乌鸦传媒

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SAN DIEGO -- The novel kinase inhibitor nintedanib slowed progression of idiopathic pulmonary fibrosis (IPF) but the effect on exacerbations was less certain, two pivotal trials showed.

The oral drug to an annual loss of 114.7 ml versus 239.9 ml with placebo in the INPULSIS-1 trial and to a similar 113.6 versus 207.3 ml with placebo in the INPULSIS-2 (both P<0.001), , of England's University Hospital Southampton, and colleagues found.

Acute exacerbations were significantly delayed in the latter trial with a hazard ratio of 0.38 versus placebo (P=0.005), but the HR went nonsignificantly against nintedanib in the first (HR 1.15, P=0.67), for a nonsignificant pooled result (HR 0.64, P=0.08), they reported at the American Thoracic Society meeting.

The findings were reported at a late-breaking clinical trial ATS session and simultaneously online in the New England Journal of Medicine.

Nintedanib (formerly BIBF-1120) inhibits a variety of tyrosine kinase receptors, including platelet-derived growth factor, fibroblast growth factor, and vascular endothelial growth factor, implicated in the pathogenesis of IPF.

The drug had disappointed in non-small cell lung cancer, with small gains in progression-free survival and no impact on overall survival with one chemotherapy drug and no effect with another.

But these results in IPF, along with positive results with another novel agent reported alongside it, offer new hope for a condition that has a worse prognosis than many cancers, , of Brigham and Women's Hospital in Boston, wrote in an accompanying editorial.

, agreed, calling the two trials groundbreaking given the lack of medical treatment options. But he noted that the drugs lessen but don't eliminate the death sentence from IPF.

"We can't quit," he cautioned at the ATS session.

Also, "although these results are a major breakthrough for patients with idiopathic pulmonary fibrosis, we should be cautious in extrapolating these findings to patients who fall outside the recruitment criteria for these trials," Hunninghake wrote. "The studies provide little insight into the use of these drugs in patients with more severe disease (FVC <50% of the predicted value) or with an acute disease exacerbation."

Other questions worth answering are durability and impact of combination treatment or in other interstitial lung diseases, he noted.

The INPULSIS trials were replicate 52-week, double-blind, phase III trials that randomized a total of 1,066 IPF patients to 150 mg of nintedanib twice daily or placebo.

Patients had to have 50% or more of the predicted FVC, a diffusion capacity of the lung for carbon monoxide that was 30% to 79% of the predicted value, and high-resolution chest CT within the prior 12 months.

Concomitant use of the equivalent of up to 15 mg of prednisone daily was allowed if stable. Other IPF therapies were only allowed after 6 months for patients whose condition had deteriorated.

In each trial, response in FVC defined by less than a 5 percentage point absolute decline in the predicted FVC at 1 year was greater with nintedanib (INPULSIS-1 52.8% versus 38.2% and INPULSIS-2 53.2% versus 39.3%, both P=0.001).

Response defined by loss in predicted FVC not more than 10 percentage points at that point was greater with the drug in INPULSIS-1 (70.6% versus 56.9%, P<0.001) but not in INPULSIS-2 69.6% versus 63.9% placebo, P=0.18).

The proportion of patients with at least one investigator-reported acute exacerbation was similar in the nintedanib and placebo groups in INPULSIS-1 (6.1% versus 5.4%) but lower with the drug in INPULSIS-2 (3.6% versus 9.6%).

"Such exacerbations are relatively rare events in patients with idiopathic pulmonary fibrosis who are in clinical trials and are difficult to assess and categorize, which may explain some of the heterogeneity in our findings," the researchers noted.

Health-related quality of life scores were similar between groups.

Numerically fewer nintedanib patients died from any cause over 1 year, but the difference wasn't significant (5.5% versus 7.8%, HR 0.70, P=0.14).

"Although these trials were not powered to detect statistically significant differences in mortality, it is comforting that nintedanib resulted in a trend toward a reduced rate of death that mirrored the reduced rate of decline in lung function," Hunninghake wrote.

The most frequent adverse event with nintedanib was diarrhea (61.5% versus 18.6% on placebo in INPULSIS-1 and 63.2% versus 18.3% in INPULSIS-2). Liver enzyme elevations were more common in both trials with the drug as well (4.9% versus 0.5% and 5.2% versus 0.9%).

Serious adverse events were similar between groups overall, but myocardial infarction was more common with nintedanib (1.6% versus 0.5% in INPULSIS-1 and 1.5% versus 0.5% in INPULSIS-2).

"The clinical significance of this finding is unknown, and further observation in larger cohorts is needed," the researchers cautioned.