贝美纳替尼（BGB324）联合多西他赛治疗既往治疗的晚期非小细胞肺癌的 1 期临床试验：一种首创、选择性 AXL 抑制剂。
Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer.
机构信息
Department of Internal Medicine (Division of Hematology-Oncology), UT Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
出版信息
Lung Cancer. 2023 Aug;182:107291. doi: 10.1016/j.lungcan.2023.107291. Epub 2023 Jul 4.
OBJECTIVES
AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC.
MATERIALS AND METHODS
Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured.
RESULTS
21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes.
CONCLUSION
Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.
目的
AXL 是一种跨膜受体酪氨酸激酶，在非小细胞肺癌（NSCLC）中高度表达并与预后不良相关。Bemcentinib（BGB324）是一种选择性口服生物可利用的小分子 AXL 抑制剂，与多西他赛在临床前模型中具有协同作用。我们在先前治疗过的晚期 NSCLC 患者中进行了一项 Bemcentinib 联合多西他赛的 I 期试验。
材料和方法
在联合多西他赛（60 或 75mg/m2，每 3 周一次）之前，先以 3+3 研究设计递增两个剂量水平的 Bemcentinib（200mg 负荷量×3 天，然后每天 100mg，或 400mg 负荷量×3 天，然后每天 200mg）。由于血液学毒性，添加了预防性 G-CSF。在开始多西他赛之前，先给予 Bemcentinib 单药治疗一周，以单独和联合评估药效学和药代动力学效应。测量血浆蛋白生物标志物水平。
结果
共纳入 21 例患者（中位年龄 62 岁，67%为男性）。中位治疗持续时间为 2.8 个月（范围 0.7-10.9 个月）。主要的治疗相关不良事件是中性粒细胞减少（86%，76%≥G3）、腹泻（57%，0%≥G3）、疲劳（57%，5%≥G3）和恶心（52%，0%≥G3）。有 8 例（38%）患者发生中性粒细胞发热。最大耐受剂量为多西他赛 60mg/m2，联合预防性 G-CSF 支持，贝美替尼 400mg 负荷量×3 天，随后每天 200mg。Bemcentinib 和多西他赛的药代动力学与先前的单药数据相似。在 17 例可评估影像学反应的患者中，6 例（35%）患者有部分缓解，8 例（47%）患者疾病稳定为最佳反应。Bemcentinib 给药与涉及蛋白激酶 B 信号转导、活性氧代谢和其他过程的蛋白调节有关。
结论
在先前治疗过的晚期 NSCLC 患者中，Bemcentinib 联合多西他赛加 G-CSF 支持具有抗肿瘤活性。AXL 抑制在 NSCLC 治疗中的作用仍在研究中。
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