121 - Pirfenidone for Cancer Patients with Grade 2 and Grade 3 Radiation-Induced Lung Injury: Long-Term Efficacy and Exploratory Analysis from a Multicenter, Randomized Phase ll Clinical Trial

03:00pm - 03:10pm ET

Room 204

Presenter(s)

Biqi Chen, MD - Sun Yat-Sen University Cancer Center, Guang Dong Province, Guangdong

B. Chen¹, B. Dong¹, X. Li¹, Q. Li², B. Chen¹, and M. Chen¹; ¹Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China, ²United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese Academy of Sciences Ion Medical Technology Co., Ltd, Guangzhou, China

Purpose/Objective(s): In a multicenter, open-label, randomized, phase 2 trial, pirfenidone provides a promising therapeutic strategy for grade 2-3 radiation-induced lung injury (RILI). Here, we reported the long-term outcomes and post hoc exploratory analyses.

Materials/Methods: This trial enrolled patients with grade 2-3 RILI diagnosed according to CTCAE v5.0 to randomly receive pirfenidone plus glucocorticoids or glucocorticoids alone from ten centers across China. The primary endpoint was the change in the percentage of carbon monoxide diffusing capacity (DLCO%) from baseline to week 24. Secondary endpoints included high-resolution CT imaging scores for ground glass, reticulation, and honeycombing. Exploratory endpoints were PFS and OS. This post-hoc analyses included 1-year CT imaging scores and long-term survival outcomes. In addition, Dynamic plasma link target 96 inflammation panel and untargeted metabolomics at baseline, 4, 8, 16, and 24 weeks after randomization were detected.

Results: In post hoc analyses, 66.7% of patients in the pirfenidone (40/60) and control (42/63) groups underwent a 1-year CT evaluation. At 1 year, ground glass improvement from baseline was 80.0% in the pirfenidone group versus 54.8% in the control group (P = 0.015). The improvement at 1-year reticulation were 57.5% in the pirfenidone group versus 28.6% in the control group (P = 0.008). With median follow-up of 37.4 (IQR: 32.0-42.8) months, PFS (P = 0.722, HR: 1.09, 95%CI: 0.67-1.78) and OS (P = 0.927, HR: 0.97, 95%CI: 0.56-1.72) were similar in two group. At 24 weeks, pirfenidone significantly downregulated 11 cytokines, including TGFß, CD8A, and CSF-1, compared with the control group. Notably, TGFß, CD8A, and CSF-1 were also consistently reduced relative to baseline. The dynamic TGFß levels were negatively correlated with DLCO% (r = -0.207, P = 0.041), FVC% (r = -0.222, P = 0.028), and FEV1% (r = -0.295, P = 0.003). Additionally, pirfenidone significantly upregulated SCF at 4, 8, 16, and 24 weeks from baseline and dynamic SCF levels positively correlated with DLCO% (r = 0.208, P = 0.040), FVC% (r = 0.422, P < 0.001), and FEV1% (r = 0.345, P = 0.001). Untargeted metabolomics revealed significant upregulation of deoxycholic acid in the pirfenidone group versus the control group at 24 weeks. Deoxycholic acid remained consistently elevated during pirfenidone treatment and showed a positive correlation with FVC% (r = 0.259, P = 0.022). Longitudinal metabolomics revealed suppressed amino acid metabolism and enhanced energy and lipid metabolism during pirfenidone treatment.

Conclusion: Updated long-term outcomes confirm the consistent efficacy of pirfenidone in cancer patients with grade 2-3 RILI. Proteomic and metabolomic analyses reveal pertinent biological processes during pirfenidone treatment that differ from glucocorticoids, providing evidence for the mechanism of pirfenidone in treating RILI patients and potential prognostic biomarkers. The trial was registered with ClinicalTrials.gov (NCT03902509).