant durvalumab. We performed a retrospective cohort study of patients with stage III NSCLC in the national Veterans Health Administration who received concurrent chemoradiation alone from 2015-2016 or concurrent chemoradiation followed by at least one dose of adjuvant durvalumab from 2017-2021. Incident pneumonitis was defined as new or worsening symptoms, radiographic changes on CT chest, at least one steroid prescription, and a likely diagnosis of pneumonitis by the treating physician within 2 years of the final radiation treatment; severity was graded by CTCAE v4.03 criteria. Pneumonitis events were ascertained by manual chart review assisted by keyword searches and steroid prescription data. Cox regression was used to identify baseline clinical factors associated with Grade 2+ pneumonitis. Our cohort included 1,994 patients with stage IIII NSCLC, 989 of whom received concurrent chemoradiation alone and 1005 of whom received adjuvant durvalumab. The overall incidence of symptomatic pneumonitis among patients receiving concurrent chemoradiation alone vs those receiving adjuvant immunotherapy was 6.8% vs 11% (Grade 2, p = 0.0005), 6% vs 8.4% (Grade 3, p = 0.007) and 1.1% vs 1.6% (Grade 5, p = 0.292), respectively. The cumulative incidence of Grade 2-5 pneumonitis at 2 years was 13.8% among patients treated with chemoradiation alone versus 22.1% for patients treated with chemoradiation followed by durvalumab (p ≤0.0001). Of those with Grade 2 pneumonitis, pneumonitis occurred in 85% of patients within one year of receiving radiation, and 84% of those with Grade 3-5 pneumonitis developed pneumonitis within one year. Patients prescribed outpatient steroids for pneumonitis had active prescriptions lasting a mean of 153 days, and among those hospitalized for pneumonitis, ¾ needed supplemental oxygen support. On multivariate analysis, the use of durvalumab is associated with higher risk of Grade 2-5 pneumonitis (HR 1.4, p = 0.004). Current smokers have a 50% risk reduction for Grade 2+ pneumonitis relative to never smokers (p≤0.001). In this largest-to-date cohort, we found that adjuvant immunotherapy is associated with higher risk of Grade 2+ pneumonitis. The increase in symptomatic pneumonitis associated with durvalumab should spur future work to refine patient selection, balance the risk/benefit of adjuvant immunotherapy, and potentially modify radiation dosimetric constraints to decrease pneumonitis rates.