Long-term outcomes of upfront combination therapy for PPF: TOP-ILD phase 2 study

Background Progressive pulmonary fibrosis (PPF) has a poor prognosis, with optimal treatment strategies remaining undefined. We previously reported favorable 24-week outcomes with upfront triple combination therapy (nintedanib, tacrolimus, prednisolone) in treatment-naïve PPF patients. Here we report 52-week outcomes for the same trial (TOP-ILD). Methods This prospective, multicenter, single-arm study enrolled 34 treatment-naïve PPF patients. Patients received prednisolone (10 mg daily) and tacrolimus (trough of 5–10 ng·mL −1 ) from day 1, and nintedanib (150 mg twice daily) from day 8. Treatment persistence, lung function changes, safety, overall survival, and time to treatment failure were assessed. Treatment failure was defined as a relative forced vital capacity (FVC) decline of ≥10% predicted, a relative diffusing capacity of the lung for carbon monoxide (DLCO) decline of ≥15% predicted, acute exacerbation, or death. Results Twenty-nine (85.3%) patients maintained triple therapy at 52 weeks. The annual rate of FVC change was +1.8±10.7%. Overall survival was 93.9%, the cumulative acute exacerbation rate was 3.0%, and the treatment failure rate was 53.7%. Treatment failure was mostly due to DLCO decline (76.5% of cases). Baseline predictors included a higher mMRC dyspnea score (HR=1.63, p=0.032), lower oxygen saturation (HR=0.73, p=0.044), and higher eosinophil percentage in bronchoalveolar lavage fluid (HR=1.11, p=0.049). Safety remained manageable. Conclusions Upfront triple combination therapy may support sustained disease stabilization with high treatment persistence in treatment-naïve PPF patients, and baseline dyspnea, hypoxemia, and BALF eosinophilia may predict treatment failure. These exploratory findings from a single-arm study are hypothesis-generating and require confirmation in controlled trials.