PDF(Pubmed)
Abstract：
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.
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.
摘要：
3％至6％的患者在开始每天90mg的布格替尼后1周内观察到症状性早发肺事件（EOP），持续7天，然后每天180mg。我们进行了一项前瞻性观察性队列研究，以测量开始使用布格替尼时的肺功能变化。
服用布格替尼的患者符合资格。具有一氧化碳扩散能力（DLCO）的肺功能检查（PFT），Borg呼吸困难量表,六分钟步行测试,和抽血的细胞计数通过飞行时间在基线进行，第2天和第8天加上或减去第15天的布格替尼。主要终点是PFT定义的EOP的发生率，预设为DLCO从基线减少大于或等于20%。由于DLCO减少的发生率高于预期，因此进行了中期分析。
总共90%(10个中的9个)经历DLCO减少,其中最低点发生在第2天或第8天。中位DLCO最低点为基线的-13.33%（范围：-34.44至-5.00）。三名参与者符合PFT定义的EOPE标准。所有患者,包括这三个，无症状，没有需要布加替尼中断或剂量减少，和所有患者升级到180毫克没有进一步的问题。尽管持续给药，到第15天,所有评估的患者都经历了DLCO恢复.呼吸困难和六分钟步行测试结果与DLCO变化无关。具有PFT定义的EOPE的患者在基线和第8天具有显著更高水平的活化中性粒细胞。
在布格替尼给药的前8天，DLCO减少90%，无任何相关症状。在第15天评估的所有6名患者中DLCO改善,尽管持续给药和剂量递增。应探索中性粒细胞活化的预处理水平作为开发EOP的生物标志物。
服用布格替尼的患者符合资格。具有一氧化碳扩散能力（DLCO）的肺功能检查（PFT），Borg呼吸困难量表,六分钟步行测试,和抽血的细胞计数通过飞行时间在基线进行，第2天和第8天加上或减去第15天的布格替尼。主要终点是PFT定义的EOP的发生率，预设为DLCO从基线减少大于或等于20%。由于DLCO减少的发生率高于预期，因此进行了中期分析。
总共90%(10个中的9个)经历DLCO减少,其中最低点发生在第2天或第8天。中位DLCO最低点为基线的-13.33%（范围：-34.44至-5.00）。三名参与者符合PFT定义的EOPE标准。所有患者,包括这三个，无症状，没有需要布加替尼中断或剂量减少，和所有患者升级到180毫克没有进一步的问题。尽管持续给药，到第15天,所有评估的患者都经历了DLCO恢复.呼吸困难和六分钟步行测试结果与DLCO变化无关。具有PFT定义的EOPE的患者在基线和第8天具有显著更高水平的活化中性粒细胞。
在布格替尼给药的前8天，DLCO减少90%，无任何相关症状。在第15天评估的所有6名患者中DLCO改善,尽管持续给药和剂量递增。应探索中性粒细胞活化的预处理水平作为开发EOP的生物标志物。
