Nintedanib in the prevention of radiation-induced lung injury in patients with unresectable stage II-III NSCLC: A protocol for a randomized, multicenter, control group study.

BACKGROUND: Radiation-induced lung injury (RILI) is a common and dose-limiting complication in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy, especially in combination with chemotherapy and/or immunotherapy. RILI encompasses acute radiation pneumonitis (RP) and chronic pulmonary fibrosis, significantly impacting patients' quality of life and treatment outcomes. Preclinical and clinical evidence suggests that nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF), may have preventive effects against RILI due to shared fibrotic pathways. However, prospective data on its prophylactic use remain limited. METHODS: This is a randomized, multicenter, unblinded, controlled trial designed to evaluate the efficacy and safety of nintedanib in preventing RILI. A total of 66 patients with unresectable stage II-III NSCLC scheduled to receive CCRT will be enrolled from three centers in China. Eligible participants will be randomized 1:1 to either the nintedanib group or the control group. Randomization is stratified by concurrent chemotherapy regimen (etoposide-based vs. taxane-based vs. pemetrexed-based). The nintedanib group will receive oral nintedanib 150 mg twice daily, initiated 1-2 weeks before radiotherapy and continued for 12 weeks, followed by a voluntary treatment period from week 13 to week 24. The control group will receive CCRT alone without nintedanib. All patients will undergo standardized CCRT comprising platinum-based doublet chemotherapy (cisplatin or carboplatin combined with etoposide, taxanes, or pemetrexed) and radiotherapy (60 Gy/30 fractions). Immunotherapy consolidation is permitted as a viable treatment option per guideline recommendations. Primary endpoint: The incidence of grade ≥2 RILI (according to CTCAE v5.0) within 6 months after radiotherapy initiation. Secondary endpoints: Time to radiological lung injury; changes in pulmonary function (FVC%, FEV1%, DLco%); tumor response outcomes (OS, PFS, ORR); safety and tolerability; and patient-reported outcomes. This trial will provide the first prospective evidence on the efficacy of nintedanib for preventing RILI in patients with unresectable stage II-III NSCLC undergoing CCRT. The results may inform clinical practice and guide future prophylactic strategies for RILI. TRIAL REGISTRATION: This study was registered on April 16, 2025, at the Chinese Clinical Trial Registry (No. ChiCTR2500100845). REPORTING GUIDELINE: This protocol was developed in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines.