Safety and tolerability of nintedanib in patients with interstitial lung diseases in subgroups by sex: a post-hoc analysis of pooled data from four randomised controlled trials

Abstract

<h2>Abstract</h2><h3>Background</h3> Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex. <h3>Methods</h3> In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex. <h3>Findings</h3> In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 [32%] male patients); and 1554 patients with other ILDs (437 [28%] female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%] female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31 (12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients). <h3>Interpretation</h3> The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib. <h3>Funding</h3> Boehringer Ingelheim.