Background
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia characterized by poor prognosis [
1,
2]. The pathogenesis of IPF is suggested to involve several profibrotic mediators, such as fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), and transforming growth factor beta [
3,
4]. Nintedanib, an intracellular tyrosine kinase inhibitor that targets vascular endothelial growth factor, FGFs, and PDGF receptors, has shown anti-fibrotic and anti-inflammatory activity in a preclinical study [
5,
6]. Recent randomised controlled trials of patients with mild-to-moderate IPF revealed that nintedanib reduced the rate of decline of forced vital capacity (FVC) and disease progression, and that adverse events (AEs) were well tolerated [
7,
8].
Limited data have suggested that nintedanib may also stabilise the decline in lung function in patients with advanced IPF [
9]. Post-hoc subgroup analyses of pooled data from two phase 3 trials, in which patients with IPF were classified according to baseline FVC % predicted (≤ 70%, > 70%; ≤ 80%, > 80%; or ≤ 90%, > 90%), showed no statistically significant inter-group differences in the effect of nintedanib on the annual rate of decline in FVC [
10‐
12]. In an exploratory subgroup analysis of the open-label extension trial, INPULSIS-ON, in which patients were classified according to baseline FVC % predicted (≤ 50%, > 50%), the decline in FVC in both subgroups was similar to that observed in the phase 3 trials. However, the number of patients with FVC ≤ 50% predicted was small (
n = 24), and the efficacy and safety analyses were only descriptive [
9].
The aim of the present study was to compare the efficacy and safety of nintedanib in patients with advanced and non-advanced IPF.
Discussion
In the present study, nintedanib reduced the lung function decline in patients with IPF in a real-world setting. A comparable reduction in the decline of lung function was observed in the advanced and non-advanced groups. The majority of patients experienced AEs, and thus, half of these individuals were discontinued from treatment. In most cases, this was a result of disease progression. The frequency of AEs in the advanced group was similar to that in the non-advanced group. However, a higher frequency of treatment interruption was observed in the advanced group, mainly as a result of disease progression.
Data from phase 3 trials have indicated that nintedanib may be effective for the treatment of IPF, regardless of lung function [
10‐
12]. However, these trials excluded patients with severely impaired lung function (FVC < 50% predicted or DLco < 30% predicted) [
8] and the updated guidelines suggested that future trials should focus on this group of patients [
1]. The present results showed that nintedanib delayed the decline in the lung function of patients with advanced IPF to an extent comparable with that observed in non-advanced cases. This is consistent with the results of previous studies [
9,
18]. In a subgroup analysis of INPULSIS-ON, the absolute mean change in FVC from baseline to week 48 in patients (
n = 24) with baseline FVC ≤ 50% predicted was similar to that in those (
n = 558) with baseline FVC > 50% predicted (− 62.3 vs. -87.9 mL), which suggested that nintedanib may have a similar effect on disease progression in patients with advanced disease and those with less advanced disease [
9]. A recent retrospective observational study, in 94 patients with IPF treated with nintedanib, also showed that median changes in FVC after 12 months were not different (∆ FVC: -6.52 vs. -2.60% predicted,
p = 0.56) between patients with baseline FVC < 50% predicted (
n = 9) and > 50% predicted (
n = 48) [
18]. However, the number of patients with advanced IPF was small [
9,
18] and the efficacy analysis was descriptive [
9]. The present study has therefore generated more robust evidence for the significant stabilising effect of nintedanib on the decline in lung function in patients with advanced IPF.
The present data indicated that nintedanib may be more effective for patients in the advanced group than for those in the non-advanced group. The rate of decline of FVC was significantly higher in the advanced group than in the non-advanced group before treatment, but this difference was not observed after treatment. A significant stabilisation of the FVC decline rate and a reduction in the rate of disease progression after treatment were also observed in the advanced group, but not in the non-advanced group. Previous reports supported our findings [
10,
18]. In a pooled analysis of the INPULSIS trial, the results of the prespecified subgroup analyses (baseline FVC ≤ 70% predicted vs. > 70% predicted) suggested a more profound effect of the treatment in the advanced group for acute exacerbation (hazard ratio: 0.52 [≤ 70% predicted] vs. 1.00 [> 70% predicted],
p = 0.175) and change from baseline in St. George’s Respiratory Questionnaire (difference in the adjusted changes between nintedanib and placebo: − 3.34 vs. -0.34,
p = 0.063). Tzouvelekis et al. also demonstrated that the change in FVC after 12 months of treatment was significantly lower in patients with baseline FVC < 80% predicted than in those without (∆ FVC: 1.42% vs. -10.11% predicted,
p = 0.03) [
18]. In addition, previous studies suggested that pirfenidone, another antifibrotic agent used in the treatment of IPF, may be more effective in patients with a greater impairment of lung function, because they cause a greater decline in lung function before treatment [
19‐
21]. Therefore, the absence of a significant reduction in the rate of decline of FVC or disease progression in the non-advanced group may be a result of the modest decrease in FVC before treatment; however, the rate of decline in TLC and the adjusted mean changes from baseline in FVC and TLC was significantly reduced after treatment in this group.
