阿西米单抗治疗至少两种既往系统性治疗失败后的慢性移植物抗宿主病：一项 I/II 期研究结果。
Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study.
机构信息
Vanderbilt University Medical Center, Nashville, TN.
University of Minnesota Masonic Cancer Center, Minneapolis, MN.
出版信息
J Clin Oncol. 2023 Apr 1;41(10):1864-1875. doi: 10.1200/JCO.22.00958. Epub 2022 Dec 2.
PURPOSE
Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development.
PATIENTS AND METHODS
This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and in phII to evaluate the overall (complete and partial) response rate (ORR) at the start of treatment cycle 7.
RESULTS
Forty enrolled patients (17 phI; 23 phII) received at least one axatilimab dose. In phI, a dose of 3 mg/kg given once every 4 weeks met the optimal biologic dose definition. Two dose-limiting toxicities occurred at the 3 mg/kg dose given once every 2 weeks. At least one treatment-related adverse event (TRAE) was observed in 30 patients with grade ≥ 3 TRAEs in eight patients, the majority known on-target effects of CSF-1R inhibition. No cytomegalovirus reactivations occurred. With the 50% ORR at cycle 7 day 1, the phII cohort met the primary efficacy end point. Furthermore, the ORR in the first six cycles, an end point supporting regulatory approvals, was 82%. Responses were seen in all affected organs regardless of prior therapy. Fifty-eight percent of patients reported significant improvement in cGVHD-related symptoms using the Lee Symptom Scale. On-target activity of axatilimab was suggested by the decrease in skin CSF-1R-expressing macrophages.
CONCLUSION
Targeting profibrotic macrophages with axatilimab is a therapeutically promising novel strategy with a favorable safety profile for refractory cGVHD.
目的
异基因造血细胞移植后，慢性移植物抗宿主病（cGVHD）仍然是导致晚期发病的主要原因。集落刺激因子 1 受体（CSF-1R）依赖性巨噬细胞促进 cGVHD 纤维化，在临床前研究中消除这些巨噬细胞可改善 cGVHD。Axatilimab 是一种人源化单克隆抗体，可抑制 CSF-1R 信号传导并抑制巨噬细胞的发育。
患者和方法
这项 I 期（phI）/II 期（phII）开放标签研究（ClinicalTrials.gov 标识符：NCT03604692）评估了 axatilimab 在≥2 线系统治疗后患有活动性 cGVHD 的年龄≥6 岁的患者中的安全性、耐受性和疗效。phI 的主要目的是确定最佳生物剂量和推荐的 phII 剂量，phII 的主要目的是在治疗周期 7 开始时评估总体（完全和部分）缓解率（ORR）。
结果
40 名入组患者（17 名 phI；23 名 phII）接受了至少一剂 axatilimab。在 phI 中，每 4 周给予 3mg/kg 的剂量符合最佳生物学剂量定义。在每 2 周给予 3mg/kg 的剂量时，发生了 2 例剂量限制性毒性。30 名患者至少出现了一次治疗相关不良事件（TRAE），8 名患者出现了≥3 级 TRAE，大多数是 CSF-1R 抑制的已知靶向效应。未发生巨细胞病毒再激活。在第 7 天治疗周期 7 时，50%的患者达到了主要疗效终点，ORR 为 50%。此外，支持监管批准的前 6 个周期的 ORR 为 82%。无论先前的治疗如何，所有受影响的器官都有反应。58%的患者使用 Lee 症状量表报告 cGVHD 相关症状有显著改善。axatilimab 的靶向活性通过皮肤 CSF-1R 表达巨噬细胞的减少来提示。
结论
用 axatilimab 靶向成纤维细胞性巨噬细胞是一种有前途的治疗方法，对难治性 cGVHD 具有良好的安全性。
Zotero 插件