INTRODUCTION We evaluated pulmonary adverse events observed within 7 days after drug initiation in phase 1-3 studies of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib. METHODS The phase 1/2 study enrolled patients with advanced malignancies (dose range, 30-300 mg qd), the phase 2 ALTA study treated patients with advanced ALK+ non-small cell lung cancer (NSCLC) post-crizotinib at either 90 mg qd or 90 mg qd for 7 days followed by 180 mg qd, and the phase 3 ALTA-1L study treated inhibitor-naive ALK+ NSCLC patients with brigatinib (90 mg → 180 mg qd) or crizotinib (250 mg bid). Early-onset pulmonary events (EOPEs) at least possibly associated with brigatinib were captured. RESULTS In phase 1/2, ALTA, and ALTA-1L, 8% (11/137), 6% (14/219), and 3% (4/136) of patients, respectively, had at least possible EOPEs on brigatinib, with frequency appearing to increase with starting dose. Across trials, at the 90-mg qd starting dose (alone or step-up dosing), 4.5% of patients (20/440) had at least possible events (median time to onset, 2 days). Twelve (3%) patients had grade ≥3 events leading to brigatinib discontinuation. Seven (1.5%) patients had grade 1-2 events and successfully continued brigatinib with or without brigatinib interruption and/or steroids/supplemental oxygen. In pooled analysis of these trials, occurrence of EOPEs was significantly associated with continuous 10-year increases in patient age in unadjusted logistic regression analysis and with ECOG performance status and number of prior regimens in multivariate regression. CONCLUSIONS Clinically apparent EOPEs can occur within days of commencing brigatinib in a subset of patients with NSCLC. Identifying clinical parameters associated with a higher risk of developing such events may help mitigate these events.

中文翻译：

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与布加替尼在晚期非小细胞肺癌中使用相关的早发性肺部事件

引言 我们评估了在间变性淋巴瘤激酶 (ALK) 抑制剂布加替尼的 1-3 期研究中药物开始后 7 天内观察到的肺部不良事件。方法 1/2 期研究招募了晚期恶性肿瘤患者（剂量范围，30-300 mg qd），2 期 ALTA 研究在克唑替尼治疗后以 90 mg qd 治疗晚期 ALK+ 非小细胞肺癌（NSCLC）患者或 90 mg qd 7 天，然后 180 mg qd，3 期 ALTA-1L 研究用布加替尼（90 mg → 180 mg qd）或克唑替尼（250 mg bid）治疗未使用抑制剂的 ALK+ NSCLC 患者。捕获了至少可能与布加替尼相关的早发性肺部事件 (EOPE)。结果 在 1/2 期，ALTA 和 ALTA-1L，分别有 8% (11/137)、6% (14/219) 和 3% (4/136) 的患者在使用布加替尼时至少可能出现 EOPE , 频率似乎随着起始剂量而增加。在所有试验中，在 90 mg qd 起始剂量（单独或逐步给药）时，4.5% 的患者 (20/440) 至少发生了可能的事件（中位发病时间，2 天）。12 名 (3%) 患者出现导致 brigatinib 停药的 ≥3 级事件。7 名 (1.5%) 患者出现 1-2 级事件并成功继续使用 brigatinib，无论是否中断 brigatinib 和/或类固醇/补充氧气。在这些试验的汇总分析中，在未调整的逻辑回归分析中，EOPE 的发生与患者年龄连续 10 年增加显着相关，在多变量回归中与 ECOG 体能状态和先前治疗方案的数量显着相关。结论 临床上明显的 EOPE 可在一部分 NSCLC 患者中开始使用布加替尼后数日内发生。