Adverse side-effects of antifibrotic drugs and outcome of treatment in idiopathic pulmonary fibrosis.

Background: Lung cancer and idiopathic pulmonary fibrosis (IPF) share some common pathogenetic pathways and thus also some treatment targets are also similar. Targeted treatment in lung cancer is more effective in patients who have drug mechanism-specific adverse events (AEs). We aimed to investigate whether outcomes of antifibrotic treatment (AFT) also relate to AEs in IPF. Methods: This is a retrospective European Multipartner IPF Registry (EMPIRE) study. A total of 2,200 patients treated with antifibrotics (AF) with at least 6-month follow-up were enrolled and stratified into two groups, with and without reported drug-related AEs. We analyzed AEs and their relation to the clinical outcome parameters: risk factors for AEs occurrence, overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and IPF acute exacerbation (AE-IPF). Kaplan-Meier method, Cox proportional hazard, and multivariate analyses were applied. Results: In the first 6 months of AFT, AEs were reported in 11% (255 patients), 13.8% in nintedanib and 9.5% in pirfenidone. Nearly a quarter of all reported AEs (23.36%) were mild, while the majority of all reported AEs (76.64%) were moderate or severe, with similar frequency in both groups. Gastrointestinal AEs were the most frequent (nintedanib 29%, pirfenidone 40% patients). The most commonly reported individual AE was diarrhea (34%), mainly in the nintedanib group (87.2%). Discontinuation rate for AEs was 3.4%, 2.65% in pirfenidone and 4.35% in nintedanib. Risk factors for AE(s) comprised older age, male gender, low body mass index, more advanced disease, and comorbidities. Significantly shorter OS (P<0.001), DSS (P<0.001), PFS (P=0.009), and shorter time to first exacerbation (P<0.02) were noted in the patients with any AEs compared to those without AEs in the whole cohort. In the pirfenidone group weight loss (P<0.001), elevated liver enzymes (P<0.003), vertigo (P=0.006), abdominal pain (P=0.003), and loss of appetite (P=0.003) were associated with shorter OS, weight loss and elevated liver enzymes with DSS (P<0.001 each), weight loss only with shorter PFS (P=0.03), whereas rash (P=0.02) and weight loss (P=0.047) with AE occurrence. In the nintedanib group, AEs lead to shorter OS, but not DSS, specifically diarrhea (P=0.01) and fatigue (P<0.001), while fatigue only to shorter PFS (P<0.001). Conclusions: The prevalence of drug-related AEs reported in the first 6 months of AFT in the patients from the EMPIRE IPF Registry was below that reported in randomized clinical trials and most real-world studies, but with a similar drug-related AE profile. Only a quarter of all reported AEs were mild, unlike in numerous published series, with most of AEs being mild to moderate. A negative correlation between drug-related AEs and the clinical outcomes was evidenced, which is opposite to the effect of AEs of targeted treatment in lung cancer.