Pirfenidone for grade 2 and grade 3 radiation-induced lung injury: a multicentre, open-label, randomised, phase 2 trial.
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BACKGROUND: Radiation-induced lung injury is a major dose-limiting toxicity in thoracic radiotherapy. Pirfenidone, an oral antifibrotic drug that is often used to treat idiopathic pulmonary fibrosis, could offer therapeutic benefits for patients with radiation-induced lung injury. We evaluated the efficacy and safety of pirfenidone in patients with grade 2 or grade 3 radiation-induced lung injury. METHODS: This multicentre, open-label, randomised, phase 2 clinical trial enrolled patients with grade 2 or grade 3 radiation-induced lung injury diagnosed according to Common Terminology Criteria for Adverse Events version 5.0 from ten medical centres across China. Eligible patients were aged 18-75 years with an Eastern Cooperative Oncology Group performance status of 0-2 and had grade 2 or grade 3 radiation-induced lung injury. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either pirfenidone plus glucocorticoids or glucocorticoids alone. Pirfenidone was given orally three times daily at doses of 200 mg in week 1, 300 mg in week 2, and 400 mg in weeks 3-24. Glucocorticoids were administered concurrently at the equivalent dose of prednisone 40 mg/day, divided into two oral doses, and maintained for 2 weeks, followed by a tapering schedule of 10 mg every 2 weeks over a period of 6 to 8 weeks. The control group received glucocorticoids only. The primary endpoint, evaluated in the modified intention-to-treat population, was the change in the percentage of carbon monoxide diffusing capacity (DLCO%) from baseline to week 24. Safety was assessed in all participants who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT03902509, and has completed enrolment. FINDINGS: Between Nov 29, 2021, and Dec 4, 2023, 134 patients were enrolled and randomly assigned, with 67 patients in each group study group. 105 (78%) of 134 patients were male and 29 (22%) were female. The median follow-up was 9·2 months (IQR 6·3-16·0). At week 24, the pirfenidone group showed an 8·0% improvement from baseline in DLCO%, whereas the control group showed a 2·4% reduction (least squares mean difference 10·4%, 95% CI 4·3-16·5; p=0·0010). The most common grade 3 or worse adverse events included pneumonia (four [6%] of 67 patients in the pirfenidone group vs eight [12%] of 67 patients in the control group), and rash (two [3%] of 67 patients in the pirfenidone group vs none in the control group). Serious adverse events occurred in 12 (18%) of 67 patients in the pirfenidone group and 11 (16%) of 67 patients in the control group. There were no treatment related deaths. INTERPRETATION: Pirfenidone in combination with glucocorticoids provides a potential therapeutic strategy for grade 2 or grade 3 radiation-induced lung injury, addressing the unmet clinical need for effective antifibrotic therapy in patients receiving thoracic radiotherapy. Further investigation is needed to validate these findings in patients with worse radiation-induced lung injury than was studied here. FUNDING: Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Key R&D Program of China, National Natural Science Foundation of China, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.