Although a significant reduction in the decline of FVC and TLC was observed in the present cohort, no such reduction was observed for DLco. The decline in DLco is an indicator of poor prognosis in IPF [
2,
22]. However, DLco is also associated with pulmonary hypertension [
22,
23]. Pulmonary hypertension is prevalent in patients with advanced IPF [
24,
25]. Compared with the previous cohorts [
8], patients in the present study had poor lung function (FVC: 79.5–80.0% vs. 56.2% predicted, DLco: 47–47.8% vs. 35.7% predicted), and one-third of the patients had suspected pulmonary hypertension (Table
1).
The incidence of AEs in the present cohort was similar to that reported in previous research (95.3% vs. 94.5–96.4%) [
8]. Comparable rates were found for diarrhoea (61.5% vs. 61.5–63.2%), nausea (24.3% vs. 22.7–26.1%) and upper respiratory infection (9.0% vs. 9.1%). However, anorexia was more frequent in the present study (45.4% vs. 8.4–12.4%). Our findings reflect the real-world experience, and other studies of patients with IPF treated with nintedanib within a compassionate use programme have generated similar results (19.1–38.7%) [
18,
26,
27]. Real-world studies [
18,
26] usually include patients with more severely impaired lung function (FVC: 64–68% vs. 79.5–80.0% predicted) than phase 3 trials [
8]. A previous study suggested that a high Gender-Age-Physiology score and a lower performance status were associated with the development of nausea or anorexia during the treatment of patients with IPF with nintedanib [
28]. Concurrent medication may also contribute to the more frequent occurrence of anorexia in the real-world setting.
In the present study, the rate of diarrhea was higher in the non-advanced group than in the advanced group. This finding may be attributable to the higher exposure to nintedanib in the non-advanced group, which included more patients without dose modification and administered a longer duration of treatment. To minimize the difference in treatment duration between the two groups, we estimated adjusted ORs for AEs, and no significant difference in the risk of AEs was observed between the advanced and non-advanced groups. This finding was consistent with that of a previous report, which showed no significant difference in the rate of adverse reactions to nintedanib between advanced (FVC < 50% predicted or diffusing capacity < 30% predicted) and non-advanced groups [
29].
Pneumonia was the most common serious adverse event in the present study, but the frequency was not different between the advanced and non-advanced groups. In the INPULSIS trials, the frequency of infection (56.3% [nintedanib] vs. 53.9% [placebo]) was also similar in both the nintedanib and placebo groups, which suggested that nintedanib was not associated with pneumonia [
30]. In our study, the frequency of pneumonia was higher than in other study (27.8% vs. 3.1%) [
31]. This result may be due to lower BMI of the patients in our study (BMI: 23.3 vs. 27.5 kg/m
2) [
31], and being underweight is generally associated with an increased risk of community acquired pneumonia (odds ratios 1.04–2.20) [
32]. No inter-group difference was found in the risk of SAEs. However, the advanced group showed a tendency for a higher risk of pneumothorax (OR: 8.611;
p = 0.068). In a recent study, pneumothorax in patients with IPF was associated with disease severity (presence of extensive reticular abnormalities) and poor outcome (hazard ratio, 2.85;
p = 0.006) [
33].
Compared with previous studies [
8,
29,
34], the rate of discontinuation because of AEs in the present cohort was high (19–26.3% vs. 53.0%), which may be attributable to the severe disease status of a large proportion of the cohort. This was also consistent with the finding that disease progression was the most common cause of drug discontinuation. Diarrhea led to premature discontinuation in 4.6% of patients, which was consistent with findings from other phase 3 trials (4.3–4.5%). However, discontinuation owing to anorexia occurred more frequently in the present cohort (8.3% vs. 1.2–1.6%) [
8]. The high discontinuation rate owing to anorexia in Asian patients in the INPULSIS trials (3.1% vs. 1.2–1.6%) [
35] is an indication that racial or cultural differences may contribute to these findings. The number of patients that were permanently discontinued from the study owing to AEs was significantly higher in the advanced group than in the non-advanced group. This was consistent with a previous report, which found that a higher proportion of patients with FVC ≤ 50% predicted discontinued treatment owing to AEs (41.5% vs. 22.5%) and disease progression (17.1% vs. 5.4%) than patients with FVC > 50% predicted [
9]. Low body weight is a factor that increases the exposure to nintedanib at equal doses [
36]; therefore, the high treatment discontinuation rate in the advanced group may be related to this factor.
The present study has some limitations. First, the study was performed at a single center and included patients with varying disease severities and comorbidities. However, the demographic features and lung function of the cohort were comparable with those of other studies, and systematic history collection, physical examination and blood tests for possible AEs were performed on all patients at follow-up visits. Second, the number of patients was relatively small and patients in the advanced group were more frequently excluded from the efficacy analysis than those in the non-advanced group. Thus, there is a possibility of selection bias because the remaining patients might be better responders to treatment after the exclusion of patients who had difficulties performing pulmonary function tests or died. However, because the number of patients excluded was not large (
n = 6), these effects would not have a significant impact on the overall results. Third, the study lacked a control group. However, a previous randomised placebo-controlled trial showed that nintedanib effectively reduced lung function decline in patients with non-advanced IPF [
8].