Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis

Zachary R Moore; Xiaojing Huang; Stephanie Lobaugh; Zhigang Zhang; Phillip Wong; Alexander Geyer; Andrew Pagano; Charles M Rudin; David R Jones; Daniel R Gomez; Joseph O Deasy; Raymond Mak; Adam M Schmitt; Paul K Paik; Andreas Rimner

doi:10.1016/j.radonc.2024.110320

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis

Radiother Oncol. 2024 May 11:196:110320. doi: 10.1016/j.radonc.2024.110320. Online ahead of print.

Authors

Affiliations

¹ Departments of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
² Departments of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
³ Departments of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: zhangz@mskcc.org.
⁴ Departments of Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
⁵ Departments of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine Weill Cornell Medical Center, New York, NY, United States.
⁶ Departments of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
⁷ Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
⁸ Departments of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
⁹ Department of Radiation Oncology Brigham and Women's Hospital/Dana-Farber Cancer Institute Boston, MA, United States.
¹⁰ Departments of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: andreas.rimner@uniklinik-freiburg.de.

PMID: 38740091
DOI: 10.1016/j.radonc.2024.110320

Abstract

Background and purpose: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP.

Materials and methods: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes.

Results: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036).

Conclusion: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.