Division of Medical Oncology, University of Ottawa, Ottawa, Ontario, Canada; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
J Thorac Oncol. 2021 Mar;16(3):486-491. doi: 10.1016/j.jtho.2020.11.013. Epub 2020 Dec 9.
Symptomatic early onset pulmonary events (EOPEs) were observed in 3% to 6% of patients within 1 week of starting brigatinib at 90 mg daily for 7 days followed by 180 mg daily. We conducted a prospective observational cohort study to measure pulmonary function changes on initiating brigatinib.
Patients initiating brigatinib were eligible. Pulmonary function test (PFT) with diffusing capacity for carbon monoxide (DLCO), Borg dyspnea scale, six-minute walk test, and blood draw for cytometry by time-of-flight were performed at baseline, day 2, and day 8 plus or minus day 15 of brigatinib. The primary end point was the incidence of PFT-defined EOPEs, prespecified as greater than or equal to 20% DLCO reduction from baseline. An interim analysis was performed owing to a higher than expected incidence of DLCO reduction.
A total of 90% (nine of 10) experienced DLCO reduction with the nadir occurring on day 2 or day 8. Median DLCO nadir was -13.33% from baseline (range: -34.44 to -5.00). Three participants met the PFT-defined EOPE criteria. All patients, including these three, were asymptomatic, none required brigatinib interruption or dose reduction, and all patients escalated to 180 mg without further issues. Despite continued dosing, by day 15, all assessed patients experienced DLCO recovery. Dyspnea and six-minute walk test results did not correlate with DLCO changes. Patients with a PFT-defined EOPE had significantly higher levels of activated neutrophils at baseline and day 8.
DLCO reduction occurred in 90% during the first 8 days of brigatinib dosing without any related symptoms. DLCO improved in all six patients assessed at day 15 despite continued dosing and dose escalation. Pretreatment levels of neutrophil activation should be explored as a biomarker for developing EOPEs.
在 90 毫克每日连用 7 天后序贯 180 毫克每日的剂量方案下，有 3%至 6%的患者在开始布加替尼治疗的 1 周内出现症状性早期肺部事件（EOPEs）。我们进行了一项前瞻性观察队列研究，以评估布加替尼起始时肺功能的变化。
符合入组条件的患者接受布加替尼治疗。在基线时、第 2 天和第 8 天（±15 天）进行肺功能检查（PFT），包括一氧化碳弥散量（DLCO）、Borg 呼吸困难量表、6 分钟步行试验和流式细胞术血液检查。主要终点是 PFT 定义的 EOPEs 的发生率，定义为从基线开始下降≥20%DLCO。由于 DLCO 下降的发生率高于预期，进行了中期分析。
共有 90%（10 例中的 9 例）患者发生 DLCO 下降，最低点出现在第 2 天或第 8 天。DLCO 最低点比基线下降中位数为-13.33%（范围：-34.44%至-5.00%）。3 名患者符合 PFT 定义的 EOPE 标准。所有患者，包括这 3 名患者，均无症状，无患者需要中断或减少布加替尼剂量，所有患者均无进一步问题地增加至 180 毫克。尽管持续给药，但在第 15 天，所有评估的患者均恢复了 DLCO。呼吸困难和 6 分钟步行试验结果与 DLCO 变化无相关性。PFT 定义的 EOPE 患者在基线和第 8 天的激活中性粒细胞水平显著更高。
在布加替尼治疗的最初 8 天内，90%的患者发生 DLCO 下降，无任何相关症状。尽管持续给药和剂量增加，所有在第 15 天评估的 6 名患者的 DLCO 均得到改善。在发生 EOPEs 时，应探索治疗前中性粒细胞激活水平作为生物标志物。
