N Engl J Med 2019 Sep 29
Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.
Abstract
Background
Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
Methods
In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
Results
A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
Conclusions
In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).
Related Questions
Do the results of FIBRONEER-ILD change your approach to antifibrotic treatment in patients with sarcoidosis related PPF?
According to the FIBRONEER-PPF data, no sarcoidosis-specific outcomes have been reported, and one can only infer that the sarcoidosis-related PPF subpopulation has tracked similarly to the other ILD subtypes, which is a big assumption. It is important to remember that in the INBUILD study, which exa...
Do you monitor CBCs to assess for drug toxicity in patients on nintedanib?
Not typically. I've never been advised to check these, but it's worth re-examining whether it's worthwhile. Looking at the side effect profile in INBUILD and INPULSIS doesn't reveal any major cytopenias. It doesn't appear to be on the FDA prescription information, either. I think this question arise...
Would you initiate antifibrotic therapy in a patient with CTD-ILD experiencing worsening symptoms and declining lung function, despite no clear evidence of fibrosis on CT scans?
If the predominant findings on CT were ground glass opacities and/or nodules without any evidence of fibrosis on CT, I would not start with an antifibrotic and, instead, would start with immunosuppression as a first-line agent. Based on the American College of Rheumatology (ACR) and American Thoraci...
What is your approach to using nintedanib in patients on baseline immunosuppression?
Typically I start antifibrotic therapy in a few situations: The most common reason is ILD progression despite adequate immune suppression, defined as no extra-pulmonary disease activity (usually joint disease, but can tailor according to the patient's disease/situation, such as by presence of rash, ...
Do you generally recommend starting nintedanib prior to immunosuppressive therapy in a patient with CTD-ILD?
Patients with autoimmune disease-associated ILDs such as those with rheumatoid arthritis-related ILD, Sjogren and inflammatory myositis-related ILD are usually on background DMARD/immunosuppressive therapy already at the time the ILD is detected. These therapies are also important in helping to redu...
Do you prescribe antifibrotics to patients with combined pulmonary fibrosis and emphysema (CPFE)?
The definition of CPFE is not very well standardized. CPFE commonly presents with upper lung-predominant emphysema and basilar/peripheral-predominant fibrosis. Pulmonary fibrosis in CPFE could be due to IPF or other ILDs. I prescribe antifibrotics for patients with CPFE-IPF and CPFE-other ILDs with ...
When do you begin antifibrotic therapy for a patient with newly diagnosed ILD that is not IPF?
The evidence behind starting anti-fibrotic therapy for non-IPF ILD is largely based on the results of the INBUILD trial where patients who have non-IPF ILD who demonstrate progression (based on at least a 10% decline in FVC or a 5% decline in FVC with worsening symptoms or radiologic progression) ha...
Do you consider the use of antifibrotics at presentation in patients with a radiographic UIP pattern of pulmonary fibrosis in the presence of positive serologies without any symptoms of CTD who have not yet demonstrated evidence of a progressive phenotype?
I really like this question, because it succinctly encapsulates several areas of clinical uncertainty that we are routinely forced to address in our ILD clinics! Let’s unravel some of the subtleties here. For starters, if the radiographic pattern is convincingly that of UIP, our patient will technic...
What indicators do you use to identify patients with CTD-ILD who do not have potential to improve from continued immunosuppressive therapy?
This is an interesting question. We need to clarify what this phrase means "who do not have potential to improve". It may be easier to identify patients who may benefit from therapy.ILD physicians work under the motto, 'stability is success'. Thus, improvement may mean 'did not deteriorate'. Minimal...
Are there any concerns about using nintedanib in a patient with progressive fibrosing ILD on background mycophenolate?
The SENSCIS trial randomized patients with SSc associated ILD to Nintedanib or placebo. I think about half of these patients were still taking MMF. There was no negative signal in the group on MMF and Nintedanib, they fared at least as well as those who got Nintedanib alone and both did better than ...
How do you treat CTD-associated organizing pneumonia?
The approach to CTD-associated organizing pneumonia is similar to that of CTD-associated NSIP and involves treatment with glucocorticoids and steroid-sparing agents. The evidence for the choice of steroid-sparing agents is extrapolated from clinical trial and observational data from systemic scleros...